Slide 1

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

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© 2005 Aeras Global TB Vaccine Foundation

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In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

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Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

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What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

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Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
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© 2005 Aeras Global TB Vaccine Foundation

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Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
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© 2005 Aeras Global TB Vaccine Foundation

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Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
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© 2005 Aeras Global TB Vaccine Foundation

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Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
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© 2005 Aeras Global TB Vaccine Foundation

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Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
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© 2005 Aeras Global TB Vaccine Foundation

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Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

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© 2005 Aeras Global TB Vaccine Foundation

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It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
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© 2005 Aeras Global TB Vaccine Foundation

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Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
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© 2005 Aeras Global TB Vaccine Foundation

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Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
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© 2005 Aeras Global TB Vaccine Foundation

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Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
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© 2005 Aeras Global TB Vaccine Foundation

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Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

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© 2005 Aeras Global TB Vaccine Foundation

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The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
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© 2005 Aeras Global TB Vaccine Foundation

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So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

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© 2005 Aeras Global TB Vaccine Foundation

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In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
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© 2005 Aeras Global TB Vaccine Foundation

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History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

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© 2005 Aeras Global TB Vaccine Foundation

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Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
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© 2005 Aeras Global TB Vaccine Foundation

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The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

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© 2005 Aeras Global TB Vaccine Foundation

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Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
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© 2005 Aeras Global TB Vaccine Foundation

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History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

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© 2005 Aeras Global TB Vaccine Foundation

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World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
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© 2005 Aeras Global TB Vaccine Foundation

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Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
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© 2005 Aeras Global TB Vaccine Foundation

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History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

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© 2005 Aeras Global TB Vaccine Foundation

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“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
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© 2005 Aeras Global TB Vaccine Foundation

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This was one
of the
strategies
used to keep
the
participants
happy.

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© 2005 Aeras Global TB Vaccine Foundation

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Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

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© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
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© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
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© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
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© 2005 Aeras Global TB Vaccine Foundation

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Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

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© 2005 Aeras Global TB Vaccine Foundation

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So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
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© 2005 Aeras Global TB Vaccine Foundation

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International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
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© 2005 Aeras Global TB Vaccine Foundation

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What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
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© 2005 Aeras Global TB Vaccine Foundation

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The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
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© 2005 Aeras Global TB Vaccine Foundation

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CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

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© 2005 Aeras Global TB Vaccine Foundation

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GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
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© 2005 Aeras Global TB Vaccine Foundation

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Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

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© 2005 Aeras Global TB Vaccine Foundation

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Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

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© 2005 Aeras Global TB Vaccine Foundation

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Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
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© 2005 Aeras Global TB Vaccine Foundation

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ACTIVITY

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© 2005 Aeras Global TB Vaccine Foundation

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How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
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© 2005 Aeras Global TB Vaccine Foundation

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Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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© 2005 Aeras Global TB Vaccine Foundation

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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

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© 2005 Aeras Global TB Vaccine Foundation

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Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
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© 2005 Aeras Global TB Vaccine Foundation

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Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
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© 2005 Aeras Global TB Vaccine Foundation

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Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
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© 2005 Aeras Global TB Vaccine Foundation

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Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

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© 2005 Aeras Global TB Vaccine Foundation

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1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
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© 2005 Aeras Global TB Vaccine Foundation

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2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
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© 2005 Aeras Global TB Vaccine Foundation

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Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

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Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

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© 2005 Aeras Global TB Vaccine Foundation

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Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
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3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
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© 2005 Aeras Global TB Vaccine Foundation

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4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
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© 2005 Aeras Global TB Vaccine Foundation

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Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
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© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
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Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

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Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
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Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

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Slide 2

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
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14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
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20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
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23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
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34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
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55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 3

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
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7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 4

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
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39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
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40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

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Slide 5

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
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6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
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7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
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11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
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13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
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14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
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17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
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20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
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34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

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Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 6

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 7

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
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7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
© 2005 Aeras Global TB Vaccine Foundation

68


Slide 8

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

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In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

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In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

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Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

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What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

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Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
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© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

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Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

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Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
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© 2005 Aeras Global TB Vaccine Foundation

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Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

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© 2005 Aeras Global TB Vaccine Foundation

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It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
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© 2005 Aeras Global TB Vaccine Foundation

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Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
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© 2005 Aeras Global TB Vaccine Foundation

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Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
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© 2005 Aeras Global TB Vaccine Foundation

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Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
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© 2005 Aeras Global TB Vaccine Foundation

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Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

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© 2005 Aeras Global TB Vaccine Foundation

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The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
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© 2005 Aeras Global TB Vaccine Foundation

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So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

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© 2005 Aeras Global TB Vaccine Foundation

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In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
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© 2005 Aeras Global TB Vaccine Foundation

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History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

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Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
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© 2005 Aeras Global TB Vaccine Foundation

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The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

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Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

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History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

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World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

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Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

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“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

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This was one
of the
strategies
used to keep
the
participants
happy.

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© 2005 Aeras Global TB Vaccine Foundation

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Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
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© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
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© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
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© 2005 Aeras Global TB Vaccine Foundation

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Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

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© 2005 Aeras Global TB Vaccine Foundation

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So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

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What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

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The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
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© 2005 Aeras Global TB Vaccine Foundation

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CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

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© 2005 Aeras Global TB Vaccine Foundation

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GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
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© 2005 Aeras Global TB Vaccine Foundation

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Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

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Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
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© 2005 Aeras Global TB Vaccine Foundation

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ACTIVITY

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© 2005 Aeras Global TB Vaccine Foundation

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How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
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© 2005 Aeras Global TB Vaccine Foundation

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Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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© 2005 Aeras Global TB Vaccine Foundation

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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

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Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

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Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

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Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
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© 2005 Aeras Global TB Vaccine Foundation

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2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

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Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

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Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
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© 2005 Aeras Global TB Vaccine Foundation

60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
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© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 9

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
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13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
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14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
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20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
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23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
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34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
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39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
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55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 10

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 11

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
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39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
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40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 12

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
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6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
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7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
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13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
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17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
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20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 13

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
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20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
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23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
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39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
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40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 14

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
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5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
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6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
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7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
© 2005 Aeras Global TB Vaccine Foundation

68


Slide 15

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

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In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

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In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

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Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

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What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

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Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
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© 2005 Aeras Global TB Vaccine Foundation

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Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

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Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
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© 2005 Aeras Global TB Vaccine Foundation

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Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
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© 2005 Aeras Global TB Vaccine Foundation

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Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

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© 2005 Aeras Global TB Vaccine Foundation

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It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
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© 2005 Aeras Global TB Vaccine Foundation

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Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
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© 2005 Aeras Global TB Vaccine Foundation

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Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
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© 2005 Aeras Global TB Vaccine Foundation

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Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
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© 2005 Aeras Global TB Vaccine Foundation

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Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

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© 2005 Aeras Global TB Vaccine Foundation

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The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
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© 2005 Aeras Global TB Vaccine Foundation

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So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

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© 2005 Aeras Global TB Vaccine Foundation

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In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
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© 2005 Aeras Global TB Vaccine Foundation

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History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

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Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

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The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

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Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

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History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

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World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

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Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

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“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

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This was one
of the
strategies
used to keep
the
participants
happy.

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© 2005 Aeras Global TB Vaccine Foundation

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Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
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© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
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© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
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© 2005 Aeras Global TB Vaccine Foundation

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Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

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© 2005 Aeras Global TB Vaccine Foundation

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So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

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International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

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What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

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The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
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© 2005 Aeras Global TB Vaccine Foundation

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CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

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© 2005 Aeras Global TB Vaccine Foundation

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GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

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Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

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© 2005 Aeras Global TB Vaccine Foundation

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Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

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Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
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© 2005 Aeras Global TB Vaccine Foundation

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ACTIVITY

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© 2005 Aeras Global TB Vaccine Foundation

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How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
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© 2005 Aeras Global TB Vaccine Foundation

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Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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© 2005 Aeras Global TB Vaccine Foundation

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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

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© 2005 Aeras Global TB Vaccine Foundation

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Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

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Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
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© 2005 Aeras Global TB Vaccine Foundation

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Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

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2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

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Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

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Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
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© 2005 Aeras Global TB Vaccine Foundation

60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 16

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
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14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
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20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
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23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
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34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
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55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 17

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
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7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 18

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
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39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
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40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 19

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
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17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 20

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 21

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
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3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
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5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
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6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
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The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

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10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
© 2005 Aeras Global TB Vaccine Foundation

68


Slide 22

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

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In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

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Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

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Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
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© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

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Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

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Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
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© 2005 Aeras Global TB Vaccine Foundation

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Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

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© 2005 Aeras Global TB Vaccine Foundation

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It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
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© 2005 Aeras Global TB Vaccine Foundation

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Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
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© 2005 Aeras Global TB Vaccine Foundation

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Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
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© 2005 Aeras Global TB Vaccine Foundation

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Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
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© 2005 Aeras Global TB Vaccine Foundation

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Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

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© 2005 Aeras Global TB Vaccine Foundation

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The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
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© 2005 Aeras Global TB Vaccine Foundation

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So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

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© 2005 Aeras Global TB Vaccine Foundation

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In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
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© 2005 Aeras Global TB Vaccine Foundation

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History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

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Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

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The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

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Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

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History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

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World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

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Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

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“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

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This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

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Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
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© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
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© 2005 Aeras Global TB Vaccine Foundation

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Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

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© 2005 Aeras Global TB Vaccine Foundation

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So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

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What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

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The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

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CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

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GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

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Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

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Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
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© 2005 Aeras Global TB Vaccine Foundation

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ACTIVITY

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© 2005 Aeras Global TB Vaccine Foundation

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How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
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© 2005 Aeras Global TB Vaccine Foundation

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Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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© 2005 Aeras Global TB Vaccine Foundation

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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

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Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

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Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

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Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

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2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

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Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
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© 2005 Aeras Global TB Vaccine Foundation

60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 23

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
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34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
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55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 24

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 25

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
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39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
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40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 26

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 27

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 28

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
© 2005 Aeras Global TB Vaccine Foundation

68


Slide 29

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
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© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

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Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

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Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

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It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
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© 2005 Aeras Global TB Vaccine Foundation

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Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
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© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
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© 2005 Aeras Global TB Vaccine Foundation

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Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
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© 2005 Aeras Global TB Vaccine Foundation

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Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

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© 2005 Aeras Global TB Vaccine Foundation

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The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
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© 2005 Aeras Global TB Vaccine Foundation

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So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

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© 2005 Aeras Global TB Vaccine Foundation

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In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

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History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

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Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
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© 2005 Aeras Global TB Vaccine Foundation

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ACTIVITY

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© 2005 Aeras Global TB Vaccine Foundation

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How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

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Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
© 2005 Aeras Global TB Vaccine Foundation

60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 30

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
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20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
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23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
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34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
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55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 31

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 32

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
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39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
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40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 33

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
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17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 34

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 35

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
© 2005 Aeras Global TB Vaccine Foundation

68


Slide 36

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

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In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

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Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
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© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

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Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

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Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
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© 2005 Aeras Global TB Vaccine Foundation

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Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

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© 2005 Aeras Global TB Vaccine Foundation

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It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
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© 2005 Aeras Global TB Vaccine Foundation

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Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
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© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
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© 2005 Aeras Global TB Vaccine Foundation

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Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
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© 2005 Aeras Global TB Vaccine Foundation

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Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

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© 2005 Aeras Global TB Vaccine Foundation

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The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
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© 2005 Aeras Global TB Vaccine Foundation

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So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

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© 2005 Aeras Global TB Vaccine Foundation

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In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

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History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

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Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

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So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

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What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
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© 2005 Aeras Global TB Vaccine Foundation

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ACTIVITY

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© 2005 Aeras Global TB Vaccine Foundation

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How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
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© 2005 Aeras Global TB Vaccine Foundation

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Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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© 2005 Aeras Global TB Vaccine Foundation

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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

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Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
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© 2005 Aeras Global TB Vaccine Foundation

60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 37

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
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55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 38

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 39

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
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39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
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40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 40

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 41

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 42

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
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6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
© 2005 Aeras Global TB Vaccine Foundation

68


Slide 43

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

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Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
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© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

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Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
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© 2005 Aeras Global TB Vaccine Foundation

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Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

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It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
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© 2005 Aeras Global TB Vaccine Foundation

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Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
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© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
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© 2005 Aeras Global TB Vaccine Foundation

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Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
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© 2005 Aeras Global TB Vaccine Foundation

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Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

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© 2005 Aeras Global TB Vaccine Foundation

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The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
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© 2005 Aeras Global TB Vaccine Foundation

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So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

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© 2005 Aeras Global TB Vaccine Foundation

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In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

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History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

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Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

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Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
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© 2005 Aeras Global TB Vaccine Foundation

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ACTIVITY

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© 2005 Aeras Global TB Vaccine Foundation

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How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
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© 2005 Aeras Global TB Vaccine Foundation

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Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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© 2005 Aeras Global TB Vaccine Foundation

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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
© 2005 Aeras Global TB Vaccine Foundation

60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 44

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
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14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
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20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
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23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
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34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
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55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 45

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
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7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 46

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
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39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
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40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 47

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
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13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
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17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 48

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 49

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
© 2005 Aeras Global TB Vaccine Foundation

68


Slide 50

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

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In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

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Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

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What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
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© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

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Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

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Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
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© 2005 Aeras Global TB Vaccine Foundation

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Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

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© 2005 Aeras Global TB Vaccine Foundation

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It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
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© 2005 Aeras Global TB Vaccine Foundation

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Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
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© 2005 Aeras Global TB Vaccine Foundation

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Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
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© 2005 Aeras Global TB Vaccine Foundation

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Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
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© 2005 Aeras Global TB Vaccine Foundation

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Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

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© 2005 Aeras Global TB Vaccine Foundation

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The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
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© 2005 Aeras Global TB Vaccine Foundation

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So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

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© 2005 Aeras Global TB Vaccine Foundation

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In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

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History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

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Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

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History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

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World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

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Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

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This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

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Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
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© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

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Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

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So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

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What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

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Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
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© 2005 Aeras Global TB Vaccine Foundation

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ACTIVITY

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© 2005 Aeras Global TB Vaccine Foundation

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How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
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© 2005 Aeras Global TB Vaccine Foundation

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Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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© 2005 Aeras Global TB Vaccine Foundation

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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

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Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

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Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
© 2005 Aeras Global TB Vaccine Foundation

60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 51

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
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14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
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20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
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34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
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55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 52

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 53

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
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39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
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40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 54

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
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6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
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11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
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13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
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14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
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17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 55

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 56

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
© 2005 Aeras Global TB Vaccine Foundation

68


Slide 57

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

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In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

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Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

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What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
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© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

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Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

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Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
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© 2005 Aeras Global TB Vaccine Foundation

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Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

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© 2005 Aeras Global TB Vaccine Foundation

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It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
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© 2005 Aeras Global TB Vaccine Foundation

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Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
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© 2005 Aeras Global TB Vaccine Foundation

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Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
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© 2005 Aeras Global TB Vaccine Foundation

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Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
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© 2005 Aeras Global TB Vaccine Foundation

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Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

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© 2005 Aeras Global TB Vaccine Foundation

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The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
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© 2005 Aeras Global TB Vaccine Foundation

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So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

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© 2005 Aeras Global TB Vaccine Foundation

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In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

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History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

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The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

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Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

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History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

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World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

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Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

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This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

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Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
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© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

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Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

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So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

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What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

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Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

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Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
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© 2005 Aeras Global TB Vaccine Foundation

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ACTIVITY

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© 2005 Aeras Global TB Vaccine Foundation

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How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
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© 2005 Aeras Global TB Vaccine Foundation

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Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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© 2005 Aeras Global TB Vaccine Foundation

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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

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Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

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Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
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© 2005 Aeras Global TB Vaccine Foundation

60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 58

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
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14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
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34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
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36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
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55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 59

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
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63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 60

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
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39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
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40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
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42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 61

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
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17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 62

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
© 2005 Aeras Global TB Vaccine Foundation

48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 63

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
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4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
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6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
© 2005 Aeras Global TB Vaccine Foundation

50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
© 2005 Aeras Global TB Vaccine Foundation

68


Slide 64

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

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In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

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Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

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What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
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© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

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Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

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Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
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© 2005 Aeras Global TB Vaccine Foundation

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Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

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© 2005 Aeras Global TB Vaccine Foundation

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It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
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© 2005 Aeras Global TB Vaccine Foundation

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Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
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© 2005 Aeras Global TB Vaccine Foundation

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Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
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© 2005 Aeras Global TB Vaccine Foundation

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Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
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© 2005 Aeras Global TB Vaccine Foundation

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Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

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© 2005 Aeras Global TB Vaccine Foundation

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The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
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© 2005 Aeras Global TB Vaccine Foundation

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So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

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© 2005 Aeras Global TB Vaccine Foundation

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In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

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History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

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Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

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Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

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History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

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World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

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Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

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This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

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Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
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© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

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Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
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© 2005 Aeras Global TB Vaccine Foundation

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Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

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So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

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What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

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Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

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Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
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© 2005 Aeras Global TB Vaccine Foundation

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ACTIVITY

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© 2005 Aeras Global TB Vaccine Foundation

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How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
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© 2005 Aeras Global TB Vaccine Foundation

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Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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© 2005 Aeras Global TB Vaccine Foundation

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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
© 2005 Aeras Global TB Vaccine Foundation

51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
© 2005 Aeras Global TB Vaccine Foundation

52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
© 2005 Aeras Global TB Vaccine Foundation

53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
© 2005 Aeras Global TB Vaccine Foundation

54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
© 2005 Aeras Global TB Vaccine Foundation

56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
© 2005 Aeras Global TB Vaccine Foundation

57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
© 2005 Aeras Global TB Vaccine Foundation

58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
© 2005 Aeras Global TB Vaccine Foundation

59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
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© 2005 Aeras Global TB Vaccine Foundation

60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
© 2005 Aeras Global TB Vaccine Foundation

61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
© 2005 Aeras Global TB Vaccine Foundation

62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
© 2005 Aeras Global TB Vaccine Foundation

64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
© 2005 Aeras Global TB Vaccine Foundation

65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
© 2005 Aeras Global TB Vaccine Foundation

66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
© 2005 Aeras Global TB Vaccine Foundation

67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 65

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
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29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
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31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
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33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
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43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
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55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 66

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
© 2005 Aeras Global TB Vaccine Foundation

18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
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38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
50
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50

Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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68


Slide 67

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
© 2005 Aeras Global TB Vaccine Foundation

12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
© 2005 Aeras Global TB Vaccine Foundation

17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
© 2005 Aeras Global TB Vaccine Foundation

19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
© 2005 Aeras Global TB Vaccine Foundation

21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
© 2005 Aeras Global TB Vaccine Foundation

22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
© 2005 Aeras Global TB Vaccine Foundation

25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
© 2005 Aeras Global TB Vaccine Foundation

26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
© 2005 Aeras Global TB Vaccine Foundation

27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
© 2005 Aeras Global TB Vaccine Foundation

28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
© 2005 Aeras Global TB Vaccine Foundation

30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
© 2005 Aeras Global TB Vaccine Foundation

32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
© 2005 Aeras Global TB Vaccine Foundation

35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
© 2005 Aeras Global TB Vaccine Foundation

37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
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39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
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40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
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41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
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44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
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45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
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46

ACTIVITY

47
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47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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48

Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
© 2005
Aeras Global
TB in
Vaccine
Foundation

49

Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

51
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51

Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
52
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52

Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
53
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53

Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
54
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54

Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

55
© 2005 Aeras Global TB Vaccine Foundation

55

1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
56
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56

2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
57
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57

Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

58
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58

Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

59
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59

Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
60
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60

3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
61
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61

4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
62
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62

Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
63
© 2005 Aeras Global TB Vaccine Foundation

63

Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
64
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64

Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
65
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65

Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

66
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66

Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
67
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67

Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

68
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Slide 68

Intermediate Clinical Research

Clinical Research Practice 2
© 2004 Aeras Global TB Vaccine Foundation

Purpose:
To provide an in depth understanding of
Good Clinical Practice and ethical guidelines
for clinical research and the protection of
research participants.

2
© 2005 Aeras Global TB Vaccine Foundation

2

In This Course You Will Learn To:








Identify the key events and documents that led to
the standards and ethical principles that guides the
conduct of clinical research today.
Recognise the key factors or guidelines for clinical
research that emerged from the primary events or
documents that guides current clinical research
ethics.
Name the key international guidelines that were
adopted and followed as part of the South African
guidelines for the conduct of clinical research.
Identify special populations that have additional
guidelines for their protection during clinical
research under SA GCP guidelines.
3
© 2005 Aeras Global TB Vaccine Foundation

3

In This Course You Will Learn To:








Describe the guidelines for the inclusion of children
and adolescents and vulnerable communities in
clinical research.
List the 4 primary means of protection offered to
study participants under GCP guidelines
throughout the conduct of a study.
Identify the 4 phases of clinical trials.
Identify who is responsible for ensuring that
research is performed and data generated in
compliance with GCP guidelines and other
applicable regulations.
4
© 2005 Aeras Global TB Vaccine Foundation

4

Do You Remember?
What is clinical research?

Why do we perform it?

What happens in clinical
research?
5
© 2005 Aeras Global TB Vaccine Foundation

5

What Is Clinical Research?






A scientific study looking for answers to
specific questions.
Method for finding safe, new and
improved vaccines, drugs, and other
treatments to improve health.
Research that relies on human volunteers.

6
© 2005 Aeras Global TB Vaccine Foundation

6

Why Do We Perform
Clinical Research?









Test new therapies and drugs.
Gather data from participants who have had a
known intervention and monitor results.
Determine the safety and effectiveness of drugs,
therapies, and other treatments.
Develop new drugs and treatments that are
safer, more effective and faster working than
any before.
Ultimately – to improve health status.
7
© 2005 Aeras Global TB Vaccine Foundation

7

The Life Cycle Of
A Clinical Research Project
Define Research Question
(What do you want to know?)

Write
Protocol
Get Regulatory
Approval
Conduct
Research

Write a
Research
Proposal

Find Funding &
Select Research Team

Analyse
Results
8

© 2005 Aeras Global TB Vaccine Foundation

Report
Results
8

Study or Trial?
All trials are studies but not all studies are trials.

Do you know what the difference is?
During a clinical trial a specific intervention
needs to be tested on humans.
Which of the studies at our site can be
classified as trials?
9
© 2005 Aeras Global TB Vaccine Foundation

9

Four Phases of Clinical Trials
Trials with a drug safety aspect has to go
through the following phases, before making
the drug or vaccine widely available to the
public.
Phase IV

Phase III
Phase II
Phase
I
10

© 2005 Aeras Global TB Vaccine Foundation

10

Phase I








New drugs/treatment are tested on
humans for the first time.
Small group of volunteers (30-50)
Healthy : 21+ years of age
Goal: Determine the effect of the drug on
a person’s body at a physical/physiological
level.
“Is the treatment safe ?”
11
© 2005 Aeras Global TB Vaccine Foundation

11

Phase II









Phase I completed = treatment safe thus far
Less than 100 Volunteers
Disease specific volunteers
Conduct Randomised trials in order to compare
the Experimental drug with a Placebo or the
standard treatment.
Goal: Determine safety and efficacy. How it
should be given, how often and how much is
safe?
“Can the treatment work ?”
12
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12

Phase III









Phase II completed
Hundreds - thousands of volunteers
Conduct Randomised and Blinded studies.
Goal: Determine safety, efficacy, benefits and
the range of possible adverse reactions in the
broader community.
Approval for the market.
“Is the new treatment better than existing
treatment or placebo?”
13
© 2005 Aeras Global TB Vaccine Foundation

13

Phase IV






Post market
Hundreds - thousands of volunteers
Goal: Determine additional information
including the drug’s risks, benefits, and
optimal use.
“Is there a better way to use this
treatment ?”

14
© 2005 Aeras Global TB Vaccine Foundation

14

It does not matter what type or
kind of clinical research we
conduct.
If there are humans involved in the
research there is one condition that
absolutely has to be met.
Do you know what it is?
15
© 2005 Aeras Global TB Vaccine Foundation

15

Protection of Human Participants

Good Clinical Practice

Good Laboratory Practice
16

© 2005 Aeras Global TB Vaccine Foundation

16

Good Clinical Practice





An international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the participation
of human volunteers.

Simply put …. GCP is the set of rules by which
we conduct our research.
17
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17

Good Laboratory Practice





Represents a set of principles that provides a
framework within which laboratory studies are
planned, performed, monitored, recorded,
reported and archived.

Simply put ….
GLP is the set of rules of research in the lab.
18
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18

Why Is Following GCP and GLP
Important ?
Compliance with these standards assures:





participant rights are protected.
the safety of human volunteers.
participant well-being is a priority.
results are used for improvement of health
and well-being of all.

19
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19

The Protection of Human
Participants

An introduction to GCP and GLP is not enough to
understand the complexities of the ways in
which the Human Research Participant must be
protected.
We need to look at the codes, declarations, reports
and guidelines that provides the:
 Ethical rules and principals and
 Foundational elements…….
……….for the conduct of clinical research.
20
© 2005 Aeras Global TB Vaccine Foundation

20

So, ……..




In the past there were abuses and
unethical behavior. Science was put ahead
of human rights,
and the..
International community responded – new
standards emerged.

21
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21

In the CRP 1 Module
We looked at the
 Nuremberg Code
 Declaration of Helsinki
 Belmont Report
 ICH GCP………..
Let’s dig a bit deeper into a bit more detail..
22
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22

History of the Nuremberg Code:


Nazi Medical War Crimes:
1939 – 1945

Photos courtesy of US Holocaust Museum

23
© 2005 Aeras Global TB Vaccine Foundation

23

Nazi Experiments Using Children:


1939 - 1945

Photos courtesy of US Holocaust Museum
24
© 2005 Aeras Global TB Vaccine Foundation

24

The Nuremberg Trial






1946: 23 Nazi
physicians on trial.

“Permissible Medical
Experiments”
The Nuremberg Code

Photo courtesy of USHMM.

25
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25

Nuremberg Code





Published in 1947
The first internationally recognized
standard for human participant research.
Consisted of 10 conditions and included:




Voluntary consent
Risk/benefit ratio
Right to withdraw from experiments.
These conditions had to be met before
research was ethically permissible.
26
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26

History of the
Declaration of Helsinki






Thalidomide disaster – late 1950’s
Results of this tragedy:
 FDA requiring pre-clinical safety reports
 Europe and UK developed reporting
systems
Led to the
Declaration of Helsinki
in 1964
Photo courtesy of The Teratology Society

27
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27

World Medical Association
Declaration of Helsinki
 Developed by the World Medical Association in
1964.
 First significant effort of the medical community
to regulate itself.
 Legally binding.

 Latest version: October 2000 with notes of
clarification in 2002 & 2004.
28
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28

Declaration of Helsinki (DOH)
Consists of 32 ethical principles and
includes:







Voluntary consent , Risk/benefit ratio and the
Right to withdraw from experiments……
and
Additional principles for medical research
combined with medical care.
Use of placebo.
Access of participants to the best proven
methods identified by the study.
29
© 2005 Aeras Global TB Vaccine Foundation

29

History of the Belmont Report:


Tuskegee Syphilis Study: 1932-1972

30
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30

“This examination is a very special one and after it
is finished you will be given a special treatment if
it is believed you are in a condition to stand it.”

“This is your last chance for special free treatment.”
31
© 2005 Aeras Global TB Vaccine Foundation

31

This was one
of the
strategies
used to keep
the
participants
happy.

32
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32

Then the Tuskegee Study Became
Public and ……


National commission – 1974



Published the “Ethical Principles



Belmont Report



Identified three basic principles.

and guidelines for the Protection
of Human Subjects.” -1979

33
© 2005 Aeras Global TB Vaccine Foundation

33

Principle

Application

Respect for Persons

Informed Consent

 Individuals should be
 Participants, to the
treated as autonomous
degree that they are
agents
capable, must be given
the opportunity to
 Persons with
choose what shall or
diminished autonomy
shall not happen to
are entitled to
them.
protection.
Key required elements:
 Information
 Comprehension
 Voluntary
participation
34
© 2005 Aeras Global TB Vaccine Foundation

34

Principle

Application

Beneficence
 Human participants
should be treated in
an ethical manner
and protected from
harm.

Assessment of Risk
and Benefit
 The nature and scope
of risks and benefits
must be assessed and
balanced in a
systematic manner.

 Research should
maximize possible
benefits and minimize
possible harm.
35
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35

Principle

Application

Justice

Selection of
Participants

 The benefits and
 There must be fair
risks of research
procedures and
must be distributed
outcomes in the
fairly and without
selection of research
bias.
participants.

Last 3 slides : Courtesy of the Claremont Graduate University: History of Ethics
36
© 2005 Aeras Global TB Vaccine Foundation

36

Did the Nuremberg Code & the
Declaration of Helsinki Change the
Conduct of Clinical Research?

NO !
The Research Community needed something to:




Ensure that the rights, safety and well-being of trial
participants are protected
Ensure the credibility of clinical trial data

37
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37

So, What Happened ?
Belmont Report - 1979
ICH GCP - 1990

CIOMS - 1993
38
© 2005 Aeras Global TB Vaccine Foundation

38

International Conference on
Harmonization 1990






World Health Organisation (WHO) – planned
to standardise requirements for registration of
new drugs:
 Many sets of guidelines all over the world.
 High cost of clinical trials and ethical
considerations of repeating trials when
drug efficacy was already demonstrated.

International Conference on
Harmonization in 1990 – Brussels
Published the ICH GCP Guidelines
39
© 2005 Aeras Global TB Vaccine Foundation

39

What Does ICH GCP Cover?



Consists of 13 Principles
Covers guidelines for the conduct of research:
 Ethics
 Essential documents
 Investigator
 Protocol
 Investigator’s Brochure
 Sponsor
40
© 2005 Aeras Global TB Vaccine Foundation

40

The Establishment of CIOMS






Council for International Organizations of
Medical Sciences
Established jointly by WHO and United
Nations Educational, Scientific and Cultural
Organisation (UNESCO) in 1949
Guidelines on how to effectively apply the
ethical principles as set forth in the DOH.
41
© 2005 Aeras Global TB Vaccine Foundation

41

CIOMS Guidelines


Consists of 15 guidelines that includes:
 Informed consent
 Standards for external review
 Recruitment of participants
…….focuses on research sponsored by or
initiated in developed countries and
carried out in developing countries

42
© 2005 Aeras Global TB Vaccine Foundation

42

GCP and National Differences






GCP is universal, but each country has its own
regulations and agencies to ensure GCP compliance.
In the United States, GCP is implemented under
45 CFR Part 46, under the U.S. Code of Federal
Regulations for the Protection of Human Subjects.


Defines the Institutional Review Board.



Provides guidelines for informed consent.

Do you recognise
these elements?

The U.S. 45 CFR Part 46 is only be applicable in South
Africa if a study is U.S. funded or otherwise subject to
U.S. regulations.
43
© 2005 Aeras Global TB Vaccine Foundation

43

Clinical Trial Approval in SA
Standard Approval Process:
1.
MCC (Regulatory Authority)
2.
Ethics Committee Approval
Multi-Centre Studies
“It is unacceptable for developed country participants
to have better standards of care offered in the study
when compared to South African participants. When
South Africa is chosen for a clinical trial while the trial
is not undertaken in the country of origin an
explanation should be sought about why this is the
case.”
SA GCP Guidelines

44
© 2005 Aeras Global TB Vaccine Foundation

44

Documents that Guide the Conduct
of Clinical Research in South Africa:


Declaration of Helsinki -2000



ICH Guidelines for Good Clinical Practice



CIOMS (Council for International Organizations of

(International Conference on Harmonization)

Medical Sciences)
“International Guidelines for Biomedical Research

Involving Human Subjects” – 1993
These are the documents that ensure the welfare and
integrity of participants in SA and must be followed by
the principle investigator.
“Guidelines for Good Practice in the conduct of Clinical Trials in Human Participants in South Africa” by the Dept.of Health

45
© 2005 Aeras Global TB Vaccine Foundation

45

Do We Have a SA GCP ?
“Guidelines for Good Practice in the Conduct of
Clinical Trials in Human Participants in South
Africa”
The purpose of these guidelines is to provide
South Africa with clearly articulated standards of
good clinical practice in research that are also
relevant to local realities and contexts.
46
© 2005 Aeras Global TB Vaccine Foundation

46

ACTIVITY

47
© 2005 Aeras Global TB Vaccine Foundation

47

How are Vulnerable Research
Participants Protected?
Some research participants are classified as
Vulnerable Research Participants who are
relatively or absolutely incapable of
protecting their own interests.
 The

research team should be aware of the
special problems of research involving
vulnerable populations
 Is the Research Justified?
 Must offer additional safeguards for their
safety and welfare.
48
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Special Populations of Participants
1.

2.

Children and
Adolescents
Women and
pregnancy

3.

Pregnant Women

4.

Fetuses in utero

5.

Fetuses ex utero

6.

Prisoners

7.

Mental disability

8.

9.

Vulnerable
communities
Other special
Groups

From the Guidelines for49Good Practice in the conduct of
clinical
trials
Human
Participant in South Africa. 2.3
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Some Specific Guidelines in Order
to Further Protect…..
Children and Adolescents
 Does not place the child
in no greater than
Minimal Risks




If more than Minimal Risk
- Direct Benefit for child
Need Consent and Assent
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Children in Research: Minors
South African Law:
Minor: Unmarried person below age 21

1 JULY 2007 CHANGED TO 18!
The consent of a parent/legal guardian
should be obtained for any research
procedure involving a minor.

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Assent In Addition to Consent
Out of Respect for Children/Adolescents as a
developing person, children should be
asked whether or not they wish to
participate.
Assent: A willingness that does not
necessarily carry the greater
understanding and legal implications
that are generally understood by
‘consent’.
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Some Specific Guidelines In Order
to Further Protect…..
Vulnerable Communities
 Could this research not be carried out in
populations from developed communities?
 The research must be responsive to the health
needs and the priorities of the community.
 Consent: content, languages and procedures
 Should not adversely affect the routine
treatment of patients.
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Ongoing Protection Throughout the
Study
As researcher/team we now have:
 Approval of the study
 Signed consent document
But
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study.
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Four Primary Means of Participant
Protection
Methods to protect our participants:
1. Ongoing Informed Consent
2. Safety Reporting
3. Data and Safety Monitoring
4. Continuing IRB Review

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1: Ongoing Informed Consent





Informed consent is an ongoing communication
process during the entire study.
The participant should maintain the ability to
understand and that he/she may withdraw from
the study at any time.
Additional Informed Consent (re-consent) should
occur when:



There are changes in the study
There is new information that may affect the
willingness to participate further.
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2: Safety Reporting
Further ongoing protection of our
participants is to report on any ill “effect”
of our intervention/drug on our
participants.
We call this Adverse Event reporting.

The process will be detailed in the study
protocol.
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Adverse Event (AE)
“Any untoward medical occurrence in a
patient or clinical investigation subject
administered a pharmaceutical product
and which does not necessarily have a
causal relationship with this treatment.”
(ICH GCP 1.2)

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Adverse Drug Reaction (ADR)
“All noxious and unintended responses to a
medicinal product related to any dose
should be considered adverse drug
reactions.” (ICH GCP 1.1)
Expected:

Unexpected:

Previously observed events

Any AE that is not expected

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Serious Adverse Event (SAE)
“Any untoward medical occurrence that at any
dose:
 Results in death.
 Is life-threatening.
 Requires inpatient hospitalization or prolongation
of existing hospitalisation.
 Results in persistent or significant
disability/incapacity or
 Is a congenital anomaly/birth defect.” (ICH GCP 1.50)
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3: Data and Safety Monitoring
Independent Committee
Essential role :

in protecting the safety of participants

and ensuring integrity of the research study
The Data Safety Monitoring Board (DSMB)
can and will stop a study if:
STOP 1. There are safety concerns.
2. The objectives of the study are met.
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4: Continuing IRB Review






Annual Reports to the
IRB from the regulatory
officer of the study.

Reports from the DSMB.
Depending on the degree
of risk to participants continuing review from
the committee itself.
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Finally.….
We now have:
 An understanding of what phase our trial is in
 Approval for our study
 Signed Consent document
 Ongoing protection right through our study

Remember
The Research Team has to ensure that the study is
performed and the data are generated in
compliance to GCP and the regulatory
authorities.
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Review








The Nuremberg Code was the first ethical code to
provide us with some guidelines for “permissible medical
experiments.”
The Declaration of Helsinki provides additional guidelines
especially relating to physicians conducting research with
therapeutic intent on patients.
The Tuskegee Study led to the development of the
Belmont Report.
The three fundamental ethical principles that guide the
ethical conduct of research are Respect for Persons,
Beneficence and Justice.
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Review


Research conduct is further guided by the ICH GCP and
the CIOMS guidelines.



The ICH GCP was initially developed to guide the ethics
and standards for drug development and registration.



The CIOMS guidelines focus on research conducted in
developing countries by developed countries.



“Guidelines for Good Practice in the conduct of Clinical
Trials in Human Participants in South Africa.” is the
document that provides SA with clear standards of GCP
and incorporates the above mentioned guidelines .
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Review




There are specific guidelines that protects
Children, Adolescents and Vulnerable
communities even further and we must be
aware of these guidelines.
In clinical research, the commitment to
participants is to safeguard their interests
throughout the study. This can be done with
ongoing informed consent, safety reporting,
continuing IRB review and safety monitoring.

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Review


Every drug trial has to go through the following Phases:
Phase I: “Is the treatment safe ?”



Phase II: “Can the treatment work ?”









Phase III: “Is the new treatment better than existing
treatment or placebo?”
Phase IV: “Is there a better way to use this treatment ?”
The research team have to ensure that the research is
performed and the data are generated in compliance to
GCP and the regulatory authorities.
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Clinical Research Practice 2

This presentation is produced by Aeras Global TB Vaccine FoundationSM in
collaboration with the University of Cape Town and the South African
Tuberculosis Vaccine Initiative.
A special thanks to Greg Hussey F.S.C.H., Tony Hawkridge, F.C.P.H.M.,
Hassan Mohammed, M. Med, Deon Minnies, Marie Buchanan,
Hons.B.Soc.Sc, Marijke Geldenhuys, MSHS CRA, Sylvia Silver, D.A., Jen
Page, M.Ed. for their contributions and support for this presentation.

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