Transcript Document

Role Of Clinical
Investigators In Clinical
Research
M.D. Nair
JIPMER
Pondicherry
19.10.2005
Clinical Research Is Part Of New Drug
Development: What Are The Major Issues Involved?
- Use of Animals for Research.
-Lack of correlation between in-vitro & in-vivo tests.
-Credibility & Correlation of Preclinical Data
for planning Clinical Trials.
-Ethical issues related to human trials.
-Significance of Human Trials vis-à-vis field use.
-Assessments Of Adverse Drug Reactions.
-Regulatory hurdles.
-New Drug Approval (NDA) Standards.
-Post-Marketing Surveillance Problems.
-High Costs Of Drug Discovery & Development.
Impact Of High Costs Of Drug Discovery: Need For An Overhaul
Report of Andersen Consulting (1997).
- To keep pace with the need for 10% annual growth,
top 10 companies need to launch 5 NCEs each per
year with average turnover of US$ 350 mio. each.
- Today, they are launching an average of 0.45 NCEs
per year and only 8% of new drugs reach the
threshold sales.
- There is need for accelerating the clinical phases
and reducing approval times.
-R&D alliances between Companies will also help.
R&D Costs For New Drug Discovery And Development
Reducing the Costs of and time for Drug Discovery and Development is one of the ways
of reducing total costs.
For a breakthrough Drug, one day’s delay in approval can cost a million Dollars in sales,
and delay in patient’s benefits.
Realising this, FDA has accelerated the Drug approval Process by charging user fees and
providing for fast track clearances for life-saving and orphan drugs.
Recent case of COX 2 Inhibitors may reverse this trend and further extend the gestation
period.
Time (In Years) To Develop A New
Drug (Average) Pre-Clinical Testing
To Approval 1960s-1990s (US FDA)
Pre-clinical
Phase
Clinical Phase
Approval
Phase
1960s
3.6
2.8
2.4
1970s
4.6
4.4
2.1
1980s
4.7
5.7
2.8
1990s
4.7
6.6
1.9
Why are New Drugs Expensive &
Unaffordable? Costs of Clinical Trials
1981-84
2001-02
Average No. of Clinical
Trials / NDA
30
68
Average No. of Patients
per NDA
1,321
4,237
Pitfalls Of The Current Model Of Drug Discovery & Development.
- High and unaffordable costs of R&D and
consequently of new drugs.
- Too many products with identical
pharmacological profile and mechanism – the
milligram battle.
- Low therapeutic rationale and advance for new
drugs.
- Many products especially biotech products
developed through technology push rather than
medical demand pull.
Can We Make Regulatory Submissions More Crisp And Meaningful
No. of Words In Documents
Pythagoras Theorem
24
Archimedes Principle
67
The Ten Commandments
179
American Declaration of Independence
300
European Legislation on when and where one
can smoke
24,942
Average IND Submission to FDA
800,000
At The Same Time Regulations in New
Drugs Research Are Needed To:
- To ensure safety and efficacy of New Drugs
by an independent authority
- To ensure that uniform and well-laid out
standards apply to all products
- To ensure that products are continuously
monitored, post-marketing
- To review safety and efficacy standards
based on new knowledge
- To recommend appropriate amendments to
Drugs and Cosmetics Act
FDA REGULATIONS MOSTLY A REACTIVE RESPONSE
1906
History of FDA, USA, concerned only with
purity.
1936
Elixir Sulfanilamide 10% solution in 70%
Diethylene Glycol implicated in 105 deaths.
Federal Food, Drug & Cosmetic Act passed
concerned with safety, not efficacy – NDA to
be approved.
Thalidomide disaster in Europe. .
1938
1961
1962
1987
Kefauver-Harris Amendment passed
regarding extensive safety and efficacy
studies – IND mandatory.
Format of IND changed.
Criticisms & Negative Perceptions On
Clinical Trials
 Trial objectives skewed in favour of
potential positive outcomes.
 Cutting out tests likely to end in negative
results.
 Manipulation of Subject inclusion &
exclusion criteria.
 Outright fraud in selection of investigators
with vested interests.
 Suppression of publication of negative
results.
To Eliminate Or Minimise These
Negatives, Clinical Trials Need To Be
Conducted Under Internationally
Accepted Good Clinical Practice (GCP)
Guidelines.
- GCP protects patients/subjects.
- GCP ensures that clinical trials produce
accurate, credible data by:
- defining standards
- defining responsibilities
Good Clinical Practice
1962
1961
Drug Amendments Act
Thalidomide
1963
IND Procedure
ORIGINS
1977
1964
Proposed FDA Regulations covering
obligations of Sponsors, Monitors
and Clinical Investigators
Declaration of Helsinki
The Emergence Of ICH
Guidelines
ICH was evolved to negotiate common
standards for the regulation of pharmaceutical
products in Europe, Japan and U.S.A.
According to its Mission Statement –
ICH exists “to provide a forum for a
constructive dialogue between the regulatory
authorities and the pharma industry on the real
and perceived differences in the technical
requirements for product registration”.
ICH (Objectives)
- Eliminate redundant & duplicative technical
development.
- Expedite global development.
- Expedite availability of new medicines.
- Maintaining safeguards on quality, safety &
efficacy.
ICH
Some key areas of interest :
Safety reporting/Adverse Events
(definitions and timings)
New standards/templates (e.g., protocol,
investigator’s brochure)
Essential documents
Clinical Research An important Component Of
The Regulatory System Has The Following
Components
-Candidate Drug
-Trial Sponsor
- CRO/Monitor
- Investigators & Trial Centres
- Trial Subjects : Healthy Volunteers &
Patients
- Biostatisticians
The Investigator’s Obligations
are spread over three phases.
1) Prior to Initiation of the trial
2) During The Trial
3) Post Trial
Prior To The Trials
- The investigator should be excited about the
study for its scientific merit rather than other
considerations.
- Should ensure that confidentiality should be
maintained.
- Should have sufficient time allocated to involve in
the trials
- Should be familiar with the product and well
acquainted all pre-clinical data & IND dossier.
- Ensure that there areadequate resources available
& allocated.
- Should discuss the Protocol & details of trials with
Sponsor/Monitor.
- Finalise local clearances, IEC, IRB etc as per the
ICH guidelines, Informed Consent Forms .
During The Clinical Studies
- Investigator should prepare a File containing all documents
related to the Trial which should be kept in a secure area
accessible to only him & his staff.
- Patient identification codes & details should be preserved at
least for 15 years and should be destroyed only with prior
permission from the sponsor.
- General medical Care should be provided to all subjects by the
investigator or family physician.
- Ensure strict adherence to randomisation, unblinding etc as per
the protocol.
-- Safety & adverse reaction reports to be regularly obtained and
action taken as per protocol to cause no or least damage to
subjects. (ICH 4.11)
-- Ensure proper completion/validation of the Case record Forms..
- Assess causality in terms of ‘not related, unlikely, possible,
probable and most probable’, send reports and take corrective
action.
INVESTIGATOR SOPs
Objectives
Ensuring
that the investigator understands the
responsibilities and obligations of the study.
Planning & conducting the study as per the approved
protocols and complying with ICH/GCP guidelines.
Ensuring that the safety & welfare of the subjects are
always the prime concern.
Proper and accurate collection , Documentation &
analysis of Data from the trials.
Cooperate in inspections, monitoring and auditing of
the study by third parties.
Investigators To Be Familiar With Documents Used By
Ethics Committee.
-GCP GuidelinesAme
-Investigator Brochure and safety Information.
-Trial Protocol.
-Consent Forms & Trial Information Sheets
-Subject Recruitment Procedures.
-Information on payment & remuneration to subjects.
-Any Amendments To The Protocols Or SOPs..
-Any other document required by IEC/IRB.
See ICH Guidelines 3.1.2.
Nature Of Regulatory Inspections
1) Study related Inspections
2) Investigator Related Inspections
-
-
Based on the pivotal nature of the study
Sponsor’s Difficulties in getting some Reports.
-
Violation of trial protocol.
-
Work involved turns out to be outside
competence of the investigator .
-
Results at variance with those of other
investigators.
Inspection Reporting Systems
1) No lapse.
2) Requires corrective action for remediable
lapses.
3) Warning letter if corrective actionnot taken
or delayed, with copies to sponsor
&reviewing IRB.
4) Inviting for possible hearings.
5) Disqualification when the Investigator has
deliberately violated the Agency’s regulatory
standards or submitted false information.
Clinical Trials Deficiencies* (1999)
Apart From Deliberate Fraud, Clinical Trials
fail due to following categories of deficiencies
Protocols
-
28%
Records & Documentation - 20%
Adverse Drug Reaction Reporting - 15%
Informed Consent
-
10%
Drug Accounting
-
10%
*Data From U.S.FDA.
FIDDES CASE- FRAUD AT ITS
WORST
From early 1990s Dr. Fiddes, President
of a California based CRO had
conducted over 200 Clinical Trials for
47 companies. Engaged in extensive
fraudulent and falsified data, he was
sentenced and jailed in Federal Prison
for 15 months, a penalty of
$ 800000 imposed in 1998 and was
disqualified as a clinical investigator in
1999.
Glaxo Paxil Case-Emergence Of Transparency In Clinical Trials
In the lawsuit against GSK, New York Attorney General Eliot Spitzer
asserted that a novel fraud of suppression of information was committed in

the promotion of Paxil for use as an anti-depressant.
In August 2004, Glaxo started posting the full details of Clinical trials in
their Website, creating a Clinical register and started inclusion of Safety &
Efficacy data, off-label drug use issues etc in Medical Information Letters to
Physicians... GSK also paid a fine of $ 2.5 million.
Profile of Regulatory Agencies: More
applicable to Developing Countries
- Need to balance the interests of the consumers as well
as the industry.
- Under-staffed and over-burdened: working on shoestring
budgets.
- No independent database to arrive at timely and scientific
judgements.
-Vulnerable to pressures from politicians and consumer
activists.
--No control
Investigators.
on
recruitment
of
Clinical
Centres
&
- Dependency on ‘Experts’ who have little stake in the
impact of their judgements on consumers or producers.
Not equipped physically or technically to ensure
compliance with GCP/ICH Guidelines
To be a Global Player in all
of the activities of
the Pharmaceutical Industry
including as a major outsourcing
destination for Clinical
Research, it is obvious that very
many systems, practices and
regulatory standards are to be put in place.
Proper regulatory systems,
interested, knowledgeable and dedicated
clinical investigators,
resources , professional approaches and an
attitudinal change are needed to succeed.
To reach and sustain a predominant position in the
Global arena, the Indian Pharmaceutical industry needs
to invest in self-imposed regulatory systems .
Regulation through legislative measures are important
but they need to be facilitating change and progress
rather than hindering them. To succeed, one needs a
change in the mindset of all stakeholders. After all, as
Edward De Bono once said,
“To Get Something, You Need To Combine
Both Method And Motivation.
- Motivation Without Method Is Ineffective.
- Method Without Motivation Usually Sits
On The Library Shelf ”