Transcript Investigator Responsibilities

Protection of Human
Research Subjects:
A Key Investigator Responsibility
Charles H. Pierce, MD, PhD, CPI
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What you can expect:
 Drug Development overview
 Protecting Human Subjects is the key
 Why human Study Participants need protecting
 FDA form 1572
 Protected Health Information
 International Conference on Harmonization
 Investigator Responsibilities: everything including
•
•
•
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Adverse Events
Informed Consent Form and process
Source documents,
Safety reporting
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Phases of Clinical Drug Development
FDA
Subjects
I
Healthy
Normals
IIa
First time
in Patients
IIb
Patients
III
Patients
Number
20 - 100
25 - 75
50 - 200
>300
>1,000
Efficacy,
Safety
Efficacy,
Safety
Efficacy,
Safety,
New uses
Measures
Value
Cost
(Millions)
Time
(Years)
Dosage,
Dose range,
MOA
Kinetics,
Efficacy,
Safety,
Safety
Equivalence
Kinetics,
Dynamics
Proof of
Concept
Confirm
Confirm
mechanism
usefulness
of action
Review
Approve or
disapprove
IV
Patients
Surveillance,
extend patent
expand market
$8
$12
$7
$43
?
Varies with
The drug and
its use
1 - 1.5
1
1 - 1.5
3-6
2-3
1-2
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Physician Investigators
Have a dual responsibility and a potential
conflict of commitment, if not interest
• Goal of clinical care is to diagnose, treat, and cure
disease or to reduce pain and suffering in individual
patients - Patient care oriented.
• The goal of clinical research is to systematically
collect information from groups of persons to
produce generalizable findings to ….. . . . in a
whole population - Drug effect oriented
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Achieving Ethical Clarity
To view clinical trials as therapeutic and
as falling under the physician-patient
relationship because some aspects of
research are associated with care
constitutes an ethical distortion that
ought to be scrupulously resisted
Miller & Rosenstein, NEJM 2003; 348(14):1383-1386
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Patient Perceptions
Whites
Blacks
Believe they could be used as
“guinea pigs” for medical research
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80
Do NOT trust doctor to fully
explain their participation on a study
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42
Docs would enroll patients on a
research study that was harmful
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37
Do not feel they can freely ask or
question their doctors
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G. Corbie-Smith et al, Arch Int Med;162:2458,2002 6
Guarantees to Protection
 Physicians and Nurses are an integral part of the
process of clinical research – built in privacy + HIPAA
 Independent oversight committee (the IRB / IEC)
 Informed Consent is a process not just a signature
 Principles of GCP in research with human subjects
 Conflict of Interest (CoI) guidelines
 Data & Safety Monitoring Plans (DSMP) / Boards (DSMB)
 Research Subject Advocacy (RSA) program
 Physician Investigator certification (CPI, CI) is available
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The power of Law: the 1572
Signing a 1572 is the PI’s commitment in writing that
she/he will be responsible for the study in question;
totally responsible and for everything
This means she/he agrees to follow:
 21 CFR 50 - Informed Consent process
 21 CFR 56 - IRB does what it should
 21 CFR 312
 21 CFR 312.64 - AE reporting
 21 CFR 312.62 - Record keeping
 21 CFR 312.68 - Being audit ready
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The commitments of the 1572
 Personally conduct or supervise the investigation
 Ensure that all associates, colleagues, and employees
assisting in the study conduct are informed of obligations
 Conduct the study in accordance with the protocol
 Comply with all requirements / obligations of the PI
including preparation and maintenance of study records
 Inform the SP of the investigational nature of the study
 Ensure that the IC process is clear / valid and all IRB
requirements are met
 Accurately report all AE’s to the sponsor
 Read and understand the Investigators Brochure (IB)
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PHI Protection
 Health Insurance Portability and Accountability
Act (Aug 96 - 14 Apr 2003)
 Effects the collection, recording, transmission,
and storage of patient health information
 The effect is your ability to access and use this
information for research
 Protected Health Information (PHI)
 Individual identifiable health information past,
present, or future physical or mental health
condition in any medium (oral, paper, or e) 10
HIPAA means
 One obtains “permission” to use PHI
 Authorization to use PHI for research
 Waiver to use the information for ….
 De-Identified data: the list is not short
 Prior agreement to use the data or limited use
 OK to use for SOC including payments
 Subject has access to the records
 The right to inspect and copy
 Access may be suspended during trail conduct
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International Conference
on Harmonization - ICH
The Efficacy topics concern the Clinical
Investigator. They are: ICH E1 - Exposure of the agent to populations
E2 - Clinical Safety
E3 - Study Reports - structure and content
E4 - Dose Response Studies
E5 - Ethnic Factors in acceptance of data
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ICH E6 Topics
E6 - Good Clinical Practice
1. Glossary
2. Principles of ICH GCP
3. The IRB / IEC
4. The Investigator
5. The Sponsor
6. The Trial Protocol and Amendments
7. The Investigators Brochure
8. Essential Documents
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ICH E6 Topics
E7 - Special Populations e.g. Geriatrics
E8 - Clinical Trial Design general considerations
E9 - Statistical Principles of Clinical Trials
E10 - Choice of Control group in clinical trials
E11 - Pediatrics
E12 - Therapeutic categories
• E12A is Clinical trials on antihypertensives
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GCP and the Investigator
E6 - Good Clinical Practice
1. Glossary
2. Principles of ICH GCP
3. The IRB / IEC
4. The Investigator
5. The Sponsor
6. The Trial Protocol and Amendments
7. The Investigators Brochure
8. Essential Documents
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Investigator Responsibilities
ICH - E6
4.1 - Investigators Qualifications
4.2 - Adequacy of Resources
4.3 - Medical Care of Study Participants
4.4 - Communication with the IRB / IEC
4.5 - Compliance with the Protocol
4.6 - Investigational Product care
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Investigator Responsibilities
ICH - E6
4.7 - Randomization & unblinding proced.
4.8 - The Informed Consent
4.9 - Records and Reports
4.10 - Progress Reports
4.11 - Safety Reporting
4.12 - Stopping or suspending a study
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Investigator Responsibilities
ICH - E6
4.1 - Investigators Qualifications
– Properly qualified to assume the responsibilities
for conduct of the study.
– Very familiar with the drug under investigation
– Will comply with Regulations and be prepared for
audits and monitoring
– Has available detailed list of all to whom
responsibility is delegated
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Investigator Responsibilities - E6
4.2 - Adequacy of Resources
– Can recruit SP in sufficient numbers & on time
– There is enough time to complete the study
– There are enough qualified staff and adequate
facilities to complete the study
– The staff are well informed about the Test Agent
and the Protocol
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Investigator Responsibilities - E6
4.3 - Medical Care of Study Participants
– All medical decisions are made by qualified physicians
– All medical acts are performed by qualified physicians
– The Investigator is responsible for care of SP when
there are “Adverse Events”*
– The primary physician of the SP is notified regarding
the participation of their patient on the (or a) study
– The Study Physician knows when and why a Study
Participant leaves a study - accounting for all SP
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Adverse Events are:
 Signs which are asymptomatic findings as: changes
in BP, temperature, rashes, etc.
 Symptoms represent a change in function such as
unsteady gait, lightheadedness, nausea, HA
 Lab result of concern i.e. well beyond the reference
range for the protocol or judgment
 Inter- current Illness occurring while on study even
if (the usual case) unrelated to the test medication
 Study conditions causing or contributing to an
abnormality i.e. shivering, hematoma, fainting...
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Investigator Responsibilities - E6
4.4 - Communication with the IRB / IEC
– Written approval is obtained before the Study begins
– Informed Consent is in the language of the SP
– The IRB has a current Investigators Brochure
– The IRB has all documents when needed
– The IRB is immediately informed of SAE (deaths etc)
– Protocol amendments are submitted on time
– The IRB / IEC gets an annual report of each study
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Investigator Responsibilities - E6
4.5 - Compliance with the Protocol
– Has signed Protocol confirming agreement to comply
with it to the letter
– Has not deviated from the Protocol without written
agreement from the sponsor and the IRB / IEC
– Has documented each and every deviation (for subject
safety reasons) from the protocol when it occurs
– Implements deviations to avoid risk but immediately
submits amendments to IRB, Sponsor and the FDA
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Investigator Responsibilities - E6
4.6 - Investigational Product care
– Accepts responsibility for the product, its usage,
and its storage according to the Protocol
– Only a Pharmacist involved under PI’s supervision
– Explains to SP, and uses test agent, properly only
– Detailed records of test agents use kept throughout
the study
– Retained unused test agent and destroy only under
the written instruction from the sponsor
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Investigator Responsibilities - E6
4.7 - Randomization and unblinding procedure
– The study randomization procedures (documented
in the protocol) are followed exactly
– The randomization code is only broken in
accordance with the protocol
– If the study was blinded, any unblinding was
documented and sponsor notified in writing
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Investigator Responsibilities - E6
4.8 - The Informed Consent
– Insure that the declaration of Helsinki and the
principles of GCP are adhered to
– Insure that there is no coercion, of subjects to be
on, or stay on, a study at any time
– Insure SP understanding* of the information they
are presented by you or your designees
– Insure that the Informed Consent is signed and
dated by the SP or SP’s legal representative
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Informed Consent “Process”
 Assure the sponsor that the IRB is functioning in
compliance with 21 CFR 56
 Seek consent only under circumstances that provide
sufficient opportunity to consider whether or not to
participate - 21 CFR 50.20
 The process must minimize the possibility of coercion
or undue influence
 Provide the ICF in a language understandable to the
subject – 6th grade reading level recommended
 Insure that the ICF contains no exculpatory language
 Confirm that the ICF contains all of the required
elements – 21 CFR 50.25
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Essential Elements of an ICF
CFR 50.25 - Essential elements of an “informed consent”
That the study is research
The risks and discomforts are described
The benefits for subject and others
Disclosure of alternative therapies or procedures
Statement regarding confidentiality of the records
Explanation of what will happen on the study
Who to contact for questions and their rights
That participation is completely voluntary
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Essential Elements of an ICF
CFR 50.25 - Additional (read: also essential) elements of
an “informed consent” are statements which state:
Statement regarding risks to the SP, an embryo, or fetus;
The circumstances regarding termination of the subjects
participation without their consent;
Any additional costs to the subject resulting from participation
in the research study;
The consequences of withdrawal and tests that would need to
be completed;
Statement regarding disclosure of new information as it
becomes available;
The approximate number of subjects involved in the study
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Investigator Responsibilities - E6
4.9 - Records and Reports
– Data is ALCOA (accurate, legible, contemporaneous,
original and attributable) and complete
– Data on the CRF’s is consistent with (exactly the
same as) that of the source documents (raw data)
– All changes to a CRF are dated and signed such that
the original data is not obscured
– Essential documents are retained at least 2 years
after the last approval of the test agent for market
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It’s the Data, s…..
 How and where the data is recorded is the Key
 Good, auditable data is “ALCOA”
 Accurate
 Legible
 Contemporaneous
 Original
 Attributable
If it is not documented, it does not exist
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Source Documents
Source documents are original documents
and records for each study subject. Be
clear - this is any and all original documents
Their purpose is to verify the existence of
the subject and verify the integrity of
collected data.
Source Documents
Examples:
 All Study related Medical Hx and Px forms
 Demography sheets
 Dosing documentation sheets
 Blood draw recording sheets
 Vital sign recording sheets
 Subject diaries
 Notes to file
 Laboratory records
 Phone records (even yellow sticky’s)
 Study related data even on scrap paper
Source Documents
Other Administrative points:
Never erase or overwrite – use single horizontal
line to strike through unwanted words etc.
No blank spaces on any page
All loose pages are identified clearly
All entries are legible and self explanatory
Corrections are clearly and consistently made
Subject / patient identifiers are consistent
All loose pages are identified clearly
All entries are initialed and dated when done
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The Handling of data is Important
Corrections:
documentation CPierce 25 Jun04
Clear documantation is …
Date Format goal is to be unambiguous:
Day = 2 digits
Month = 3 letters
Year = 2 digits
i.e. 25/Jun/04 or 25-Jun-04
08/Sep/03 or 08-Sep-03
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Investigator Responsibilities - E6
4.10 - Progress Reports
– A written report is submitted to the IRB /IEC at least
annually is required but….
• Low Risk – yearly is OK
• Moderate Risk – twice a year
• High Risk – monthly to quarterly as needed
– A written report is submitted to the IRB / IEC if the
PI notes any change that might significantly change
the conduct of the trial
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Investigator Responsibilities - E6
4.11 - Safety Reporting
– All SAE’s are immediately reported to the sponsor
and followed up by a written report forthwith
– Study Participants are not to be identified to
anyone
– All AE’s critical to the safety evaluation are reported
to the sponsor per protocol
– The sponsor and the IRB are given all details in the
event of a death of a SP while on study
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Monitoring Data Safety
 Subject Safety under the microscope
 Data & Safety Monitoring Plans (DMP, DSMP)
 Data & Safety Monitoring Committee (DMC, DSMB)
- Separate and independent
- No conflict of interest (scientific, financial, etc)
 When to discontinue a study – one of the main
functions of a DSMB is to establish “stopping rules”:

Clear evidence of harm or harmful AE’s
 No likelihood of demonstrating benefit
 Overwhelming evidence of benefit
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Aims of a DSMP
 To ensure the safety of all participating
subjects to the greatest extent possible
 On-going oversight and monitoring of the
conduct of a study
 To ensure the validity and integrity of the data
 To periodically decide whether of not the study
should continue or be stopped
 To specify the responsibilities and charter of
the DSMB if one is required
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Adverse Events (AE’s)
AE’s are one of the key ways the Clinical Investigator
has of monitoring the safety of subjects or patients
in her/his charge.
Determining the relationship between the study drug
and an AE requires not only the physicians power of
observation but great care.
The algorithm: 1 - Likely / almost certainly
2 - Probably
3 - Possibly
4 - Unlikely / remotely possible
5 - Unrelated
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Investigator Responsibilities - E6
4.12 - Premature stopping or suspending a study
– All SP are informed if a study is terminated or even
suspended
– The institution, the sponsor, and the IRB are
informed in writing if the PI terminates the study
– The institution and the IRB are informed in writing if
the sponsor terminates the study
– The institution and the sponsor are informed in
writing if the IRB terminates the study
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Investigator Responsibilities - E6
4.13 - Final Report(s) by Investigator
– The Principal Investigator is expected to file a
written report at the conclusion of a study
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Final Report
Upon completion of the study, the investigator
must notify the IRB and the sponsor.
The final report should contain the
introduction, description of the methods,
results, and discussion of the findings.
Of greatest importance to the Investigator is
the section dealing with the effect of the test
article on the Study Participants as reflected
in the AE / test article relationship
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What the FDA is Finding
 Protocol is not followed - I/E criteria, tests & timing,
route of admin., timing of events
 Informed Consent inadequacies - Timing, elements
missing, risks listed, copies
 Test article accountability problems - Dispensing,
inventory & receipt records
 Reporting deficiencies - AE’s, final reports, Yearly IRB
reporting
 IRB approvals missing - Timing, amendments, ICFs,
Advertising
 Records in disarray - Corrections, storage requirements,
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equipment maintenance
An Answer
 Investigator Certification
 AAPP - Certified Physician Investigator (CPI)
 ACRP - Certified Clin. Res. Investigator (CCRI)
 SoCRA - Certified Clin. Res. Professional (CCRP)
 DIA - Certified Clinical Investigator (CCI)
 Study Personnel Certification
 ACRP - CCRA (’95), CCRC (’92)
 SoCRA - CCRP (’91)
 IRB Certification

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Summary
The overall role of the clinical investigation
team is to protect the rights and safety of
volunteers and patients enrolled in
studies.
Moreover, the clinical investigation team is
charged with ensuring that the data
obtained from trial subjects is accurate
and valid.
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Clinical Investigator
Responsibilities
In the end…
…a physician doing clinical research is still a
physician with all that that entails. She/he
takes great care in all aspects of the care of
those with whom she/he is responsible. This
care includes accurate record keeping,
patient safety and clear documentation of
ones thought process
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Addendum
The Drug / Adverse Event
relationship algorithm
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AE / Study Drug
Relationship Algorithm
1 - Likely / almost certainly
2 - Probably
3 - Possibly
4 - Unlikely / remotely possible
5 - Unrelated
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1 - Likely / almost certainly
a causal relationship exists when the event:
- is a well known effect of the drug (PDR, IB)
- follows a clear temporal sequence from the
drugs administration
- ceases with discontinuation of the test agent
(and reoccurs on restarting)
- is not related to study / environment
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2 - Probably
A causal relationship exists when the event:
- is a known or suspected effect of the drug
- follows a reasonable temporal sequence from
the test med’s administration
- ceases or diminishes with discontinuation of
the study medication
- cannot be readily explained by Study
participant or study factors
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3 - Possibly
A causal relationship exists when the event:
- is a known, or possible, effect of the drug
- follows a fair temporal sequence from the
drug’s administration; but
- could be explained by subject/patient or
study factors
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4 - Unlikely/remotely possible
That a causal relationship exists when the event:
- is not known, or suspected to be an effect
of the test medication; or
- is a possible or known effect of the drug
but does not follow a reasonable time
sequence from the drug’s administration
- can be readily explained by either Study
Participant or study factors
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5 - Unrelated
as a causal relationship when the event:
- is not known to be an effect of the test
agent; and
- does not follow a temporal sequence from
the drug’s administration; and
- can be readily explained by study
participant and / or study factors
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