Transcript Informed Consent Considerations - Dana

DF/HCC
DANA-FARBER / HARVARD CANCER CENTER
Review, Approval and Oversight of
Cancer Research involving Human
Subjects at the DF/HCC
Office for Human Research Studies (OHRS)
(617) 632-3029

[email protected]
Beth Israel Deaconess Medical Center / Brigham and Women’s Hospital / Children’s Hospital Boston /
Dana-Farber Cancer Institute / Harvard Medical School / Harvard School of Public Health / Massachusetts General Hospital
General Overview
The DF/HCC scientific review
committees and the DFCI IRBs review
all adult and pediatric cancerrelated research on behalf of
BIDMC; BWH; CHB; DFCI and MGH.
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National Cancer Center Grant
DF/HCC Scientific Review Committees-five
committees and an ongoing expedited
review process that fall under the protocol
review and monitoring system process for
oncology research set out in the NCI Cancer
Center Support Grant.
The Cancer Center Grant requires that we
keep the scientific review and IRB review
functions separate and distinct.
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National Cancer Institute
Cancer Center Support Guidelines require:
1. Scientific review for merit, feasibility,
prioritization and accrual
2. No guidelines for determining which post
approval events such as amendments;
deviations; violations; or adverse events
require re-review by a scientific review
committee.
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Scientific Review vs. IRB Review
There are differences between scientific
review and IRB review, e.g.,
-conditional approvals
-annual progress review
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Institutional Review Boards
DFCI IRBs operate under a Federal Wide
Assurance that we have with the U.S.
Department of Health and Human Services.
DFCI IRBs operate under Federal regulations
that specifically dictate the operations and
substantive review of the IRBs.
DFCI IRBs, on behalf of the DF/HCC,
currently have oversight of over 1750 open
research protocols involving human subjects.
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DFCI IRBs
Information Relating to the Operation
of IRBs
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DFCI IRBs
IRBs A and B:
 meet on an alternating basis every
Tuesday from 12-2 pm.
 expertise to review any matter, but focus
on new protocols and amendments.
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DFCI IRBs
IRBs C and F:
 meet on an alternating basis every
Thursday morning from 8-10 am.
 expertise to review any matter but focus
on continuing reviews; amendments;
adverse events; and other events.
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DFCI IRBs
IRB D:
 meets twice monthly on Mondays from 10-12 pm
 was known as the “social and behavioral IRB” or
the “minimal risk IRB”, in fact…
 reviews any research that is not technically
clinical intervention research as well as research
that is greater than minimal risk.
• additional bone marrow aspirates;
• additional blood draws;
• tissue repository research etc.
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DFCI IRBs
IRB E:
 “rapid response IRB”
 small number of members and can
respond quickly to an emergent situation.
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DFCI IRBs
IRB G:
 Pediatric Panel
 Meets 1st and 3rd Monday of each month
 Expertise to review any pediatric matter
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Institutions in the News
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JHU-FDA Warning Letter to PI
March 31, 2003
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“Our records indicate that you are aware of your
sponsor obligations…we note that on September 15,
1997, you submitted an IND application to the
FDA…(FDA) notified you in writing on October 24,
1997, that you were prohibited from initiating any of
the submitted protocols due to significant safety
concerns and other protocol deficiencies… including
inadequate chemistry, purity, and pre-clinical data;
inadequate and confusing study procedures and
protocols, lack of inclusion criteria, discontinuation
criteria, and defined safety parameters; and lack of
methodology for adverse event monitoring,
treatment, and follow-up of subjects.”
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Government Shutdowns
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Massachusetts Eye and Ear Infirmary
UCLA
VA Health Sys. Greater Los Angeles
Rush Presbyterian St Luke’s Med Ctr.
University of Illinois Chicago
Duke University Med Ctr.
Univ. Texas Medical Branch Galveston
University of Oklahoma Tulsa
Johns Hopkins University
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Most Common FDA Findings
• Failure to obtain informed consent of
subjects prior to administration of
study drug (21 CFR 312.60; 21 CFR
50.20)
• Failure to provide informed consent
information in language understood by
the subject (21 CFR 50.20)
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Most Common FDA Findings
• Failure to obtain informed consent of
subjects involved in research in
accordance with 21 CFR 50
• Legally effective informed consent not
obtained from subject or
representative (21 CFR 812.100,
50.20, 50.27)
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Columbia University-FDA
warning letter
February 21,2014
Investigator Warning Letter Ralf
Zimmerman
1. Enrolled 28 of 50 subjects prior to obtaining
consent
2. Provided 10 subjects with investigational agent
prior to obtaining consent
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Still happens…
Weill Medical College, May 2004
OHRP Findings:
OHRP’s review of IRB documents reveals evidence that the IRB
does not always make the required findings when reviewing
research involving children, and when the findings are made,
they are sometimes inappropriate (e.g. for protocol #0204165, which involved a dose-finding, safety study of a drug in
pediatric hypertensive patients, the IRB found that the
protocol was approvable under HHS regulations at 45CFR
46.404). Based on OHRP’s discussions with the IRB
chairperson and IRB members, OHRP is concerned that the
IRB lacks a detailed understanding of HHS regulations at 45
CFR part 46, subpart D, which require specific IRB
determinations related to the risks and potential benefits when
children are involved as subjects of research.
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Weill Medical College, May 2004
OHRP Findings:
(a) For protocol #0296-223, subjects were enrolled outside the protocol age range
prior to IRB review and approval of the amended protocol.
(b) Protocol #0800-354 stated that subjects would be randomized between
metformin and placebo. During our interview, the investigator stated that, among
other things, the protocol was changed to a single arm study without prior IRB
review and approval.
(c) For protocol #0801-842, between August 12, 2002 and July 22, 2003, the
protocol was changed from a double-blind study to a single blind study. OHRP
could find no evidence of IRB review and approval of this protocol modification.
Further, the continuing review form reviewed by the IRB on July 22, 2003 stated
“no changes since last continuing review.”
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Weill Medical College, May 2004
OHRP Action
 In view of the above determinations and
in order to ensure adequate protections
for human subjects, OHRP hereby restricts
the WMC assurance (FWA 93), pending
satisfactory completion of the required
corrective actions described below.
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Emory
Emory halts enrollment in cancer clinical trials
Action at Winship Cancer Institute follows critical audit of procedures
By Craig Schneider
The Atlanta Journal-Constitution
Tuesday, June 16, 2009
Emory University’s Winship Cancer Institute has stopped accepting new patients
into clinical trials after a critical audit, even as it seeks to enhance its standing
in the fight against cancer.
The center voluntarily halted accepting new patients May 15 following a critical
audit of record-keeping for research purposes. The audit was performed by
the Eastern Cooperative Oncology Group, a cancer research group that works
with Winship.
The audit found deficiencies in the research files regarding patients,
including missing test results and CAT scans, unreported vital signs
such as blood pressure and heart rate, and unreported logs on how
often a patient took his or her drugs.
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OHRP Compliance Findings: Repeated
Deficiencies in Human Subjects Research
Unapproved Research
Unapproved Protocol Changes
Unreported Adverse Events
Unreported Unanticipated Problems
Conflicts of Interest
Misleading or Deficient Informed Consent
Inadequate Initial and Continuing IRB Review
Avoidable Injuries & Deaths
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Historical Overview
The development of protections for
human subjects in research.
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Historical Overview:
International
Nazi Doctor Trials
 Nuremberg Code – 1947
 Informed Consent
Declaration of Helsinki
 World Medical Association, Ethical Principles for
Medical Research Involving Human Subjects
 1964 (revised 2000)
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Historical Overview
Public Health Service (PHS) Policy
 Prior Review of Research by “Institutional
Associates” (PPO 129, February 8, 1966)
United States Public Health Service
 Syphilis Study at Tuskegee (1932 -1972)
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Historical Overview:
United States -- 1974
Congressional Hearings
 Senator Walter Mondale
 Senator Edward Kennedy
HHS Regulations
National Research Act
 National Commission for the Protection of
Human Subjects of Biomedical and
Behavioral Research, July 12, 1974
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Historical Overview:
The Belmont Report – April 18, 1979
Ethical Principles and Guidelines for the Protection of
Human Subjects of Research
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Respect for
Persons
Informed Consent
Capacity to Consent
Beneficence
Do no harm
Maximize Benefit
Justice
Equitable Selection of Subjects
Equitable Burdens and Benefits
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Federal Oversight of Human
Subject Research
Federal Policy for the Protection of Human
Subjects (Common Rule)
 Adopted 1991
HHS Regulations
 Revised 1981, 1991
FDA Regulations
 Revised 1981, 1991
No Mandatory Protections if not covered by
above
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DHHS Federalwide Assurance (FWA)
FWA requires compliance with 45 CFR 46
for Federally Funded/Supported
Research
All FDA regulated research must comply
with applicable FDA regulations even in
the absence of Federal Funding or
Support
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Federal Policy (Common Rule) for
the Protection of Human Subjects
18 Federal Agencies Adopted DHHS Subpart A
Some Agencies Required Additional Protections
 VA requires compensation for research-related injuries
 DoD additional level of review (e.g., HSRRB) for certain
types of research
Some Agencies Never Adopted the Federal Policy
 Department of Labor – Miners and Coal Dust
 Appalachian Regional Commission – Telemedicine
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DHHS Regulations:
45 CFR Part 46
Subpart A  Core Protections  Common Rule
 IRB Review
 Informed Consent
Subpart B  Additional Protections
 Pregnant Women, Fetuses, and Neonates
Subpart C  Additional Protections
 Prisoners
Subpart D  Additional Protections
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 Children
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Subpart A: Core Human Subject Protections
Federal Policy (Common Rule), DHHS, FDA
IRB Review
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(DHHS 45 CFR Part 46 and FDA 21 CFR Part 56)
Initial Review
Prospective Review of All Changes
Reporting/Review of Unanticipated Problems
Reporting/Review of Adverse Events
Continuing Review at Least Annually
Informed Consent
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(DHHS 45 CFR Part 46 and FDA 21 CFR Part
Eight Required Elements
Written Documentation
Language Understandable to Subjects
No Coercion or Undue Influence
No Waiver of Subjects Rights
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Roles and Responsibilities:
Institutional Responsibility
Institutional Commitment and Infrastructure
Authorized Institutional Official
IRB Chair, IRB Members, IRB Staff
Data Safety Monitoring Committees/Boards
(DSMBs)
Other Institutional Committees (Audit)
Research Investigators and Co-Investigators
Everyone Else Involved in the Research
Enterprise (sponsors)
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Roles and Responsibilities:
Institutional Review Board (IRB)
Review and Approve Proposed Research
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Risks Minimized through Sound Research Design
Risks Reasonable Relative to Benefits
Subject Selection Equitable
Informed Consent Obtained
Informed Consent Documented
Privacy and Confidentiality Protections Adequate
Safety Monitoring is Adequate
Protections for Vulnerable Subjects are Adequate
Exercise Continuing Oversight of Research
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Roles and Responsibilities:
Institutional Review Board (IRB)
IRBs are also required to review HHS grants to
ensure that the protocol submitted to the IRB is
consistent with the grant application
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Risks Minimized Through Sound
Research Design
Family of Subject who died in Gene Therapy Trial
sponsored by Targeted Genetics is suing the
company, the IRB and the principal investigator.
The basis of the lawsuit is not so much objections to
the informed consent document as the contention
that “someone with a mild case of rheumatoid
arthritis should not be enrolled in a gene therapy
trial.”
The science of the protocol could not justify
enrollment of this type of subject in the research.
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Roles and Responsibilities:
Principal Investigators
Accept responsibility for all aspects of the research
Ensure adequate training for entire research team
Ensure adequate supervision of entire research
team
Know and ensure compliance with
 All regulatory requirements
 All IRB requirements
 All protocol requirements
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Ensure adherence to enrollment criteria
Monitor and report unanticipated problems and
adverse events to sponsor and IRB
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Roles and Responsibilities:
Principal Investigators
University of Pittsburgh, FDA warning letter,
September 15, 2009-John M Kirkwood
1.
2.
3.
4.
failed to conduct procedures required by protocol
changed protocol without going through the IRB and FDA
failed to follow-up and collect adverse event information
failed to report serious adverse events experienced by three
subjects
5. failed to prepare and maintain case histories
6. failed to monitor the progress of the clinical investigation
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Applying the Regulations
to Research Involving
Human Subjects
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Definition of Research:
HHS, Federal Policy (Common Rule)
“Research” means:
 A systematic investigation
 Designed to develop or contribute to
 Generalizable knowledge
 Includes:
•
•
•
•
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Research development
Testing
Evaluation
Pilot Studies
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Definition of Research
“Research” means:
 A systematic investigation designed to develop or
contribute to generalizable knowledge
• What does “Systematic” mean?
– Carried out according to a plan
– Permitting logical conclusions to be drawn
• What does “Generalizable” mean?
– Beyond the immediate situation
– Beyond the institution
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Manhattan Eye, Ear and Throat
Hospital Incident
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Definition of Human Subject:
“Human Subject” means:
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a living individual
about whom an investigator…conducting
research obtains:
1) data through intervention or interaction with
the individual, or
2) identifiable private information
-- 45 CFR 46.102(f)
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VCU Twin Study
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Definition of Human Subject:
“Private Information” means:
 Information about behavior in a context in which
an individual can reasonably expect that no
observation or recording is taking place
 Information, provided for specific purposes, that
the individual can reasonably expect will not be
made public (e.g., a medical record)
-- 45 CFR 46.102(f)
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IRB Requirements and
Procedures
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Institutional Review Board (IRB):
Mission, Duties, Authorities
Mission  To protect the rights and welfare of individuals
participating in research involving human subjects
Duties  To approve, disapprove, modify, suspend research
as necessary to ensure protections for human subjects in
research
Authority  To exercise final authority within the institution
for ensuring adequate protections for subjects. Officials of the
institution may not approve research if it has not been
approved by an IRB.
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Institutional Authority Beyond Regulations  Delegated
to IRB
 Ethical Issues on behalf of institution
 Sanctioning Investigators for noncompliance
 Use of “tainted” data
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IRB Review and Approval
Routine oversight mechanisms:
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Initial Review
Continuing Review
Review of Adverse Events
Review of Unanticipated Problems
Special oversight mechanisms
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Data & Safety Monitoring Boards (DSMBs)
Consent Monitors
Random Audits of Research
Continuing Education
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IRB Approval (Initial or Continuing)
Includes Findings That …
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Risks are minimized through sound research
design
Risks are reasonable relative to anticipated
benefits
Selection of subjects is equitable
Informed consent will be obtained
Informed consent will be documented
Privacy and Confidentiality provisions are adequate
Data safety monitoring is adequate
Appropriate safeguards are included for vulnerable
subjects
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Types of IRB Review
Determination whether activity is Human
Subject Research
Verification of Exemption
Expedited Review
Convened (Full Board) Review
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NOTE: Initial and Continuing Review require votes
of the convened IRB, meeting all quorum
requirements, unless specific conditions for use of
expedited review are satisfied
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Institutional Review Board (IRB):
Composition
Minimum of 5 members
Diverse in gender and racial background
Sufficiently qualified in experience and expertise
 (e.g., pediatric expertise required to review research
involving children)
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One scientific member
Non-scientific member
One member not otherwise affiliated with the
institution
Expertise in vulnerable populations for regular
review of such research
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Convened (Full Board) Review
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Majority of Total Membership Must Be Present
Non-Scientist Member Must Be Present (not lay
member)
Approval Requires a Majority of Those Members
Present
Vote Must Be Documented
Same Requirements for Initial and Continuing
Review
Important that documentation demonstrate that the
IRB is making the appropriate regulatory
determinations
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IRB Meetings and Record
Keeping
All members receive complete set of materials
Adequate time to review materials
Minutes of meetings must be comprehensive
Attendance and votes should be recorded
OHRP permits teleconferencing if each
participating member (i) has received all
pertinent material prior to the meeting; and (ii)
can actively and equally participate in the
discussion of all protocols
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Types of IRB determinations
Approval
Conditional Approval
Deferral
Disapproval
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Conditional Approval
From OHRP Common Findings
Contingent Approval of Research with
Substantive Changes and no Additional
Review by the Convened IRB.
 OHRP finds that the IRB frequently
approves research contingent upon
substantive modifications or clarifications
without requiring additional review by the
convened IRB.
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Expedited Review:
Minor Changes to Approved Research
MINOR changes in previously approved
research
During the established approval period
Conducted by Chair or IRB member
designated by Chair
Must be reported to full IRB
No disapprovals, e.g., a decision to
disapprove a requested deviation must be
sent to the full board.
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-- 45 CFR 46.11059
Expedited Review
Minimal Risk Research in the Following
Categories:
1) Clinical studies of drugs and medical devices
where an IND (drugs) or IDE (devices) is not
required.
2) Collection of blood samples by finger stick, heel
stick, ear stick, or venipuncture:
a) from healthy, non-pregnant adults weighing at least
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100 lbs: 550 ml in 8-wk period, limited to 2
collections per week;
b) from other adults and children, not more than 50 ml
or 3 ml per kg in 8-wk period, limited to 2 collections
per week.
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Expedited Review
Minimal Risk Research in the Following
Categories:
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3) Prospective collection of biological specimens by
noninvasive means
4) Collection of data through noninvasive procedures
(not involving general anesthesia or sedation)
employed in clinical practice, excluding procedures
involving x-rays or microwaves. Where medical
devices are employed, they must be cleared/
approved for marketing. (Studies intended to
evaluate the safety and effectiveness of the
medical device are no generally eligible for
expedited review, including studies of cleared
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medical devices for new indications.)
Expedited Review
Minimal Risk Research in the Following
Categories:
5) Research involving materials (data,
documents, records, or specimens) that:
• have been collected
• will be collected for non-research purposes
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6) Collection of data from voice, video,
digital, or image recordings made for
research purposes.
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Expedited Review
Minimal Risk Research in the Following
Categories:
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7) Research on individual or group behavior
or characteristics -- cognition, motivation,
identity, language, communication,
cultural beliefs/practices, social behavior;
survey, interview, oral history, focus
group, program evaluation, human factor,
quality assurance methodologies.
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Expedited Review
Minimal Risk Research in the Following
Categories:
8) Continuing review of research previously
approved by the convened IRB where
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a) the research is permanently closed to new
enrollments, all subjects have completed all researchrelated interventions, and research remains active only
for long-term follow-up of subjects; or
b) no subjects have been enrolled and no additional risks
have been identified; or
c) remaining research activities are limited to data
analysis.
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Expedited Review
Minimal Risk Research in the Following
Categories:
9) Continuing review of research… where… the IRB
has determined and documented at a
convened meeting that the research involves
no greater than minimal risk, and no additional
risks have been identified.
Critical Catchall Provision
– Note documentation requirement
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Expedited Review:
Compliance Problems
Inappropriate use of expedited review
 greater than minimal risk
 no appropriate category
 failure to document category and determination
Greater than minor changes to approved
research
Inappropriate use for Continuing Review
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Exempt Research
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Six Exemptions:
45 CFR 46.101(b)
1) Research conducted in:
 Established or commonly accepted
educational settings
 Involving normal educational practices
• Instructional strategy comparisons
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Six Exemptions:
45 CFR 46.101(b)
2) Research involving the use of:
 Educational tests (cognitive, diagnostic, aptitude,
achievement), survey procedures, interview
procedures, or observation of public behavior
UNLESS
• information is recorded in an (directly or indirectly)
identifiable manner (NOTE: Coded = identifiable)
AND
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• disclosure would place subject at risk of criminal or civil
liability or be damaging to financial standing,
employability, or reputation
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Six Exemptions:
45 CFR 46.101(b)
Special Consideration involving Children
 Survey and Interview Research Involving
Children IS NOT Exempt
 Passive Observation of Public Behavior Involving
Children IS Exempt
 Participant Observation of Public Behavior
Involving Children IS NOT Exempt
IRB Needs Copy of All Surveys and Interview
Scripts (unless standard test known to IRB)
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Six Exemptions:
45 CFR 46.101(b)
3) Research involving the use of:
 Educational tests (cognitive, diagnostic,
aptitude, achievement), survey procedures,
interview procedures, or observation of public
behavior
WHERE
• subjects are elected or appointed public
officials or candidates for public office
or
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• Federal statutes require confidentiality without
exception
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Six Exemptions:
45 CFR 46.101(b)
4) Research involving the collection or study
of:
 existing data, documents, records, specimens,
if:
• the sources are publicly available
or
• the information is recorded by the investigator in such
a manner that subjects cannot be identified, directly or
through identifiers linked to the subjects.
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NOTE: Even brief recording of identifiers or codes
disqualifies the exemption
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Definition of “Existing”
“Existing” means:
 All data has been collected (i.e., on the
shelf) prior to the research
 For a purpose other than the proposed
research
 Includes data (or specimens) collected in
research and non research activities.
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Six Exemptions:
45 CFR 46.101(b)
5) Research and demonstration programs
designed to study, evaluate, or examine
(Federal) Public Benefit or Service Programs
6) Taste and food quality evaluation and
consumer acceptance studies involving:
 wholesome foods without additives
 additives, chemical, contaminants below safe
levels determined by FDA, EPA, USDA
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Informed Consent
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Eight Required Elements:
45 CFR 46.116(a)
1.
2.
3.
4.
5.
6.
7.
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8.
Statement that study is research and information on
purposes/duration/procedures/experimental procedures
Reasonably foreseeable risks or discomforts
Reasonably expected benefits
Alternative procedures (including availability offprotocol where applicable)
How confidentiality will be maintained
Information on compensation for injuries (unless
minimal risk)
Contact Persons for info on research, injury, subjects’
rights
Voluntary participation, no penalty or loss of benefits
for refusal or withdrawal
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Six Additional Elements
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Statement that there may be risks which are
unforeseeable
Under what circumstances investigator could
terminate subject’s participation
Additional costs to subject
Consequences of subjects withdrawal from
research
Statement that will be told of new findings
Approximate number of subjects in study
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The Support Trial
Conducting research on the current
standard of care
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Informed Consent:
Special Issues
There is no such thing as “passive consent”
 consent is required unless formally waived
 documentation is required unless formally waived
There is no such thing as a “secondary
subject”
 if an investigator obtains “identifiable private
information” about a living individual, the
individual is a human subject, regardless of the
source
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Waiver of Informed Consent
(Not Permitted Under FDA Regulations)
IRB must find and document that 4 criteria
met:
1. Minimal risk research
2. Waiver or alteration will not adversely affect the
rights and welfare of the subjects
3. Research could not practicably be carried out
without the waiver or alteration
4. Subjects will be provided with additional
pertinent information
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Documentation of Informed Consent
Written consent document
 In language understandable to the subject
or the subject’s Legally Authorized
Representative (LAR)
• Verification of translated consent document
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 Signed by subject or subject’s LAR
 Copy SHALL be given to subject
 Opportunity to read before signing
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Documentation of Informed
Consent
Short form written consent document
requires :
1. oral presentation
2. witness to oral presentation
3. an IRB approved written summary
•
•
•
given to subject
signed by witness
signed by person obtaining consent
4. short form documenting oral presentation
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•
•
signed by subject or LAR
signed by witness
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Waiver of Documentation of Informed
Consent (Not Permitted by FDA Regs)
The Signed Consent Document provides the
only link to the subject’s identity and
principal risk is breach of confidentiality
The research presents no greater than
minimal risk of harm to subjects and
involves no procedures requiring consent in
a non-research context
IRB may require a subject information sheet
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After IRB Approval
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Adverse Events v. UPIRSO
FDA Regulatory
Terms
Adverse Events
Unanticipated
Problems Involving
Risks to Subjects
and Others
Reportable events
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HHS Regulatory
Language
Unanticipated
Problems Involving
Risks to Subjects
and Others
Reportable Events
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Risks to Subjects
Adverse events vs. unanticipated problems
 A risk or problem is unanticipated if it is not in the protocol
or consent document.
 Risks discussed in the protocol should be included in the
consent document
Questions raised as a result of an unanticipated risk:
 Does the informed consent form need to be amended?
 Do previously enrolled subjects need to be re-consented?
 Does a report need to be made to any government office?
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Protocol Deviations
Very detailed
protocol
Missing a dose
Intervention on the
wrong day
All become protocol
deviations
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Human
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Studies
Write protocols
more broadly
Range for dosing
Ranging for timing
Less likely that
differences in
regimen will
become a protocol
deviation
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Protocol Deviations
University of Oklahoma – July 2000
suspension of research
Testing of a vaccine on subjects with
melanoma
Three year trial
Numerous violations of study protocol
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Human
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Studies
 shipping vaccine to subjects for self-injection
 inadequate staffing
 inadequate supervision of sponsor’s
manufacturing facilities
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Protocol Deviations
Univ. of Oklahoma
June 29, 2000 letter from OHRP to Univ. OK
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Studies
 “OHRP finds that the principal investigator
implemented substantive changes to the research
project without IRB approval. The changes made
without IRB approval included, but are not
limited to the following:
 (a) The investigator deviated from the IRBapproved inclusion and exclusion criteria. In
specific, 11 of the first 18 subjects enrolled in the
protocol did not satisfy all IRB-approved
inclusion/exclusion criteria. Of note, the IRB
Chair unilaterally approved these deviations
retroactively…”
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Protocol Deviations
Univ. of Oklahoma (cont.)
 (b) Sample size was increased above the total
subject number approved by the IRB (15 for
phase I and 25 for phase II); by November 17,
1999, total subject enrollment had increased to
more than 90.
 (c) The study vaccine was shipped to some
subjects’ homes for self-administration by the
subjects. Of note, the IRB-approved protocol
prior to November 19, 1999 stated the following:
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• the Nurse Coordinator will give all injections. She will
record any transient erythematous reactions and refer
patients with any other side effects… to Dr. McGee…
Patients will be required to remain in the physician’s
office for 30 minutes afterward.”
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Protocol Deviations
Univ. of Oklahoma (cont.)
 (d) Some subjects were allowed to self-monitor
for adverse local reactions following vaccine
administration.
 (e) The investigator added several remote study
sites and co-investigators.
 (f) Non-physicians were used to perform some
protocol-stipulated physical exams that were to
have been performed by a physician under the
IRB-approved protocol.”
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FDA Issues
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FDA Regulations
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Informed Consent - 21 CFR Part 50
IRB Review - 21 CFR Part 56
Investigational Drugs - 21 CFR Part 312
 Marketing Approval - 21 CFR Part 314
Biologics - 21 CFR Part 600
 Biologics Licensing – 21 CFR Part 601
Investigational Devices - 21 CFR Part 812
 Pre-Market Approval – 21 CFR Part 814
Financial Disclosure – 21 CFR Part 54
Electronic Records – 21 CFR Part 11
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FDA Regulations
Informed Consent -- 21 CFR 50
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Eight Required Elements
Written Documentation
Language Understandable to Subjects
No Coercion or Undue Influence
No Waiver of Subjects Rights
IRB Review -- 21 CFR 56
 Initial Review
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
Prospective Review of All Changes
Reporting/Review of Unanticipated Problems
Reporting/Review of Adverse Events
Continuing Review at Least Annually
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FDA Regulations
Drugs and Biologics
 Investigational New Drug Application
(IND)
 21 CFR Part 312
Devices
 Investigational Device Exemption (IDE)
 21 CFR Part 812
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FDA Regulations:
When is an IND Needed?
Any use in which a marketed or un-marketed drug is
administered or dispensed to, or used involving, one
or more human subjects, except for:
 Use of a marketed drug in course of medical practice, or
 Investigation of a marketed drug where there is:
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• No intent to support a new indication for use or other
significant change in labeling;
• No intent to support a significant change in advertising;
• No factor such as route of administration, dosage, or patient
population that increases or decreases the acceptability of
risks associated with the product;
• Compliance with FDA Informed Consent and IRB Review
requirements; and
• No promotion or representation of the drug as safe or
effective for the purpose under investigation.
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FDA Regulations:
Responsibilities of Sponsors
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Maintaining the IND
Obtaining Qualified Investigators and
Monitors
Providing Necessary Information/Training for
Investigators
Monitoring the Investigation
Controlling the Investigational Agent
Reporting Significant Adverse Events to
FDA/Investigators
Maintaining and Retaining Accurate Records 97
FDA Regulations:
Responsibilities of Investigators
Specific Responsibilities:
 Ensuring Conduct of the Research per the
Investigator Agreement, Investigational Plan, and
All Applicable Regulations
 Protecting the Rights, Safety, and Welfare of the
Research Subjects
 Controlling access to and use of the test article
(drug / biologic / device)
 Monitoring and Reporting Adverse Events
 Maintaining and Retaining Accurate Records
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FDA Reporting Requirements:
IND - Adverse Event Reporting
Investigator must report promptly (immediately if
alarming) to the Sponsor any adverse effect that
may reasonably be regarded as caused by the drug
(21 CFR 312.64)
Sponsor must notify FDA of any adverse experience
associated with the drug that is both serious and
unexpected
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 Serious Adverse Drug Experience = death, life-threatening,
hospitalization, persistent /significant disability / incapacity,
congenital anomaly / birth defect (21 CFR 312.32)
 Unexpected Drug Experience = any adverse drug
experience, the specificity or severity of which is not
consistent with the current investigator brochure or IND
application (21 CFR 312.32)
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FDA Reporting Requirements:
IDE - Adverse Event Reporting
Investigator must report any unanticipated adverse device
effect to Sponsor and the IRB as soon as possible and within
10 working days [21 CFR 812.150]
Sponsor must report any unanticipated adverse device effect
to FDA, all reviewing IRBs, and investigators
[21 CFR 812.150]
Unanticipated Adverse Device Effect = any serious adverse
effect on health or safety, or any life-threatening problem or
death, caused by or associated with a device if not previously
identified in nature, severity, or degree of incidence in the
investigational plan or application
[21 CFR 812.3]
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FDA Regulation Exceptions & Exemptions:
Emergency Use of a Test Article
Without Informed Consent – 21 CFR
50.23(a)
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Studies
 Life Threatening Situation Necessitating the Use
 Inability to Communicate with Subject for Legal
Consent
 Insufficient Time to Obtain Consent from Legally
Authorized Representative (LAR)
 No Alternative Therapy Available
 Certification in Writing from Investigator and an
other Nonparticipating Physician of the Above
 Report to IRB Within 5 Working Days
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FDA Regulation Exceptions & Exemptions:
Emergency Use of a Test Article (cont.)
No IRB Review – 21 CFR 56.104 (c)
 Life Threatening Situation Necessitating
the Use
 No Alternative Available
 Insufficient time for IRB review
 Report to IRB Within 5 Working Days
 Subsequent Use Requires IRB Review
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FDA Regulations: Single Patient IND
Commonly referred to as
compassionate use
Requires Informed Consent and IRB
review 21 CFR 312.34
See OHRS website for guidance
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Studies
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FDA Device Regulations:
“Compassionate Use”
Compassionate Use of an Unapproved Device may
be approved by FDA when it is the only option for a
patient with a serious condition
Requires as many of the following as possible:
 Informed Consent
 Institutional Approval
 Concurrence of IRB Chair (but NOT IRB
APPROVAL)
 Independent Assessment of Uninvolved Physician
 Authorization of the Sponsor
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FDA Regulations: Devices
SR Devices vs. NSR Devices
IRB Must Make a Specific Determination
 Significant Risk Device = Investigational device that
presents a potential for serious risk to the health, safety, or
welfare of subjects, including implants
 Non-Significant Risk Device = Investigational devices
that does NOT present the potential for serious risk to the
health, safety, or welfare of subjects
• Non-Significant Risk is NOT the same as Minimal Risk
 Once IRB-approves the research as not involving a
Significant Risk Device, the research is considered to have
an approved IDE, unless the FDA has notified the sponsor
otherwise.
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FDA Regulations:
“Off-Label Use”
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FDA-approved products (i.e., marketed
products) may be used by physicians outside
of labeled indications FOR THE PRACTICE OF
MEDICINE
Such use in RESEARCH (i.e., as part of a
systematic investigation designed to develop
or contribute to generalizable knowledge)
requires IRB REVIEW
Such use intended to support a CHANGE in
labeling requires IRB REVIEW and an IND /
IDE
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FDA Regulations:
Humanitarian Device Exemption (HDE)
Humanitarian Use Device (HUD)
 Device tested but not profitable for
marketing
Requires:
 IRB Review (Limited) and Approval
 No Research Informed Consent
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Studies
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FDA Regulations:
Planned “Emergency” Research
Ordinarily Requires IRB Review and
Informed Consent of Subject or Subject’s
Legally Authorized Representative (as
determined by State Law for Research
Contexts)
Exception from Informed Consent
Requirement Involves Many Specific IRB
Determinations and Approval by FDA or
OHRP
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Studies
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Protections for Vulnerable
Subjects
Under Sections 46.111
Vulnerable to Coercion or Undue Influence
 eg: Handicapped, Disabled, Economically or
Socially Disadvantaged Persons
HHS Subpart B
 Pregnant Women, Human Fetuses, and Neonates
HHS Subpart C
 Prisoners
HHS Subpart D
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 Children
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HHS Subpart B: Research Involving
Pregnant Women, Human Fetuses,
and Neonates
Subpart B -- Revised December 2001
 Research involving pregnant women
 Research involving fetuses
 Research involving neonates of uncertain
viability, nonviable neonates, or viable
neonates
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Studies
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HHS Subpart B: 45 CFR 46.204
Research Involving Pregnant Women or Fetuses
Any research that TARGETS pregnant
women or fetuses requires a special and
specific regulatory review.
Any such research should be submitted
directly to senior staff at OPRS since the IRB
will need special training for the review and
approval of this type of research.
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Studies
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HHS Subpart C: 45 CFR 46.303(c)
Research Involving Prisoners
Definition of a Prisoner
 Any individual involuntarily confined or
detained in a penal institution under a
criminal or civil statute
 Individuals detained in other facilities as
an alternative to criminal prosecution or
incarceration in a penal institution
 Individuals detained pending
arraignment, trial, or sentencing
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Studies
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HHS Subpart C:
Research Involving Prisoners
Subpart C
 Prisoner representative on OHRP
approved roster
 Additional duties under 46.305
 Finding of permissible category under
46.306
 Certification to OHRP
 Concurrence from OHRP
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Studies
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Lawsuit Involving Prisoners
DOJ funded research in Pennsylvania prison:

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mandatory drug testing (urine vs. hair)
no consent
solitary confinement for refusal to be tested
facts of case not contested
Acres of Skin
 Dow, U Pennsylvania, City of Philadelphia
 Prisoners told experiments were harmless
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Research involving Children
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Definition of Minimal Risk
Definition impacts:
 Pediatric Studies
 Important for determining whether a
research protocol or change in research
can be expedited or must go to the full
board.
 Waiver of Consent
 Document of Consent
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Definition of Minimal Risk:
FDA, HHS, Federal Policy
“Minimal Risk” means:
 The probability and magnitude of
harm or discomfort
 Are not greater than those ordinarily
encountered in daily life;
or
 During the performance of routine
physical or psychological
examinations or tests.
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Studies
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HHS Subpart D & FDA Subpart D:
Research Involving Children
Category Determinations Required
• Specific Approval Criteria for Each Category
• Protocol-Specific Justification Required
 Not greater than minimal risk
 Greater than minimal risk
• Prospect of direct benefit
 Greater than minimal risk
• No prospect of direct benefit
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 Research not otherwise approvable
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Subpart D: 45 CFR 46.404 & 21 CFR 50.51
Research involving no greater than
minimal risk
Children may be involved in research
where the IRB finds that:
 The research presents no greater than
minimal risk to the child
 Adequate provision are made for
obtaining
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• The assent of the child
• The permission of the child’s parents or
guardians
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NICHD Trial
In the minutes of the NICHD IRB, they
noted that for one protocol, there was
more risk to children in crossing the
street than in spending two days in the
hospital hooked up to an IV line….
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Studies
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Subpart D: 45 CFR 46.405 & 21 CFR 50.52
Greater than minimal risk but presenting
prospect of direct benefit to individual subjects
Children may be involved in research where the
IRB finds that more than minimal risk to children
is presented by (i) an intervention or procedure
that holds out the prospect of direct benefit for
the individual subject, or (ii) a monitoring
procedure that is likely to contribute to the
subject’s well-being if:
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a) The risk is justified by anticipated benefit to subjects;
b) The relation of anticipated benefit to risk is at least as
favorable as available alternatives;
c) Assent of child and permission of parents are sought.
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Subpart D: 45 CFR 46.406 & 21 CFR 50.53:
Research involving greater than minimal risk
and no prospect of direct benefit to individual
subjects
Children may be involved in research
presenting more than minimal risk without
the prospect of direct benefit or increased
well being for the subject if:
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Human
Research
Studies
 Risk is a minor increase over minimal risk
 Research presents situations reasonably equal to
to those inherent in their actual situations
 Research is likely to yield generalizable
knowledge about disorder or condition
 Adequate provisions for obtaining child assent
and parental permission.
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Fenfluramine Study
Office for
Human
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Studies
New York State Psychiatric Institute
Mount Sinai School of Medicine
Queens College
The study focused on 34 boys between the
ages of 6 and 10 who had brothers with
violent tendencies as reflected in court
cases.
The boys were given fenfluramine.
Did children with siblings who were juvenile
delinquents have a greater propensity
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towards juvenile delinquency.
Fenfluramine Study
Since the study did not provide any
benefit, was it likely to yield
generalizable knowledge about an
underlying condition or disorder?
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Subpart D: 45 CFR 46.407 & 21 CFR 50.54:
Research not otherwise approvable but presenting
opportunity to understand, prevent, or alleviate a
serious problem affecting health or welfare of children
IRB finds the research presents opportunity
as above
HHS Secretary, after consultation with panel
of experts & public review and comment,
determines:
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Human
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Studies
 The research presents reasonable opportunity as
above
 The research will be conducted in accordance
with sound ethical principles
 Adequate provisions are made for obtaining child
assent and parental permission
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Subpart D: Research Involving Children
Parental Permission Required
Permission of Both Parents Required If
Greater than Minimal Risk, unless:
 One parent not reasonably available
 One parent has sole custody
Standard HHS Waiver Not Contained in FDA
Regulations
HHS Waiver in Interest of Child Not
Contained in FDA Regulations
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Studies
45 CFR 46.408
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Subpart D: Research Involving Children
— Assent of Child Required
Developmentally Appropriate as
Determined by IRB
Documentation as Determined by IRB
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Human
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 Unless the Research Holds the Prospect of
Direct Benefit Available Only in the
Research
Or
 Unless Waived by IRB per criteria at 45
CFR 46.116(d)
45 CFR 46.408
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What happens if a child reaches
the legal age of consent?
Subject is a child enrolled in research
Subject reaches the age of majority
IRB can:
 waive informed consent if can meet 4
regulatory requirements
 otherwise, investigators have to reconsent the individuals
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Conflicts of Interest
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Human
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Studies
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Types of Conflict of Interest
Individual
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Clinical investigators
Study coordinators
Research technicians
Research officials
IRB members
Institutional
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Human
Research
Studies
 Financial holdings of the
institution
 Decisions regarding
research funding or
allocation of resources
for research
Financial
Consulting fees
Stock ownership
Honoraria
Salary
Intellectual property
rights
 Enrollment bonuses
 Spouse / dependent
finances
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Professional
 Pressure to publish
 Professional rivalries
 Career advancement
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DF/HCC Additional Oversight
MCC
DSMC
DSMB
Audit Committee
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Questions?
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