pwc b carleton college october 10, 2002 tom puglisi, phd protecting human subjects -- what everyone...
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Carleton College
October 10, 2002
Tom Puglisi, PhD
Protecting Human Subjects --
What Everyone Needs to Know
The Protection of Human Subjects in Research
Medical Research Summit
Michele Russell-Einhorn, JD
Tom Puglisi, PhD
May 5, 2003
©2002 PricewaterhouseCoopers. PricewaterhouseCoopers refers to the individual member firms of the world-wide PricewaterhouseCoopers organisation. All rights reserved.
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Government Shutdowns
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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Research Involving Human Subjects
Human Research Halted at Major Institutions– Deficient Informed Consent– Inadequate Initial and Continuing IRB Review– Multiple Areas of Concern
Death in Gene Transfer Research– Conflicts of Interest– Unreported Deaths and Injuries
Media Attention – Congressional Hearings – Distrust
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Research Involving Human Subjects
“What’s at Stake is the Integrity of Research
and
Public Confidence in Research”
-- HHS Secretary, Donna Shalala, May 2000
Historical Overview
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Historical Overview
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
Dr. Henry Beecher’s Review of Medical Literature
Radiation Experiments
Cancer Cell Injections
“Tea Room Trade” Study
Kansas City “Jury Deliberations” Research
Social Psychology Research – Conformity / Authority
Historical Overview
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Historical Overview
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
Historical Overview -- 1974
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Historical OverviewHistorical Overview:The Belmont Report – April 18, 1979
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
Respect for PersonsInformed Consent
Capacity to Consent
BeneficenceDo no Harm
Maximize Benefit
JusticeEquitable Selection of Subjects
Equitable Burdens and Benefits
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Roles and Responsibilities
Institutions
Institutional Review Boards (IRBs)
Research Investigators
Sponsors
Data Safety Monitoring Boards (DSMBs)
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Roles and Responsibilities:Institutional Responsibility
Institutional Commitment and Infrastructure
Authorized Institutional Official
IRB Chair, IRB Members, IRB Staff
Other Institutional Committees
Research Investigators and Co-Investigators
Study Coordinators and Research Staff
Everyone Else Involved in the Research Enterprise
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Roles and Responsibilities:Authorized Institutional Official
Legal Signatory for Institution (e.g., Assurance)
Overall Organizational Responsibility
Ensure Adequate placement of IRB within Institutional Structure
Ensure Adequate resources for IRB (staff, computers, office space, etc.)
Inspire and Enforce Institutional Culture of Respect and Compliance (e.g., Oversight and Monitoring of Research)
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Roles and Responsibilities:Institutional Review Board (IRB)
Review and Approve Proposed Research– Risks Minimized through Sound Research Design– Risks Reasonable Relative to Benefits– Subject Selection Equitable– Informed Consent Obtained and 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:Principal Investigators
General Responsibilities of Principal Investigators:
Accept and exercise 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, IRB requirements, and protocol requirements
Ensure adherence to enrollment criteria Monitor and report unanticipated problems and
adverse events to sponsor and IRB
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Federal Oversight of Human Subject Research
HHS Regulations – Revised 1981
FDA Regulations– Revised 1981
Federal Policy for the Protection of Human Subjects (Common Rule)– Adopted 1991
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DHHS Regulations: 45 CFR Part 46
Subpart A – Basic Protections (“Common Rule”)– IRB Review– Informed Consent– Institutional “Federalwide Assurance” (FWA)
Subpart B - Protections for Pregnant Women, Fetuses, and Neonates
Subpart C - Protections for Prisoners
Subpart D - Protections for Children
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Federal Policy (Common Rule)for the Protection of Human Subjects
17 Federal Agencies Adopted HHS Subpart A
Some Agencies Required Additional Protections– VA requires compensation for research – related
injuries
Some Agencies Never Adopted the Federal Policy– Department of Labor - Miners and Coal Dust– Appalachian Regional Commission – Telemedicine– Department of Transportation - Sleepy Truck Drivers
No Federal Regulation for Research Not Covered Under The Common Rule or FDA Regulations
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DHHS Federalwide Assurance (FWA)
For Federally-Supported Research– Common Rule Protections of HHS Subpart A– IRB Review & Informed Consent
For HHS-Supported Research– Protections of HHS Subparts A,B,C,D
MPA-FWA Institutions– Voluntary application of all HHS Subparts to all
research, regardless of funding source
Applying the Regulations toResearch Involving Human
Subjects
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Definition of Research:45 CFR 46.102(d)
Research means:– a systematic investigation– designed to develop or contribute to generalizable
knowledge
Research includes:– research development, testing, evaluation,
i.e., pilot studies
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Definition of Human Subject:45 CFR 46.102(f)
“Human Subject” means: – a living individual– about whom an investigator… conducting research
obtains:
1. data through intervention or interaction with the individual, or
2. identifiable private information
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Definition of Human Subject:45 CFR 46.102(f)
“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)
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Definition of Minimal Risk:45 CFR 46.102(i)
“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.
IRB Requirementsand Procedures
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Institutional Review Board (IRB)
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 Review Board (IRB): Composition
Minimum of 5 members
Diverse in gender and racial background
Sufficiently qualified in experience and expertise
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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IRB Approval Includes Findings That . . .
Review, Approve (§46.111), Exercise Continuing Oversight: 1. Risks are minimized through sound research design2. Risks are reasonable relative to anticipated benefits3. Selection of subjects is equitable 4. Informed consent will be obtained 5. Informed consent will be documented6. Privacy and Confidentiality provisions are adequate7. Data safety monitoring is adequate8. Appropriate safeguards are included for vulnerable
subjects
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IRB Oversight Includes...
Continued ethical evaluation of the research
Monitoring of the research
Monitoring of the informed consent process
Analysis (as received) of new information, adverse events, and unanticipated problems involving risks to subjects and others
Formal Continuing Review at intervals appropriate to the degree of risk and no less than annually
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Oversight Issues for IRBs
Special oversight mechanisms:– Data & Safety Monitoring
Boards (DSMBs)– Consent Monitors– Random Audits of Research– Continuing Education
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Types of IRB Review
• Verification of Exemption
• Expedited Review
• Convened (Full) Review
• Continuing Review
NOTE: Initial and Continuing Review Require Vote of the Convened IRB, Meeting All Quorum Requirements, Unless Specific Conditions for Use of Expedited Review are Satisfied
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Convened (Full Board) Review
• Majority of Total Membership Must Be Present
• Non-Scientist Member Must Be Present
• Approval Requires a Majority of Those Members Present
• Vote Must Be Documented
• Same Requirements for Initial and Continuing Review
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Expedited Review:Initial or Continuing Review
Conducted by Chair or IRB member designated by Chair
Only minimal risk research
Must fit into a category on November 1998 list
All other provisions and requirements apply
Can only approve research -- Cannot disapprove
Must be reported to full 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 designed by Chair
Must be reported to full IRB
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Expedited Review 45 CFR 46.110
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 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 45 CFR 46.110
Minimal Risk Research in the Following Categories:
(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 medical devices for new indications.)
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Expedited Review 45 CFR 46.110
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
(6) Collection of data from voice, video, digital, or image recordings made for research purposes.
(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 45 CFR 46.110
Minimal Risk Research in the Following Categories:
(8) Continuing review of research previously approved by the convened IRB where (a) the research is permanently closed to new enrollments, all subjects have completed all research-related 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 45 CFR 46.110
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.
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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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Continuing Review 45 CFR 46.109(e)
Required to occur within one year (no grace period)
IRB must review all relevant materials
Continuing review is opportunity to see what has happened once the research started. (NOTE: At initial review the research had not yet begun)
More than status reports should be reviewed -- review must be substantive and meaningful
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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 recent approval of 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
Exempt Research
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Six Exemptions:45 CFR 45.101(b)
(1) Research conducted in:– established or commonly accepted educational
settings– involving normal educational practices
e.g. instructional strategieseffectiveness comparisons
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Six Exemptions:45 CFR 45.101(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
– 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 45.101(b)
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
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Six Exemptions:45 CFR 45.101(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 officeor
– Federal statutes require confidentiality without exception
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Six Exemptions:45 CFR 45.101(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.
NOTE: Even brief recording of identifiers or codesdisqualifies the exemption
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Six Exemptions:45 CFR 45.101(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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Verification of Exemptions
Exemptions must be verified by a trained and qualified institutional official
Exemptions may not be determined by the investigator
Informed Consent
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Informed Consent
Legally effective informed consent– Legally Authorized Representative (LAR) under State law
No coercion or undue influence (recruitment)
Obtained by Investigator/Staff trained and authorized by IRB
Language understandable to the subject
No exculpatory language
Eight required elements
Six additional elements
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Eight Required Elements
(1)Statement that study is research and information on purposes/duration/procedures/experimental procedures
(2)Reasonably foreseeable risks or discomforts
(3)Benefits which may be reasonably expected
(4)Alternative procedures
(5)How confidentiality will be maintained
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Eight Required Elements (cont.)
(6)For more than minimal risk, information on compensation for injuries
(7)Contact names -- at least one not associated with the research recommended
(8)Statement that participation is voluntary and the subject can withdraw at any time without penalty or loss of benefits to which the subject is otherwise entitled
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Six Additional Elements
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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Informed Consent Generally
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
Deception Research– Requires a formal waiver of consent
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Risks to Subjects
A risk or problem is unanticipated if it is not in the protocol or consent document.
Risks discussed in the protocol should usually 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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Waiver of Informed Consent(Not Permitted Under FDA Regulations)
IRB must find and document that 4 criteria met:1. Minimal risk research2. Waiver or alteration will not adversely affect the
rights and welfare of the subjects3. Research could not practicably be carried out
without the waiver or alteration4. 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 LAR
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 – 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 the 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
Advanced IRB Issues
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FDA Regulations
Informed Consent - 21 CFR 50
IRB Review - 21 CFR 56
Investigational Drugs - 21 CFR 312– Marketing Approval - 21 CFR 314
Biologics - 21 CFR 600– Biologics Licensing – 21 CFR 601
Investigational Devices - 21 CFR 812– PreMarket Approval – 21 CFR 814
Financial Disclosure – 21 CFR 54
Electronic Records – 21 CFR 11
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FDA Regulations
Informed Consent -- 21 CFR 50– 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– 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:Responsibilities of Sponsors
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 and to Investigators
Maintaining and Retaining Accurate Records
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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:Investigational New Drug Application (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– 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:Investigational Device Exemption (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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Requirements for Reporting to the IRB
Required by HHS Human Subject Regs. [45 CFR 46.103(b)(5)] and FDA IRB Regs [21 CFR 56.108(b), 312.66]
– Unanticipated problems involving risks to subjects or others
– Serious or continuing noncompliance with Regs. or IRB
Adverse Events (required by FDA for devices only)– Local IRB Policy Determines Requirements
1) Any serious adverse events experienced by subjects
2) Any adverse events reported to the study sponsor
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FDA Regulation Exceptions and Exemptions:Emergency Use of a Test Article
Without Informed Consent – 21 CFR 50.23(a)– 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
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 Regulation Brain Teasers: 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 Regulation Brain Teasers: “Off-Label Use”
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 Brain Teasers: “Standard of Care” Comparisons
Systematic comparison of FDA-approved products (i.e., marketed products) used for approved indications constitutes RESEARCH and requires IRB REVIEW
Systematic comparison of competing STANDARDS OF CARE constitutes RESEARCH and requires IRB REVIEW
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FDA Regulation Brain Teasers: “Compassionate Use”
Does not Appear in IND Regulations or Guidance
Often Confused With:– Emergency Use of a Test Article (without IRB Review
and/or without Informed Consent)– Treatment Use of Investigational Drugs (with or
without a Treatment IND) Requires IRB Review and Informed Consent
– Use of Orphan Drugs (disease affects < 200,000 Americans) Requires IRB Review & Informed Consent
– Parallel Track Use Requires IRB Review & Informed Consent
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FDA Regulation Brain Teasers: “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 Regulation Brain Teasers: 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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FDA Regulation Brain Teasers: 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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Vulnerable Research Subjects
Pregnant Women, Human Fetuses, and Neonates
Prisoners
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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HHS Subpart B: 45 CFR 46.204Research Involving Pregnant Women or Fetuses
Pregnant women or fetuses may be involved in research if all of the following conditions are met:
a) Where appropriate, preclinical studies on pregnant animals and clinical studies on nonpregnant women have provided data to assess potential risks
b) Risk to the fetus is caused solely by procedures holding out the prospect of direct benefit for the woman or the fetus or the risk to the fetus is no greater than minimal and the purpose is to develop important biomedical knowledge that cannot be obtained by other means
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HHS Subpart B: 45 CFR 46.204Research Involving Pregnant Women or Fetuses
c) The risk is the least possible for achieving the objectives of the research
d) If the research holds out the prospect of direct benefit to the pregnant woman or to both the pregnant woman and fetus or the research holds out no prospect of direct benefit but present no more than minimal risk to the fetus as in (b) above, the informed consent of the pregnant woman is obtained
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HHS Subpart B: 45 CFR 46.204Research Involving Pregnant Women or Fetuses
e) If the research hold out the prospect of direct benefit solely for the fetus, the informed consent of the pregnant woman and the father is obtained, except the father’s consent need not be obtained if he us unable to consent because of unavailability, incompetence, or temporary incapacity, or if the pregnancy resulted from rape or incest
f) Consenting individuals are fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate
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HHS Subpart B: 45 CFR 46.204Research Involving Pregnant Women or Fetuses
g) For children who are pregnant, assent of the pregnant child and permission of the child’s parents are obtain in accordance with Subpart D
h) No inducements, monetary or otherwise, are offered to terminate a pregnancy
i) Individual engaged in the research have no part in any decisions as to the timing, method, or procedures to terminate a pregnancy
j) Individual engaged in the research have no part in determining viability of a neonate
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HHS Subpart B: 45 CFR 46.205(a)Research Involving Neonates of Uncertain Viability and Nonviable Neonates
Neonates of uncertain viability and nonviable neonates may be involved in research if all of the following conditions have been met:
1) Where scientifically appropriate, preclinical and clinical studies have provided data for assessing potential risk to neonates
2) Each individual providing consent is fully informed regarding reasonably foreseeable impact of the research on the neonate
3) Individuals engaged in the research have not part in determining viability of the neonate
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HHS Subpart B: 45 CFR 46.205(b)Research Involving Neonates of Uncertain Viability
Until viability is ascertained, neonates of uncertain viability man not be involved in research unless the additional conditions are met:
1.The IRB determines that (i) the research holds out the prospect of enhancing the survival of the neonate to viability and any risk is the least possible for achieving that objective or (ii) the purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate from the research
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HHS Subpart B: 45 CFR 46.205(b)Research Involving Neonates of Uncertain Viability
2) The legally effective informed consent of either parent of the neonate If neither parent is able to consent because of
unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent’s legally authorized representative is obtained
Consent of the father or the father’s legally authorized need not be obtained if the pregnancy resulted from rape or incest
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HHS Subpart B: 45 CFR 46.205(c)Research Involving Nonviable Neonates
After delivery, nonviable neonates may not be involved in research unless all of the following conditions are met:
1) Vital function of the neonate will not be artificially maintained
2) The research will not terminate heartbeat or respiration of the neonate
3) There will be no added risk to the neonate from the research
4) The purpose of the research is to develop important biomedical knowledge that cannot be obtained by other means
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HHS Subpart B: 45 CFR 46.205(c)Research Involving Nonviable Neonates
5. The legally effective informed consent of both parents is obtained.
The waiver provisions of Subpart A do not apply. If either parent is unable to consent because of
unavailability, incompetence, or temporary incapacity, the informed consent of one parent will suffice
The consent of the father need not be obtained if the pregnancy resulted from rape or incest
The consent of a legally authorized representative of either or both parents of a nonviable neonate will not suffice
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HHS Subpart B: 45 CFR 46.205(d)Research Involving Viable Neonates
After delivery, a neonate that has been determined to be viable is a child and may only be included in research to the extent permitted by Subpart D.
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HHS Subpart C: 45 CFR 46.303(c)Research Involving Prisoners
Definition of 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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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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Additional IRB DutiesHHS Subpart C: 45 CFR 46.305
Research is permissible within a 46.306 category
Advantages of participating are not coercive given the limited choice prison environment
Risks commensurate with those accepted by nonprisoner volunteers
Selection procedures are fair
Language is understandable to the subject population
Participation has no affect on parole, and prisoners are so informed
Adequate provisions will be made if there may be a need for follow-up care, and given varying lengths of sentences, and prisoners are so informed
If HHS-supported, institution (IRB) certifies to OHRP that it has carried out its duties under these sections
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Categories of Permissible Research HHS Subpart C: 45 CFR 46.306(b)
(i)
The study of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects.
(ii)
The study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects.
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Categories of Permissible Research HHS Subpart C: 45 CFR 46.306(b)
(iii)
Research on conditions particularly affecting prisoners as a class - ONLY AFTER DHHS CONSULTATION WITH EXPERTS AND PUBLICATION OF A NOTICE TO APPROVE IN THE FEDERAL REGISTER.
(iv)
Research on practices, both innovative and accepted, which have the intent and reasonable probability of involving the health or well-being of the subject. IF CONTROL GROUP WITH NO BENEFIT, CONSULTATION WITH EXPERTS AND FEDERAL REGISTER IS NOTICE REQUIRED.
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Lawsuit Involving Prisoners
DOJ funded research in Pennsylvania prison:– 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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HHS Subpart D & FDA Subpart D:Research Involving Children
Subpart D
IRB Category Determinations Required– Specific Approval Criteria for Each Category– Protocol-Specific Justification Required
Not greater than minimal risk research
Greater than minimal risk -- prospect of direct benefit
Greater than minimal risk -- no prospect of direct benefit
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 The assent of the child The permission of the child’s parents
or guardians
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Subpart D: 45 CFR 46.405 & 21 CFR 50.52:Greater than minimal risk but presenting the prospect of direct benefit to the 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:
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, but likely to yield generalizable knowledge about the subject’s disorder or condition.
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
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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Subpart D: 45 CFR 46.407 & 21 CFR 50.54:Research not otherwise approvable but presenting an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children
IRB finds the research presents opportunity as above
HHS Secretary / FDA Commissioner, after consultation with panel of experts and following public review and comment, determines 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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Research involving ChildrenSubpart D: Parental Permission Required
45 CFR 46.408 & 21 CFR 50.55
• Both Parents’ Permission Required If Greater than Minimal Risk
• Standard HHS Waiver Not Contained in FDA Regulations
• HHS Waiver in Interest of Child Not Contained in FDA Regulations
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Research involving ChildrenSubpart D: Assent of Child Required
45 CFR 46.408 & 21 CFR 50.55
• Developmentally Appropriate as Determined by the IRB
• Documentation as Determined by the IRB
• Unless the Research Holds the Prospect of Direct Benefit Available Only in the Research or
• Unless Waived by the IRB per criteria at 45 CFR 46.116(d)
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Research involving ChildrenSubpart D: Ward of the State
45 CFR 46.409 & 21 CFR 56
• Where greater than minimal risk and providing no direct benefit to the child, research with wards is permitted only if:
– Related to status as wardsor
– Conducted in settings where majority of children are not wards
• Child advocate required who is not otherwise associated with the research
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Social and Behavioral Research:Recurring Controversy about Regulation
• Applicability to Social and Behavioral Research
• Compatibility with Social and Behavioral Research
• Applicability by Discipline?
• Review of Exempt Research
• Student Research
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Definition of Research:45 CFR 46.102(d)
• Research means:– a systematic investigation– designed to develop or contribute to generalizable
knowledge
• Research includes:– research development, testing, evaluation, – i.e., pilot studies
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Definition of Human Subject:45 CFR 46.102(f)
“Human Subject” means: – a living individual– about whom an investigator… conducting research
obtains:
1. data through intervention or interaction with the individual, or
2. identifiable private information
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Definition of Human Subject:45 CFR 46.102(f)
“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)
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Social and Behavioral Issues –Institutional Evaluations / Quality Assurance
• Is the activity “Research” ?• Research means:
– A Systematic Investigation
– Designed to develop or contribute to generalizable knowledge
• What does “Generalizable” mean :– Beyond the immediate situation
– Beyond the institution
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Social and Behavioral Issues –What if the Purpose / Intent Changes ?
• When did the purpose change ?
– After the investigation was completed
– IRB review of existing data
– Consent / Waiver of Consent
– During the investigation– IRB review for collected data
– IRB review for prospective data
– Consent / Waiver of Consent
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Social and Behavioral Issues –“Secondary subjects”
• “Target” subjects vs “Secondary” subjects
• Who is a subject?
• A subject is a living individual about whom an investigator conducting research obtains:
– Identifiable Private Information
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Definition of Human Subject:45 CFR 46.102(f)
“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)
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Social and Behavioral Issues –Existing Data Sets
• Data sets containing only non-coded, non-identifiable information do not involve human subjects
• Data sets “anonymized” before transfer to the investigator do not involve human subjects
• “Anonymized” means
– No codes or links of any kind, available to anyone, anywhere
– But note possible OHRP exception
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Social and Behavioral Issues –Existing Data Sets
• “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 nonresearch activities.
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Social and Behavioral Issues –Existing Data Sets
• “Publicly available” data sets are exempt• “Publicly available” means:
– Generally available to anyone
– Commercially available
– ?
• Access to data sets with identifiable private information is exempt if:
– Investigator does not record identifiers
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Social and Behavioral Issues –Existing Data Sets
• Other use of data sets containing identifiable private information requires IRB review
• IRB may determine that:
– Additional informed consent is needed
– Original informed consent covers the new research
– Informed consent requirements can be waived under 45 CFR 46.116(d)
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Epidemiology Research
Epidemiology Research– May include medical records– May require linking of records from multiple
data sets– Investigator must have legitimate access
identifiable private information– Waiver of Informed Consent at 45 CFR
46.116(d) may be applicable
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Social and Behavioral Issues –Research Involving Deception
• Requires waiver of informed consent requirement under 45 CFR 46.116(d)
• IRB must find and document that 4 criteria are met:– No greater than minimal risk to subjects– Waiver or alteration will not adversely affect the
rights and welfare of the subjects– Research could not practicably be carried out
without the waiver or alteration– Subjects will be provided with additional
pertinent information
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Social and Behavioral Research:My IRB is Unreasonable ! !
Academic freedom gives me the right to conduct my research
This research is harmless and shouldn’t need IRB review
Requiring informed consent will lower participation rates
Having to sign a consent form will scare subjects away
Individual consent is meaningless among my subjects
College students are adults
“Subject Pool” requirements are an educational prerogative
“Passive Consent” is traditional in my field
Mom, dad, and sibs aren’t subjects my research
My use of these data sets shouldn’t need IRB review
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Dealing with the “Unreasonable” IRB
Regulations Require Professional Competence (§46.107):
– IRBs must have the Scientific and Professional Competence to understand the research they review (including Social and Behavioral research)
– IRBs must understand regulatory options so as to apply them appropriately
Possible Solutions– Increase Academic Diversity of Existing IRB– Create Social and Behavioral Sciences IRB– Educate IRB Members (and investigators)
OHRP Compliance Determinations
Analysis of Common Concerns
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OHRP Compliance Determinations:Letters Issued 10/01/1998 to 06/30/2002
• 269 Letters to 155 Institutions
• 18 Institutions Site-Visited
• 1,120 Citations of Noncompliance or Deficiency
• 142 Institutions (92%) Had at Least One Citation
– Median = 4
– Range: 0 - 53
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OHRP Compliance Findings:Common Areas of Noncompliance
• Initial and continuing IRB review
• Expedited IRB review procedures
• Reporting of unanticipated problems
• IRB review of protocol changes
• Informed consent
• IRB membership, expertise, staff, support, and workload
• Documentation of IRB procedures, activities, and findings
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All Site-Visited Institutions Institutions
Cited Deficiency (N = 155) (N = 18)
Research conducted without IRB review 17% 22% Deficiency in IRB initial review process 55% 94% Deficiency in IRB continuing review process 45% 72% Deficiency in use of expedited IRB review procedure 17% 61% Deficiency in satisfying reporting requirements 17% 39% Deficiency in IRB review of protocol changes 25% 39% Deficiency in application of exempt categories of research 6% 28% Failure to obtain informed consent of subjects 16% 11% Deficiency in documentation of informed consent 8% 6% Deficiency in IRB-approved informed consent docs/process 51% 78% Deficiency in IRB membership 11% 61% IRB members lack sufficient understanding of regulations 7% 44% Indequate IRB meeting space, staff, and resources 8% 50% Overburdened IRB 5% 28% Deficiency in IRB records, including IRB minutes 37% 78% Deficiency in written IRB policies and procedures 55% 72%
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Number of Percent of Category of Deficiency Citations Citations
Deficiency in IRB initial review process 277 25%
Deficiency in IRB-approved informed consent documents/process 304 27%
Deficiency in IRB continuing review process 109 10%
Deficiency in written IRB policies and procedures 88 8%
Deficiency in IRB records, including IRB minutes 70 6%
Deficiency in IRB membership/training/support/workload 49 4%
Deficiency in IRB review of protocol changes 45 4%
Deficiency in use of IRB expedited review procedure 46 4%
Deficiency in satisfying reporting requirements 35 3%
Research conducted without IRB approval 25 2%
Failure to obtain informed consent of subjects 26 2%
Other miscellaneous deficiencies 46 4%
Total 1120 100%
Distribution of Noncompliance Findings (269 Letters)OHRP Compliance Oversight Data - 10/1998 to 6/2002
Table 2: Distribution of OHRP-Cited Deficiencies for All Institutions
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Number of Percent of Category of Deficiency in IRB Initial Review Citations Citations
Deficiency related to criteria required for IRB approval 88 32%
Deficiency related to findings for research involving children 39 14%
Contingent approval with substantive changes/clarifications 33 12%
without further review by convened IRB
Deficiency related to findings for waiver of informed consent requirements 30 11%
IRB review without quorum 25 9%
Failure to review federal grant applications 16 6%
Deficiency related to findings for research involving prisoners 14 5%
Other miscellaneous deficiencies 32 12%
Total 277 100%
Distribution of Noncompliance Findings (269 Letters)OHRP Compliance Oversight Data - 10/1998 to 6/2002
Table 3: Distribution of OHRP-Cited Deficiencies Related to Initial IRB Review
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Number of Percent of Category of Deficiency Related to Informed Consent Citations Citations
Deficiency in description of purpose, procedures, and duration 63 19%
Deficiency in description of risks and discomforts 56 17%
Deficiency in description of benefits 20 6%
Deficiency in description of alternatives 20 6%
Deficiency in description of other elements of informed consent 61 18%
Language too complex 31 9%
Use of exculpatory language 7 2%
Failure to obtain informed consent of subjects 26 8%
Deficiency in documentation of informed consent 12 4%
Other miscellaneous deficiencies 34 10%
Total 330 100%
Distribution of Noncompliance Findings (269 Letters)OHRP Compliance Oversight Data - 10/1998 to 6/2002
Table 4: Distribution of OHRP-Cited Deficiencies Related to Informed Consent
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Managing Complaints and Site Visits
Managing internal complaints– Types of complaints– Managing investigation of complaints– Reporting to regulatory authorities
Managing a government site visit– Corrective action plan– IRB operations assessment
Related Issues
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Health Insurance Portability and Accountability Act (HIPAA)
• HIPAA Passed by Congress and Signed by President in 1996
• Required HHS to Issue a Rule or Congress would legislate.
• History of Privacy Rule:
– December 28, 2000: Final Rule
– March, 2001: Rule Opened for Additional comment
– August 14, 2002 Regulations Amended
• Compliance Deadline: April 14, 2003
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HIPAA Privacy RuleIn General --
HIPAA covers the Use and Disclosure of “Protected Health Information” by “Covered Entities”
• Protected Health Information (PHI) is:– Individually identifiable health information
• A “Covered Entity” is:– Health Care Provider, Plan, or Clearinghouse
• Consent is not required to use or disclose PHI for treatment, payment, or health care operations
• Other use or disclosure of PHI, including Research, generally requires “Authorization”
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HIPAA Privacy RuleIn General --
Use or Disclosure of “Protected Health Information”for research purposes requires either:
• A written Authorization from the subjector
• Verification that the research involves:=> De-Identified Information=> Limited Data Sets=> Reviews Preparatory to Research=> Decedents’ Informationor
• A Waiver approved by the Privacy Board / IRB
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HIPAA Privacy RuleIn General --
• The Privacy Rule permits Use and Disclosure of Protected Health Information as required under applicable statute or regulation
• The Privacy Rule provides individuals with:=> The right to Access Protected Health Information about themselves=> The right to obtain an Accounting of Disclosures of their Protected Health Information
• Does not supercede more stringent State requirements
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Authorization
Generally, uses and disclosures of protected health information in research must be conducted pursuant to a valid Authorization….
• 6 Core elements
• 3 Required statements
• 2 Additional requirements
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Authorization = Most Advantageous Route to Research
• No Representations (Assurances) Required
• No Privacy Board Review Required
• No Accounting of Disclosures Required
• No “Minimum Necessary” Limitations
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Conflict of Interest in Research: Current Requirements and Recent Guidance
Conflict of Interest:
• Any situation in which financial, professional, or personal obligations
• May compromise or appear to compromise
• Professional judgment in designing, conducting, analyzing, reporting, or supporting research.
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Types of Conflict of Interest
• Financial
– Consulting fees
– Stock ownership
– Honoraria
– Salary
– Intellectual property rights
– Enrollment bonuses
– Spouse / dependent finances
• Professional
– Pressure to publish
– Professional rivalries
– Career advancement
• Individual– Clinical investigators– Study coordinators– Research technicians– Research officials– IRB members
• Institutional– Financial holdings of the
institution– Decisions regarding
research funding or allocation of resources for research
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What Prompted the Recent Focus on Financial COIs in Research?
• Researchers and Institution held equity interest in research technology significantly above FDA requirements
• Two prominent research institutions involved–Gene-transfer research–Cancer research
center
• Results– NIH Conference to examine
the issue of financial COIs– Development of recent
guidance, including draft interim recommendations from DHHS
– Authorship and sponsorship of research (statement by the International Council of Medical Journal Editors)
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Current Regulations
• IRB Regulations– 45 CFR 46.107(e)– 21 CFR 56.107(e)
• If an institution has an IRB, conducts research involving FDA-regulated test articles, and receives PHS funding, all three sets of regulations must be followed.
• FDA– 21 CFR Part 54– Investigator Disclosure to
Sponsors
• Public Health Service (PHS)– 42 CFR Part 50, Subpart F– Responsibilities for
institutions receiving research funds from PHS Agencies (NIH, etc.)
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FDA Regulations
• Require:– Disclosure of potentially conflicting financial interests of investigator
(including spouse and dependent children)
• When to disclose?– Compensation depends on the outcome of the clinical study – Investigator has significant equity interest in the sponsor (in excess
of $50,000 during study and for 1 year after completion)– When investigator has a proprietary interest in the test product
(including patent, trademark, copyright, or licensing agreement) – When investigator has received significant payments of other sorts
(defined as a value of more than $25,000, exclusive of the costs of conducting the study, during the study and for 1 year after completion)
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PHS Regulations:Investigator Requirements
• Disclosure of “significant financial interests” • Anything of monetary value • Salary and other payments for services• Equity interests• Intellectual property interests
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PHS Regulations:Investigator Need Not Disclose
• Salary, royalties, or other remuneration from the institution
• Income from seminars, lectures, or teaching engagements sponsored by public or non-profit entities
• Equity interests (including spouse and dependent children) which do not exceed $10,000 and does not represent more than 5% ownership in any single entity
• Salary, royalties, and other payments, which when aggregated for the investigator, spouse, and dependent children, are not expected to exceed $10,000 over the next 12 months
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PHS Regulations:Institutional Requirements
• Develop policies and procedures per PHS regulations
• Inform investigators of their responsibilities
• Designate an institutional official(s) to solicit and review financial disclosure statements
• Issue guidelines to identify, manage, reduce, or eliminate conflicts
• Allocate space for maintaining records for 3 years
• Establish enforcement mechanisms/sanction
• Certify in each PHS funding application that a written and enforced administrative process for financial COIs exists
• Assure PHS that any financial COIs will be managed, reduced, or eliminated before funds spent (or at least on an interim basis, for 60 days after initial report)
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IRB Requirements:45 CFR 46.107(e) & 21 CFR 56.107(e):
• “No IRB member may participate in initial or continuing review of research in which they have a conflicting interest except to provide information requested by the IRB”
• Includes professional, personal, and financial conflicts.
• IRB members must recuse themselves
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IRB “Best Practice” Standards
• IRB policies defines what might constitute a conflicting interest or has procedures for determining conflicting interest
• Conflicted IRB member absents self from meeting during IRB deliberation and vote
• IRB minutes document recusal and absence from deliberation and vote
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Reporting of Conflicts of Interest to Regulatory Bodies
• FDA (=Investigator)– Investigator conducting
research on FDA-regulated test article discloses to research sponsor
– Disclosure applies to investigator, spouse, and dependent children
– If potential conflict, report steps taken to minimize bias using Form FDA 3455
– No financial interests, use Form FDA 3454
• PHS (=Institution)– Investigator supported by funds
from any PHS Agency discloses significant financial interest to the institution
–Disclosure applies to investigator, spouse, and dependent children
– Institution must certify to PHS Agency that significant financial interests have been eliminated, reduced, or managed
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Recent Guidance
• Department of Health and Human Services (DHHS)– Draft Interim Guidance
(January 10, 2001)
• American Association of Medical Colleges (AAMC)– Task Force on Financial
Conflicts of Interest in Clinical Research (December 2001)
• General Accounting Office– Report GAO-02-89,
November 2001)
• Association of American Universities– Task Force on Research
Accountability: Individual and Institutional Financial Conflict of Interest (October 2001)
• American Medical Association– Council on Ethical and Judicial
Affairs Report 3-I-00, Managing Conflicts of Interest in the Conduct of Clinical Trials (December 2000)
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Management Decisions for Conflicts of Interest Policy Development
• Who’s covered by the Policy?– Institutions may wish to cover
other individuals involved in research, research decisions, research oversight, and the institution’s financial holdings.
• Disclosure thresholds– FDA and PHS policies have
different disclosure thresholds.– For consistency and simplicity,
institutions may chose to adopt a single disclosure threshold.
• Examples of management plans:– Public disclosure of financial
interests– Divestiture of the interest– Monitoring of the research by
independent reviewers– Modification of research plan– Disclosure in informed consent
documents, manuscripts, oral presentations based on the research
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Conflict of Interest Recommendations Distilled from Recent Guidance
• Conflict of interest committee– More representation from lay
public
• Administrative positioning of the IRB high within the organization.– IRB should not be the sole locus
of responsibility for conflicts of interest
• Design educational programs for all research staff, IRB, institutional officials with research and finance decision-making responsibilities
• Make policies, procedures, and documents available on-line
• Expand scope to include all research, regardless of funding for the sake of fairness and consistency
• Establish “firewall” between offices responsible for financial and research decisions
• “Rebuttable presumption” and “compelling circumstances” as conflict standards
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Billing Compliance
Institutional Responsibility
Patient Care vs. Research
National Coverage Decision
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