Ethical and Regulatory Oversight of Human Subjects Research

1
Ethical and Regulatory Oversight of Human
Subjects Research

• Presented by
• Marisue Cody, PhD
• Deputy Director, PRIDE

2
Objectives

• Describe the ethical underpinnings of human
  subjects protection
• Describe the oversight structure of human
  subjects research in the VA
• Describe the responsibilities of the institution
• Describe the responsibilities of the investigator

3
Timeline of historical events
4
Nazi experiments

• Used unconsenting concentration camp victims as
  subjects and subjected them to great pain,
  suffering, disfigurement, and death

5
The Nuremberg Code

• Set of ethical principles developed by U.S.
  military tribunal post WWII (1949)
• Consent
• Right to withdraw
• Weighing of risks and benefits

6
Thalidomide tragedy

• Use in pregnant women resulted in thousands of
  babies born with digits or limbs
• Lead to 1962 Drug Amendments Act prove efficacy
  not just safety

7
The Declaration of Helsinki

• Issued by the World Medical Association (1964,
  amended 5x, 2000 most recent)
• Well-being of the human subject should take
  precedence over the interests of science and
  society
• Physicians responsibility is to safeguard the
  health of the people
• Medical research should be subject to review,
  approval, and oversight of an independent ethics
  committee

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Studies identified by Henry Beecher

• NEJM 1966 review of 22 unethical published
  studies including
• Jewish Chronic Disease Hospital case injected
  live cancer cells into patients without informing
  them
• Willowbrook case injected isolated strains of
  hepatitis into institutionalized mentally
  retarded children to understand the natural
  history of the disease and effects of gamma
  globulin

9
U.S. PHS syphilis study at Tuskegee

• 40-year research study designed to gain an
  understanding of the natural history of untreated
  latent syphilis
• During course of study, penicillin was identified
  to be effective treatment but subjects denied
  access to treatment

10
National Research Act

• Mandated regulations to protect human subjects
• Created National Commission to examine ethical
  issues

11
The Belmont Report

• National Commission 1979
• Respect for persons, operationalized by obtaining
  informed consent
• Beneficence, minimizing possible harms and
  maximizing possible benefits
• Justice, fair or equitable selection of subjects

12
Guideline for GCP from ICH (1996)

• Joint effort of the European Union, Japan, and
  the U.S. to develop a common approach to research
  leading to approval of new drugs

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HRPPP (Human Research Participant Protection
Programs)

• Institute of Medicine report 2001
• Preserving the Public Trust
• Broader system with multiple functional elements
• Advocated accreditation of the HRPPP

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Authority Responsibilities

• United States Code (U.S.C.)
• Code of Federal Regulations (CFR)
• Directives
• Handbooks
• Manuals
• Memorandums
• Professional standards

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Oversight Authority
16

• All research covered by the Common Rule
• FWA option (all research that is not exempt)
• Who?
• Institution
• IRB

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• FDA regulated drugs, biologics and devices
• Who?
• Investigators
• IRBs

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Under Secretary for Health
Office of Research Oversight
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Institutional Responsibilities
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Regulatory Guidelines for the Institution

• DHHS FWA
• FDA none
• VA
• VHA Directive 2003-031 (funding of the facility
  HRP)
• VHA Directive 1200 (Facility RD program)
• VHA Handbook 1200.1 (RD Committee)

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Assurance of Compliance (.103)

• Statement of principles governing the institution
• Designation of one or more IRBs
• List of IRB members
• Written procedures the IRB will follow
• Written procedures for reporting unanticipated
  problems involving risk, and any suspension or
  termination of IRB approval
• Executed by individual authorized to act for the
  institution (in the VA this is the Medical Center
  Director)

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Federalwide Assurance (FWA)

• This documents your institutional commitment to
  comply with the Common Rule.
• It is required from each institution engaged in
  covered research
• http//www.hhs.gov/ohrp/policy/index.htmlengagem
  ent

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Review by institution (.112)

• Research approved by an IRB may be subject to
  further review by official of the institution
• Those officials MAY NOT approve the research if
  it is not approved by the IRB

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Medical Center Director Responsibilities (VHA
Directive 1200)

• Responsible for RD program, advised and assisted
  by RD Committee
• RD funds used for research
• Research reimburses medical care appropriation
  for research participation
• Ensure ethical conduct of research

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Institutional Review Board
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Institutional Review Board (IRB)

• Fulfill regulatory requirements set forth in
  Common Rule (38 CFR 16)
• Authority and responsibilities detailed in VHA
  Handbook 1200.5
• FDA (21 CFR 56)

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Common Rule and VHA 1200.5

• Common Rule
• Establish IRBs
• Ensure Informed Consent of Subjects
• VHA Handbook 1200.5
• Medical Center Responsibilities
• IRB Composition Responsibilities
• Investigator Responsibilities
• Investigational Drugs Devices in VA

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What is covered? (.101)

• All research involving human subjects conducted,
  supported or otherwise subject to regulation by
  any federal department or agency which takes
  action to make this policy application.
• In the VA, that is all research involving human
  subjects conducted completely or partially in VA
  facilities, approved off-site locations,
  facilities, and/or by VA researchers while on
  official VA duty time (VHA Handbook 1200.5, p. 6).

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Research
a systematic investigation, including research
development, testing and evaluation, designed to
develop or contribute to generalizable
knowledge. (45 CFR 46.102d)
Widespread information
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Human subject

• means a living individual about whom an
  investigator (whether professional or student)
  conducting research obtains(1) data through
  intervention or interaction with the
  individual, or(2) identifiable private
  information

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Investigator Responsibilities
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Investigators Responsibilities

• Common Rule
• Obtain legally effective informed consent
• VHA 1200.5 Paragraph 10
• Training and credentialing
• Research plan
• Consent process
• Reporting of SAEs and/or AEs
• Amendments
• IRB Review
• Record retention
• HIPAA

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Study Staff

• Delegated authority
• Training and credentialing

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FDA and GCP (ICH E6)

• Investigator qualifications and agreements
• Permit auditing and inspection
• Maintain list of appropriately qualified
  personnel to whom delegated significant
  trial-related duties
• Adequate resources (patients, time, staff)
• Medical care of trial subjects
• Communicate with the IRB
• Compliance with the protocol
• Investigational product accountability
• Informed consent of trial subjects

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QUESTIONS