Ethical

1
Ethical Regulatory Oversight of VA
Human Subjects Research

• K. Lynn Cates, M.D.
• Assistant Chief Research Development Officer
• Director, PRIDE
• HRPP 101
• January 25, 2011

2
Objectives

• Ethical basis of human subjects protection
• Requirements for protection of human subjects in
• VA Research

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
• Nazi Doctors Trial
• Charges of murder, torture, and other atrocities
• 15 of 23 defendants found guilty
• 7 sentenced to death

5
The Nuremberg Code

• Contained in the 1947 judgment from the Nazi
  Doctors Trial
• Marks the beginning of the modern era of human
  subjects protection

6
The Nuremberg Code

• Informed consent of volunteers must be obtained
  without coercion in any form
• Human experiments should be based upon prior
  animal experimentation
• Anticipated scientific results should justify the
  experiment
• Only qualified scientists should conduct medical
  research
• Physical and mental suffering and injury should
  be avoided
• There should be no expectation of death or
  disabling injury from the experiment

7
Thalidomide Tragedy

• Approved as a sedative in Europe in 1950s
• Not FDA approved in United States
• Manufacturer supplied it to physicians and paid
  them to do research to study its safety and
  efficacy
• By 1961 recognized that use in first trimester
  pregnancy caused abnormal development of arms and
  legs
• Banned world-wide
• Lead to 1962 Drug Amendments Act
• Must now prove efficacy, not just safety

8
The Declaration of Helsinki

• Issued by the World Medical Association in 1964
  (amended 5 times)
• 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 (in later version)

9
U.S. PHS Study of Untreated Syphilis in the Negro
Male at Tuskegee

• 1932 - subjects were enrolled but were not
  informed about their disease or that the research
  would not benefit them
• 1943 - penicillin was accepted as treatment for
  syphilis but arranged to have local draft board
  exempt subjects with syphilis to keep them from
  being treated
• 1951 - penicillin was widely available, but
  withheld
• Never-again scientific opportunity
• Nuremberg Code had no impact
• 1972 exposed by Associated Press reporter

10
National Research Act of 1974

• Passed by U.S. Congress
• Required regulations to protect human subjects
• Informed consent
• Review of research by IRBs
• Created National Commission for the Protection of
  Human Subjects of Biomedical and Behavioral
  Research to examine ethical issues
• 1979 the Commission wrote the Belmont Report
• Boundaries between practice research
• Basic ethical principles

11
The Belmont Report

• Respect for persons - operationalized by
  obtaining informed consent
• Beneficence - minimizing possible harms and
  maximizing possible benefits
• Justice - fair or equitable selection of subjects
• Whenever research supported by public funds leads
  to new developments, advantages should not only
  go to those who can afford them, and research
  should not unduly involve persons from groups not
  likely to benefit from the research

12
The Common Rule

• Federal Policy for the Protection of Human
  Subjects
• Originally issued in 1974 as Part 46 of Title 45
  of the Code of Federal Regulations (Subpart A) by
  DHEW
• Adopted in 1991 by 15 agencies
• Currently adopted or applies to 17 federal
  agencies
• VA 38 CFR Part 16
• FDA did not adopt the Common Rule

13
Accreditation of Human Research Protection
Programs

• Institute of Medicine report 2001
• Preserving Public Trust Accreditation and Human
  Research Participant Protection Programs
• Accreditation Standards
• Accreditation Standards are not regulations
• 1999 VHA Under Secretary for Health testified to
  Congress about mandatory accreditation of VA
  Human Research Protection Programs (HRPPs)

14
Requirements for Protection ofHuman Subjects

• Mandatory
• United States Code (U.S.C.) - Laws
• Code of Federal Regulations (CFR)
• Directives - Policies
• Handbooks - Policies
• Memoranda
• Suggested
• Guidance
• Other voluntary adoption
• Accreditation standards
• Professional standards

15
The Dream of Anyone Working in Human Research

• Where is the one place
• I can find
• Everything I need to know
• In Large Font
• Examples
• Some pictures

16
Answer to Your Dreams

• Forget about it!

17
The Common Rule

• What is covered by the Common Rule?
• 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 applicable
  to such research.
• 45 CFR Part 46.101 (for VA 38 CFR Part 46.101)

18

• All HHS human research is covered by the Common
  Rule at 45 CFR Part 46
• Who is covered?
• Institutions that receive HHS funding and their
  IRBs

19

• What is covered by FDA regulations?
• All research involving FDA regulated drugs,
  biologics, devices, foods, and tobacco.
• Who is covered?
• Investigators
• IRBs

20

• Basic FDA Human Research Protections Governing
  the Conduct of Clinical Investigations in Human
  Subjects
• 21 CFR Part 50 Informed Consent
• 21 CFR Part 56 IRB Regulations
• These regulations are near-identical to the
  Common Rule which governs protection of
  subjects in federally funded research

21
The Department of Veterans Affairs

• All VA Research
• Who is covered?
• VA institutions
• VA investigators and research staff
• VA IRBs

22
What is VA Research?

• Approved by the RD Committee
• Conducted by VA investigators (PIs, Co-PIs, Local
  Site Investigators (LSIs) on VA time
• Compensated, WOC, or IPA appointments
• Using VA resources
• On VA property
• Funded by VA, by other sponsors, or unfunded
• VHA Handbook 1200.01

23
VA Offices Dealing With Human Research Protection

• VHA Office of Research Oversight (ORO)
• Oversight
• Compliance
• Assurances
• Misconduct
• VHA Office of Research Developments (ORD)
  Program for Research Integrity Development
  Education (PRIDE)
• Policy Guidance
• Training
• Accreditation
• VA Central IRB

24
Under Secretary for Health
Office of Research Oversight
25
Requirements for VA Institutions

• VHA Directive 1200, Veterans Health
  Administration Research and Development Program
• VHA Handbook 1200.01, Research and Development
  (RD) Committee
• VHA Handbook 1200.05, Requirements for the
  Protection of Human Subjects in Research
• VHA Handbook 1058.03, Assurance of Protections
  for Human Subjects in Research
• 1200 ORD is responsible office
• 1058 ORO is responsible office

26
VHA Directive 1200VHA Research and Development
Program

• Provides overview of VHA Research and Development
  policies and procedures
• Describes general responsibilities of
• Chief Research and Development Officer (CRADO)
• Veterans Integrated Service Network (VISN)
  Director
• Medical Center Director

27
VHA Handbook 1200.01Research Development
Committee

• Every VA facility conducting research must have a
  Research and Development (RD) Committee
• All VA Research requires approval by the RD
  Committee
• Describes responsibilities of
• Medical Center Director
• Chief of Staff
• Associate Chief of Staff/RD
• Administrative Officer/RD
• RD Committee
• Investigators

28
VHA Handbook 1200.05, Requirements for the
Protection of Human Subjects in Research

• Operationalizes the Common Rule at 38 CFR Part 16
• Issued by July 15, 2003
• Revised July 31, 2008
• Revised October 15, 2010 (must be implemented by
  March 31, 2011)
• Responsible office PRIDE

29
VHA Handbook 1058.03, Assurance of Protections
for Human Subjects in Research

• Each VA facility engaged in human subject
  research must provide a written Assurance (i.e.,
  Federalwide Assurance or FWA)
• FWAs for VA facilities must be submitted to the
  Office for Human Research Protections (OHRP)
  through the Office of Research Oversight (ORO)
• FWA must be approved by both ORO and OHRP before
  any human subject research is initiated
• Responsible office ORO

30
Federalwide Assurance (FWA)

• Documents your institutional commitment to comply
  with the Common Rule (38 CFR 16)
• Required from each institution engaged in
  covered research
• VHA Handbook 1058.03, Assurance of
  Protections for Human Subjects in Research

31
Assurance of Compliance (38 CRF 16.103)

• 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 risks to
  subjects or others
• Serious or continuing noncompliance
• Suspension or termination of IRB approval
• Executed by individual authorized to act for the
  institution (i.e., Medical Center Director)

32
Review by Institution (38 CFR 16.112)

• Research approved by an IRB may be subject to
  further review by and approval or disapproval by
  officials of the institution
• Those officials may not approve the research if
  it has not been approved by an IRB

33
Institutional Review Board (IRB)

• Fulfill regulatory requirements - Common Rule
• (45 CFR 46 38 CFR 16)
• VA IRB authority and responsibilities - VHA
  Handbook 1200.05
• FDA IRB regulations - FDA (21 CFR 56)

34
IRB (38 CFR 16.109)

• Authority to approve, require modifications, or
  disapprove research
• Require that information given to subjects is in
  compliance with 38 CFR 16.116
• Require documentation of informed consent
• Notify investigators in writing of its decision
• Conduct continuing review
• Have authority to observe consent process
  research

35
Criteria for IRB Approval (38 CFR 16.111)The
111 Criteria

• Required
• Risks to subjects are minimized
• Risks are reasonable in relation to benefits
• Selection of subjects is equitable
• Informed consent will be sought prospectively
• Informed consent is appropriately documented
• Research plan makes adequate provisions for
  safety monitoring
• There are adequate provisions to protect privacy
  and confidentiality
• When appropriate
• Additional protections for vulnerable subjects

36
QUESTIONS
36