Ethical & Regulatory Oversight of VA Human Subjects Research

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 • Physician’s 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 R&D 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 & Development’s (ORD) Program for Research Integrity Development & Education (PRIDE) • Policy & Guidance • Training • Accreditation • VA Central IRB

24. Deputy Under Secretary for Health Chief R&D Officer (CRADO) AsstCRADO (PRIDE) 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 (R&D) 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 (R&D) Committee • All VA Research requires approval by the R&D Committee • Describes responsibilities of • Medical Center Director • Chief of Staff • Associate Chief of Staff/R&D • Administrative Officer/R&D • R&D 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