1. Ethical and Regulatory Oversight of Human Subjects Research in the VA C. Karen Jeans, PhD, CCRN, CIP COACH Program Analyst September 29, 2010

2. Objectives Describe the ethical underpinnings of human subjects protection Describe the oversight structure of human subjects research in the VA

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 that were missing or deformed 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 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)

8. 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

9. National Research Act of 1974 Mandated regulations to protect human subjects Created National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to examine ethical issues

10. 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

11. 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

12. International Council of Harmonization (1996) – E6 Good Clinical Practice Joint effort of the European Union, Japan, and the U.S. to develop a common approach to research leading to approval of new drug

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

14. Authority & Responsibilities United States Code (U.S.C.) Code of Federal Regulations (CFR) Directives Handbooks Manuals Memorandums Accreditation standards Professional standards Guidance

15. The Dream of Anyone Working in Human Research Where is the One Book Where I Can Find: (a) Everything I need to know? (b) In Large Font (c) Examples (d) Some pictures

16. Oversight Authority

17. All research covered by the Common Rule Who? Institution IRB

18. What is “covered” by 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 application” From 45 CFR Part 46.101

19. All research involving FDA regulated drugs, biologics, devices, foods, and tobacco. Who? Investigators IRBs

20. It is Sometimes Hard to Figure out What FDA Regulates Yes Yes NO

21. 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

22. The Department of Veterans Affairs All research which constitutes VA research Who? Institutions Investigators and research staff IRBs

23. What is VA research? Research involving human subjects conducted completely or partially in VA facilities, approved off-site locations, facilities, by VA researchers while on official VA duty time.

24. Deputy Under Secretary for Health Chief R&D Officer (CRADO) Special Projects Deputy CRADO Minority Asst CRADO (PRIDE) Asst CRADO (GW, Biosafety) Technology Transfer Congressional/ VSO Liaison Congressional/ VSO Liaison Field Services & Communications Finance Administration Business Functions Clinical Service R&D Service Health Service R&D Service Rehabilitation R&D Service Biomedical Laboratory R&D Service Science Functions Under Secretary for Health Office of Research Oversight

25. The Office of Research and Development

26. The Department of Veterans Affairs VHA Handbook 1200.05: Requirements for the Protection of Human Subjects in Research Operationalizes the Common Rule VHA Handbook 1200.5 originally issued by the VA Office of Research and Development (ORD) on July 15, 2003 Revised July 31, 2008

27. Institutional Responsibilities

28. Requirements for the Institution Department of Health and Human Services – Federal Wide Assurance FDA – none VA VHA Handbook 1058.03: Assurance of Protections for Human Subjects in Research VHA Directive 1200: Veterans Health Administration Research and Development Program) VHA Handbook 1200.01: Research and Development (R&D) Committee

29. 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)

30. 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.html#engagement

31. 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

32. 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 Each non-VA institution engaged in human subject research conducted or supported by VA must provide a written Assurance FWAs for VA facilities must be submitted to the Office for Human Research Protections (OHRP) through the Office of Research Oversight (ORO) Must be approved by both ORO and OHRP before any human subject research is initiated

33. VHA Directive 1200: Veterans Health Administration Research and Development Program Provides overview of 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

34. VHA Handbook 1200.01: Research and Development (R&D) Committee Every VA facility conducting research must have, or establish, a Research and Development (R&D) Committee of record. 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 Investigator

35. Institutional Review Board

36. Institutional Review Board (IRB) Fulfill regulatory requirements set forth in Common Rule (38 CFR 16) Authority and responsibilities detailed in VHA Handbook 1200.05 FDA (21 CFR 56)

37. IRB Review of Research (.109) Authority to: Approve, require modifications to seek approval, or disapprove Require that information given to subjects is in compliance with.116 Shall require documentation of informed consent or waive documentation Notify investigators in writing of its decision Conduct continuing review and have authority to observe consent process and research

38. Criteria for IRB Approval (.111) A. Required determinations: 1. Risks to subjects are minimized (i) By using procedures consistent with sound research design… (ii) When appropriate, using procedures already being performed… 2. Risks are reasonable in relation to benefits 3. Selection of subjects is equitable 4. Informed consent will be sought prospectively 5. Informed consent is appropriately documented 6. Research plan makes adequate provisions for safety monitoring 7. There are adequate provisions to protect privacy and confidentiality B. When appropriate, additional protections for Vulnerable Subjects

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

40. 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

41. Human subject - FDA Individual who is or becomes a participant in research, either as a recipient of the test article or as a control (21 CFR §50.3(g)) or on whom or on whose specimen an investigational device is used or as a control. A subject may be in normal health or may have a medical condition or disease (21 CFR §812.3(p))

42. Clinical Investigation - FDA Clinical investigation means any experiment that involves a test article and one or more human participants and that is one of the following: [21 CFR §50.3(c)] [21 CFR §56.102(c)] Subject to requirements for prior submission to the Food and Drug Administration under §505(i) or §520(g) of the Act. Not subject to requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be submitted later to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit.

43. Summary