1. Human Research Protection Program 101 March 19, 2007 Cincinnati, OH

2. The Common Rule and VHA 1200.5: One and the Same? Presented by: Marisue Cody Presented by: Marisue Cody

3. Objectives  Evaluate applicability of the Common Rule  Define the scope of regulations described in VHA 1200.5  Describe the areas of overlap between the Common Rule and VHA 1200.5

4. 17 Federal Agencies that Signed the Common Rule:  Dept of Agriculture  Dept of Energy  Dept of Commerce  Dept of Justice  Dept of Defense  Dept of Education  Dept of Transportation  Dept of HHS  HUD  National Science Foundation  NASA  AID  Social Security Administration  CIA  Consumer Product Safety  EPA  Dept of Veterans Affairs

5. Code of Federal Regulations  38 CFR 16 refers to the VA  21 CFR 56 (IRB) and 50 (informed consent) refers to the FDA  45 CFR 46 refers to DHHS

6. Subparts  B: Additional Protections for Pregnant Women, Human Fetuses and Neonates involved in Research  C: Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects  D: Additional Protections for Children Involved as Subjects in Research

7. What are the Common Rule and VHA 1200.5?  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 17 agencies VA: Part 16 of Title 38 of the Code of Federal Regulations

8. What is VHA Handbook 1200.5?  Handbook describing procedures for the protection of human subjects  VHA 1200.5 issued July 15, 2003  Handbook vs. Federal Regulations Same regulatory weight (not optional) Applicability

9. 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

10. IRB Composition & Responsibilities

11. IRB Membership (.107)  At least 5 members with varying backgrounds  Gender balance, more than one profession  At least 1 scientist, at least 1 non-scientist  At least 1 member not affiliated  May not participate if has a COI  Invite consultant if require expertise

12. IRB Composition– VHA 1200.5 Licensed Physician for FDA regulated products ACOS/AO/RCO MAY serve as non-voting members Members of a VA IRB Appointed by the Medical Center Director Initial appointment 3-years Chair of a VA IRB Initial appointment 1-year Affiliate IRB (Paragraph 5) Two VA IRB voting members One VA IRB voting member must have scientific expertise

13. IRB Functions & Operations  Follow written procedures  Review must take place at a convened meeting with a majority present, including a non-scientist. Approval must be by the majority present.

14. VHA 1200.5 Written procedures for operation (turn to page 13-14) More detail, plus some extras: Reporting to the R&D Committee Projects needing verification from sources other than the investigator Reporting requirements Conducting audits Education requirements Reporting to Privacy Officer Reporting to VHA Information Security Officer

15. 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

16. Additional VHA 1200.5 requirements Prior to initiation Research reviewed and approved by IRB AND R&D If approval is contingent on substantive modifications, subsequent review must be by the convened IRB If approval is contingent on specific minor conditions, the IRB chair or designee may approve it on behalf of the IRB

17. Continuing Review in VHA 1200.5 Requires submission of a written progress report that includes: Brief summary Number of subjects entered and withdrawn Gender and minority status Number of subjects – vulnerable populations Copy of proposal and all approved amendedments Copy of current consent document for the IRB to review

18. Continuing Review Written Progress Report (cont.) Copy of current HIPAA Authorization document Information that may impact on risk benefit ratio Research findings to date Summary of DSMB or DMC meetings Assurance that all SAEs and UAEs have been reported New scientific findings in the literature, or other relevant findings

19. Lapse of approval Automatically suspended Local research office to notify the PI IRB in consultation with COS may allow continuation of research interventions if it is in the best interest of individual subjects Inform other agencies as appropriate Re-approval must occur prior to re-initiation

20. Expedited Review (.110) List of categories is published in the Federal Register (on OHRP website & is the same as Appendix B) Must be no more than minimal risk, OR minor change in already approved protocol Carried out by IRB Chair or designee, cannot disapprove the research Have a process to inform the IRB members May be restricted by agency head

21. VHA 1200.5  No differences except the labeling of the expedited categories

22. Criteria for IRB Approval (.111) 1.Risks to subjects are minimized 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 8.Protection of Vulnerable Subjects 9. Conflict of Interest 10. Ensure Investigator educational requirements and certifications

23. 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

24. Suspension or termination of IRB approval (.113)  IRB has authority to suspend or terminate a project not being conducted in accordance with its requirements or is associated with unexpected harms to subjects  Must be reported

25. Cooperative research (.114)  With approval of the department or agency head, an institution participating in a cooperative project may enter into a joint review arrangement, rely upon the review of another qualified IRB, or make similar arrangements for avoiding duplication

26. IRB records (.115) Proposals reviewed, scientific evaluations (if any), sample consent documents, progress reports, reports of injuries Minutes of IRB meetings Continuing review activities Correspondence List of IRB members Written procedures Statements of significant new findings Shall be retained for at least 3 years

27. Extras in IRB records (1200.5)  Minutes must include Minutes available in 3 weeks Additional safeguards to protect vulnerable subjects Determination of level of risk  Correspondence with R&D Committee  Retain records for 5 years Records are the property of the VA Non-redacted minutes of affiliate IRB

28. Informed Consent

29. General requirements for informed consent (.116)  Basic elements Study involves research Description of risks Description of benefits Disclosure of alternative procedures Extent of confidentiality If more than minimal risk, compensation for injury Whom to ask questions of Statement that it is voluntary

30. General requirements for informed consent (.116)  Additional elements Unforeseeable risks Anticipated circumstances where participation may be terminated Additional costs Consequences of withdrawal Significant new findings Approximate number of subjects

31. General requirements for informed consent (.116)  Alteration or waiver (c) The research is conducted by or subject to the approval of state or local government officials and is designed to study, evaluate or otherwise examine a public benefit program, AND It could not practicably be carried out without the waiver or alteration

32. General requirements for informed consent (.116)  Alteration or waiver (d) 1.Involves no more than minimal risk 2.Will not adversely affect the rights and welfare of subjects 3.Could not be practicably carried out without the waiver, AND 4.Whenever appropriate the subjects will be provided pertinent information

33. Documentation of informed consent (.117)  Written consent Approved by the IRB Signed by the subject or LAR Copy given to person signing the form  Must be read to the subject or LAR, who is given adequate opportunity to read it before it is signed, or given a short form

34. Documentation of informed consent (.117)  Waiver of requirements (c) Only record linking the subject with the research and breach of confidentiality would be harmful, OR Research presents no more than minimal risks and involves no procedures for which written consent is normally required outside of the research context

35. VHA 1200.5 Appendix C  10-1086 must be used Signed, dated by: Subject or LAR Witness (to signature only) Person obtaining consent  Progress note Consent Entry Termination  Flag medical record  Filed in Case History

36. Subparts B-D

37. Subpart B-Additional Protections for Pregnant Women, Human Fetuses and Neonates  Definitions  Duties of the IRB  Risks and benefits  Consent

38. VHA Handbook 1200.5 Appendix D  Paragraph 4 Forbids research with a fetus, in-utero or ex-utero (including human fetal tissue) Forbids research related to in vitro fertilization Allows participation of pregnant women, rules are consistent with Sub-part B section 204

39. Subpart C-Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects  Definitions  Duties of the IRB  Permitted Research

40. VHA Handbook 1200.5 Appendix D  Paragraph 5 Requires a waiver from the CRADO If waiver is granted, must follow Subpart C regulations

41. Subpart D-Additional Protections for Children Involved as Subjects in Research  Definitions  Duties of the IRB  Risks of Research  Requirements for permission by parents or guardians and for assent by children

42. VHA Handbook 1200.5 Appendix D  Paragraph 7 Requires a waiver from the CRADO VHA Directive 2001-028 Guidance for waiver process Requires IRB to have specific policies and procedures regarding children in research IRB must have expertise If waiver is granted, must follow Subpart D regulations

43. Research Involving Human Subjects with Surrogate Consent  Common Rule Section 117 – “subject’s legally authorized representative”  VHA Handbook 1200.5 Paragraph 11 Appendix D Paragraph 6

44. Paragraph 11 a.Under appropriate conditions (1)Research problem must be unique (2)Priority of who can sign consent (3)How determination is made regarding capacity (turn to page 21) b.IRB must find that the research meets the conditions in Appendix D

45. Appendix D, Paragraph 6 c. Conditions for approval (1)Only persons with impaired decision making capacity are suitable as research subjects (2)Research entails no significant risks; or if possibility of harm, there must be at least a greater probability of direct benefit (3)Procedures assure participant’s representatives are well informed about their roles and obligations

46. Investigational Drugs & Devices

47. Investigational Drugs  VHA Handbook 1108.04  VA differs from FDA on how it defines investigational drugs  Yields to FDA on investigational drug regulatory jurisdiction when there is conflict

48. Investigational Devices  Conducted according to FDA regulations at 21 CFR Part 812  Significant risks (SR) vs. Nonsignificant risk (NSR)  Receipt, control, custody and dispensing

49. Investigator Responsibilities

50. Investigator’s Responsibilities  There is NOTHING regarding investigators in the Common Rule  VHA 1200.5 Paragraph 10 Training and credentialing Research plan Consent process Reporting of SAEs and/or AEs Amendments IRB Review Record retention HIPAA