IRB Responsibilities

1. IRB Responsibilities Marisue Cody, PhD September 6, 2006 Baltimore, MD

2. Authority & Responsibilities • United States Code (U.S.C.) • Code of Federal Regulations (CFR) • VHA Directives • VHA Handbooks • VHA Manuals • OHRP Guidance • FDA Guidance

3. Oversight Authority

4. 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): Institutional Review Boards

5. Application of the Common Rule

6. 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.

7. Research … a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to “generalizable” knowledge. (38 CFR 16.102d) Widespread information…

8. 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

9. Exemptions to what is covered. • Research conducted in established educational settings, involving normal educational practices • Research involving the use of educational tests, survey procedures, interview procedures, or observation of public behavior • Same as # 2, but covers elected officials • Research involving use of existing data, specimens • Research and demonstration projects by approval of agency heads • Taste and food quality

10. VHA Handbook 1200.5 • What is covered? • 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.

11. Covers any clinical investigation: • “any experiment that involves a test article and one or more human subjects” • Exemptions • Emergency use of a test article • Taste and food quality evaluations and consumer acceptance studies

12. IRB Composition & Responsibilities

13. 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

14. 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

15. 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.

16. VHA 1200.5 Written procedures for operation 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

17. Office of Human Research Protection Significant Findings • Lack of diversity of IRB membership • Lack sufficient understanding of HHS regulations • Lack of expertise for vulnerable populations • Inadequate IRB resources • Overburdened IRB • Lack of IRB knowledge of local context • Lack of appropriate written IRB policies and procedures

18. 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

19. 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

20. Criteria for IRB Approval (.111) • 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 8. Additional protections for vulnerable subjects Additional VA requirements: 9. Conflict of interest is evaluated and managed 10. Ensure Investigator educational requirements and certifications

21. Office of Human Research Protection Significant Findings • IRB lacks sufficient information to make determinations required for approval • How risks to subjects are minimized • Subject recruitment and enrollment criteria • Equitable selection of subjects • Provisions to protect privacy and maintain confidentiality of data • Additional safeguards of vulnerable subjects

22. Continuing Review (.109(e)) • An IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year

23. 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

24. 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

25. 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

26. Office of Human Research Protection Significant Findings • Inadequate continuing review • Determinations regarding risks, potential benefits, informed consent, & safeguards • Insufficient information including: • Number of subjects accrued • Summary of adverse events, unanticipated problems, complaints, & withdrawals • Summary of interim findings & recent literature • Relevant multi-center trial reports

27. 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

28. Office of Human Research Protection Significant Findings • Inappropriate use of expedited review for initial or continuing review • Applied to minimal risk research that is not in the approved categories • Applied to greater than minimal risk research • Inappropriate use for review of protocol changes • Change not “minor” • Failure to advise IRB members

29. 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

30. 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 • This is only done in the VA with other VA facilities or the University affiliate through a memorandum of understanding.

31. 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

32. 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

33. Office of Human Research Protection Significant Findings • Poorly maintained files—difficult to reconstruct a complete history of IRB actions • Failure to determine that criteria for approval are satisfied • Failure to document consideration of additional safeguards for vulnerable subjects • Failure to document determinations for waiver of consent or documentation of consent • Lack of appropriate written IRB procedures

34. Informed Consent

35. 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

36. 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

37. 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

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

39. 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

40. 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

41. VHA 1200.5 Appendix C – additional consent requirements • 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

42. Office of Human Research Protection Significant Findings • Deficient informed consent documents – lack of required elements and additional elements • Language too complex • Exculpatory language used • Inappropriate boilerplate informed consent documents • Enrollment procedures did not minimize possibility of coercion or undue influence

43. Waiver of written consent (56.109): • No more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context, OR • Meets requirements for emergency research (50.24)

44. Four conditions for exemption of informed consent (21 CFR 50.24 (a)) • The subject is confronted by a life-threatening situation. • Informed consent cannot be obtained from the subject. • Time is not sufficient to obtain consent from the subject’s legal representative. • No alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the subject’s life.