The Roles of IRB & Investigators in Clinical Research

1. The Roles of IRB & Investigators in Clinical Research

2. Definitions IRB: A specially constituted review body established or designated by an entity to protect the welfare of human subjects recruited to participate in biomedical or behavioral research. RESEARCH: A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. HUMAN SUBJECTS: A living individual about whom an investigator conducting research obtains data through intervention or interaction with the individual, or identifiable private information.

3. Landmark Document • The Nuremburg Code Permissible Medical Experiments” Trials of War Criminals before the Nuermberg Military Tribunals under Control Council Law No. 10, 1949 • Helsinki Declaration World Medical Association General Assembly, Edinburgh, Scotland, October 2000 • Belmont Report of 1979 Report of the National Commission for the Protection of Human Subjects ot Biomedical and Behavioral Research, DHEW, April 1979

4. The federal regulations are intended to implement the basic ethical principles governing the conduct of human research. These ethical principles are set forth in the Belmont Report. No one should be involved in human research at any level without being familiar with these ethical principles.

5. Policies Cited from the CFR Citation Title 21 CFR 50 FDA - Protection of Human Subjects, Informed Consent 21 CFR 56 FDA - Institutional Review Boards 45 CFR 46, Subpart A DHHS - Basic Policy for Protection of Human Research Subjects (Common Rule) 45 CFR 46, Subpart B DHHS - Research Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization 45 CFR 46, Subpart C DHHS - Additional Protection for Children Involved as Subjects in Research 45 CFR 46, Subpart D DHHS - Additional Protections Pertaining to Research Involving Prisoners as Subjects

6. Differences BetweenFDA and DHHS Regulations • The basic requirements for IRBs and for Informed Consent are congruent between the two sets of regulations. Differences center on differences in applicability: • The Common Rule applies to all research involving human subjects conducted, supported by any federal department or agency. • FDA regulations are applied primarily to use of FDA regulated products: drugs, devices, or biologics.

7. Institutional Review Boards CODE OF FEDERAL REGULATIONS TITLE 45PUBLIC WELFARE DEPARTMENT OF HEALTH AND HUMAN SERVICESNATIONAL INSTITUTES OF HEALTHOFFICE FOR PROTECTION FROM RESEARCH RISKS PART 46PROTECTION OF HUMAN SUBJECTS * * * Revised June 18, 1991Effective August 19, 1991

8. §46.108 IRB functions and operations In order to fulfill the requirements of this policy each IRB shall: (a) Follow written procedures in the same detail as described in 46.103 (b)(4) and to the extent required by 46.103 (b)(5). (b) Except when an expedited review procedure is used review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary concerns are in nonscientific areas. In order for the research to be approved, it shall receive the approval of a majority of those members present at the meeting

9. IRB Responsibilities • Conducting initial review • Conducting continuing review • Notifying the investigators about IRB decisions • Determining which studies require review more often than annually • Review and approval of changes in research activities • Determining which device studies pose significant or non-significant risk

10. IRB Responsibilities (Cont.) • Ensuring that changes in approved research are not initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards • Ensuring prompt reporting to appropriate institutional officials, regulatory agencies and funding sources of: • unanticipated problems involving risks to subjects or others • serious or continuing noncompliance with federal regulations • suspension or termination of IRB approval

11. IRB Authority • The IRB reviews, and has the authority to approve, require modification in, or disapprove all research activities, including proposed changes in ongoing, previously approved, human subject research. • The IRB has the authority to suspend or terminate the approval of ongoing, previously approved research that is not being conducted in accordance with the IRB's requirements or that has been associated with unexpected, serious harm to subjects.

12. Continuing Review • The IRB conducts continuing review of ongoing, approved research at intervals appropriate to the degree of risk, but not less than once per year. • For approved research, the IRB determines which activities require continuing review more frequently than every twelve months. • Continuing IRB reviews are preceded by receipt of appropriate progress reports from the investigator, including available, study-wide findings. • Continuing review must be substantive and meaningful.

13. IRB Membership • At least 5 members • at least one scientist and one lay person • Sufficiently qualified through experience and expertise • Diversity

14. Criteria for IRB Approval • Risks to subjects are minimized • Risks are reasonable in relation to anticipated benefits • Selection of subjects is equitable • Informed consent is sought from each subject • Informed consent is appropriately documented.

15. Additional Criteria Where Appropriate • Data collection is monitored to ensure subject safety • Privacy and confidentiality of subjects is protected • Additional safeguards are included for vulnerable populations.

16. Expedited Review • Some specified categories of minimal risk research may be reviewed by the IRB through an expedited review procedure. • Expedited review may be carried out by the IRB chair or by one or more designated IRB members. • All of the requirements for IRB approval of research apply equally to expedited review. Expedited review should not be viewed as a less rigorous review. • Under expedited review, the reviewers may exercise all of the authorities of the IRB, except that the reviewers may not disapprove the research.

17. Expedited review procedures may be used for- • Research appearing on the list and found by the reviewer to involve no more than minimal risk • Minor changes in previously approved research during the authorized approval period of one years or less.

18. Important Considerations • IRB’s responsibility is the protection of human subjects • IRB activity is governed by a strict set of regulations with oversight from the Office for Research Protection (OPRR)

19. Requirements for IRB Convened Meetings • a majority of the members of the IRB must be present and at least one nonscientist must be present • if the required number of members is lost during a meeting, no action may be taken until it is restored • in order for research to be approved, it must receive the approval of a majority of those members present at the meeting

20. IRB Minutes • Minutes of IRB meetings must include: • attendance at the meetings • actions taken by the IRB • the vote on these actions including the number of members voting for, against, and abstaining • the basis for requiring changes in or disapproving research • documentation of specific findings required by the regulations, and • a written summary of the discussion of debated issues and their resolution

21. IRB Records • copies of all research proposals reviewed, scientific evaluations, if any, that accompany the proposals, approved sample consent documents, progress reports submitted by investigators, and reports of injuries to subjects; • minutes of IRB meetings; • records of continuing review activities; • copies of all correspondence between the IRB and the investigators; • a list of IRB members; • written procedures for the IRB • statements of significant new findings provided to subjects

22. Important Considerations • IRB is NOT responsible for fostering of research • Regulations are vague and subject to collective interpretation of the IRB members • IRB members review protocols outside of their area of expertise • protocols must be clear and understandable

23. Important Considerations • Protocols are usually reviewed by two members • usually one with expertise/experience • one with general knowledge • IRB submission is NOT an NIH grant nor is it a submission to the FDA • Lack of scientific merit renders a protocol unethical

24. IRB Initial Review The process of protocol review and approval not only improves the protection of research participants, it improves the research itself. The IRB is a speed bump on my road to progress. IRB P.I.

25. Continuing Review The progress report is just one more opportunity for the IRB to obstruct my research. Continuing review of every protocol is an important component of human subject protections. IRB P.I.

26. Adverse Events Reporting Give me a break! What does the IRB know about adverse events? An IRB must be made aware of adverse events - this is the only way to provide continuing assessment of the risks and potential benefits of the study. IRB P.I.

27. The Relationship Between the Investigator and the IRB The IRB Finally! Have a nice trip! See you next time!! The P.I.

28. The Relationship Between the Investigator and the IRB Here’s a phone card, call to check in. Call immediately if something bad happens. If we don’t hear from you, your trip is cancelled! What! The P.I. The IRB

29. The Relationship Between the Investigator and the IRB And remember… plan to get together a few times during your trip. Oh joy! The IRB The P.I.

30. Investigators’ Responsibilities • Regulatory Documentation • IRB Correspondence • Informed Consent Process • Recruitment Procedures • Subject Selection Criteria • SAE Reporting • Drug/Device Accountability • CRF/Source Documentation • Record Keeping • Allocation of Responsibilities

31. Protocol FDA 1572, 1571 CVs Enrollment log Monitoring log Staff signature log IB or DM Copy of normal lab values Lab Certification Clinical Investigator Financial Disclosure form All correspondence to and from sponsor and/or FDA Regulatory Documentation

32. IRB Documentation • All correspondence (e.g. e-mails, submission…) between investigators /study staff and HRC • IRB Initial approval • IRB continuing review • Amendments • Violations/deviations (including sponsor-approved protocol deviations)

33. Recruitment Procedures • Recruitment methods stated in the protocol • Identify potential subjects • Make initial contact • Recruitment material • IRB approval

34. Informed Consent Process • IRB approval • Different versions (expiration date) • Investigator sign and date consent form • Subject sign and date consent form • Copy to subjects

35. Subject Selection Criteria • Eligibility checklist • Signature/initials and date • Protocol deviation

36. Adverse Event Reporting • Institution/sponsor guidelines vs. Federal Regulations • Interventional vs. non-interventional • Serious vs. Non-serious

37. Drug/Device Dispensing Accountability: Dispensing log Shipping/receiving CRF/SD: Consistency Dated signature /initials Cross-outs Drug Dispensing and CRF

38. Record Keeping • Regulatory binder/folder • IRB Binder/folder • Study file for EACH subject

39. Allocation of Responsibilities • Initial submission • Progress report for continuing review • SAE/AE reporting • Obtaining informed consent

40. Handling Non-Compliance • Reporting • Note to File • Corrective Actions • Follow-up

41. Common Findings 1. Source Documentation 2. Lab Documentation 3. Investigator Brochure 4. NIH Progress Report/DSMB 5. Curriculum Vitae (CVs) 6. Study Logs 7. Eligibility Criteria Checklist 8. Consent Form Issues 9. Protocol deviations, violations 10. Record Keeping

42. Helpful Websites • FDA - http:// www.fda.gov • NIH - http:// www.nih.gov • OHRP- http://ohrp.osophs.dhhs.gov • FDA IRB Guidance document - http:// www.fda.gov/oc/oha/IRB/toc.html • Code of Federal Regulations - http:// www.access.gpo.gov/nara/cfr/cfr-table-search.html

43. Helpful Websites (Cont.) • OHRP Compliance Oversight • http://ohrp.osophs.dhhs.gov/compovr.htm • OHRP Compliance Findings & Guidance • http://ohrp.osophs.dhhs.gov/references/findings.pdf • OHRP Education Materials • http://ohrp.osophs.dhhs.gov/educmat.htm • FDA Warning Letters • www.fda.gov/foi/warning.htm

44. Helpful Websites (Cont.) • FDA Information Sheets • http://www.fda.gov/oc/oha/irb/toc3.html#contreview • FDA MedWatch (AE Reporting) • http://www.fda.gov/medwatch/report/desk/tpcfinal.htm#toc • PRIM&R • http://www.primr.org/ • Bioethics Resources • http://www.nih.gov/sigs/bioethics/