Protecting Human Subjects: What everyone needs to know…

1. Protecting Human Subjects:What everyone needs to know… Office for Human Research Studies (OHRS) September 2008 (617) 632-3029  ohrs@dfci.harvard.edu

2. Human Subject Protection Training • Michele Russell-Einhorn, JD • Senior Director, Office for Human Research Studies • Amanda Hammond, JD • Deputy Director, Office for Human Research Studies

3. Purpose of Training • To review regulatory issues involved in the protection of human subjects in research to ensure adequate substantive review, consistency and thoroughness of IRB review and approval and continuing oversight of research involving human subjects.

4. Background • Review NCI Guidelines • Review DFCI IRB Structure

5. National Cancer Center Grant • DFCI IRBs review alladult and pediatric cancer-relatedresearch on behalf of BIDMC; BWH; CHB; DFCI and MGH. • DFCI Scientific Review Committees—two adult and one pediatric—provide scientific review for oncology research that falls under the Cancer Center Grant. One scientific progress review committee. • The Cancer Center Grant requires that we keep the scientific review and IRB review functions separate and distinct.

6. Scientific Review vs. IRB review • What are the guidelines for determining which amendments; deviations; violations; or adverse events require review by both committees?

7. Scientific Review vs. IRB Review • Scientific Progress Review as compared to IRB Continuing Review

8. Institutional Review Boards • DFCI IRBs operate under a Federal Wide Assurance that we have with the U.S. Department of Health and Human Services. • DFCI IRBs operate under Federal regulations that specifically dictate the operations and substantive review of the IRBs. • DFCI IRBs, on behalf of the DF/HCC, currently have oversight of over 2100 open research protocols involving human subjects.

9. DFCI IRBs • IRBs A and B: • meet on an alternating basis every Tuesday from 12-2 pm. • expertise to review any matter, but focus on new protocols and amendments.

10. DFCI IRBs • IRBs C and F: • meet on an alternating basis every Thursday morning from 8-10 am. • expertise to review any matter but focus on continuing reviews; amendments; adverse events; and other events.

11. DFCI IRBs • IRB D: • meets twice monthly on Mondays from 10-12 pm • was known as the “social and behavioral IRB” or the “minimal risk IRB”, in fact… • reviews any research that is not technically clinical intervention research as well as research that is greater than minimal risk. • additional bone marrow aspirates; • additional blood draws; • tissue repository research etc.

12. DFCI IRBs • IRB E: • “rapid response IRB” • small number of members and can respond quickly to an emergent situation.

15. JHU-FDA Warning Letter to PIMarch 31, 2003 • “Our records indicate that you are aware of your sponsor obligations…we note that on September 15, 1997, you submitted an IND application to the FDA…(FDA) notified you in writing on October 24, 2997, that you were prohibited from initiating any of the submitted protocols due to significant safety concerns and other protocol deficiencies… including inadequate chemistry, purity, and pre-clinical data; inadequate and confusing study procedures and protocols, lack of inclusion criteria, discontinuation criteria, and defined safety parameters; and lack of methodology for adverse event monitoring, treatment, and follow-up of subjects.”

17. Government Shutdowns • Massachusetts Eye and Ear Infirmary • UCLA • VA Health Sys. Greater Los Angeles • Rush Presbyterian St Luke’s Med Ctr. • University of Illinois Chicago • Duke University Med Ctr. • Univ. Texas Medical Branch Galveston • University of Oklahoma Tulsa • Johns Hopkins University

18. Still happens… Weill Medical College, May 2004 • OHRP Action • In view of the above determinations and in order to ensure adequate protections for human subjects, OHRP hereby restricts the WMC assurance (FWA 93), pending satisfactory completion of the required corrective actions described below. • Required Actions • WMC must develop a satisfactory corrective action plan to address the above…

19. Historical Overview:International • Nazi Doctor Trials • Nuremberg Code – 1947 • Informed Consent • Declaration of Helsinki • World Medical Association • Ethical Principles for Medical Research Involving Human Subjects • 1964 (revised 2000)

20. Historical Overview • Public Health Service (PHS) Policy • Prior Review of Research by “Institutional Associates” (PPO 129, February 8, 1966) • United States Public Health Service • Syphilis Study at Tuskegee (1932 -1972)

21. Historical Overview:United States -- 1974 • Congressional Hearings • Senator Walter Mondale • Senator Edward Kennedy • HHS Regulations • National Research Act • National Commission for the Protection of • Human Subjects of Biomedical and Behavioral Research, July 12, 1974

22. Historical Overview:The Belmont Report – April 18, 1979

23. DHHS Federalwide Assurance (FWA) FWA requires compliance with 45 CFR 46 for Federally Funded/Supported Research All FDA regulated research must comply with applicable FDA regulations even in the absence of Federal Funding or Support

24. Federal Oversight of Human Subject Research • Federal Policy for the Protection of Human Subjects (Common Rule) • Adopted 1991 • HHS Regulations • Revised 1981, 1991 • FDA Regulations • Revised 1981, 1991 • No Mandatory Protections if not covered by above

25. Federal Policy (Common Rule) for the Protection of Human Subjects • 18 Federal Agencies Adopted DHHS Subpart A • Some Agencies Required Additional Protections • VA requires compensation for research-related injuries • DoD additional level of review (e.g., HSRRB) for certain types of research • Some Agencies Never Adopted the Federal Policy • Department of Labor – Miners and Coal Dust • Appalachian Regional Commission – Telemedicine

26. DHHS Regulations:45 CFR Part 46 • Subpart A  Core Protections  Common Rule • IRB Review • Informed Consent • Subpart B  Additional Protections • Pregnant Women, Fetuses, and Neonates • Subpart C  Additional Protections • Prisoners • Subpart D  Additional Protections • Children

27. Core Human Subject Protections:Federal Policy (Common Rule), DHHS, FDA • IRB Review(DHHS 45 CFR Part 46 and FDA 21 CFR Part 56) • Initial Review • Prospective Review of All Changes • Reporting/Review of Unanticipated Problems • Reporting/Review of Adverse Events • Continuing Review at Least Annually • Informed Consent(DHHS 45 CFR Part 46 and FDA 21 CFR Part 50) • Eight Required Elements • Written Documentation • Language Understandable to Subjects • No Coercion or Undue Influence • No Waiver of Subjects Rights

28. Roles and Responsibilities • Institution • Institutional Review Boards (IRBs) • Research Investigators • Sponsors • Data Safety Monitoring Boards (DSMBs)

29. Roles and Responsibilities:Institutional Responsibility • Institutional Commitment and Infrastructure • Authorized Institutional Official • IRB Chair, IRB Members, IRB Staff • Other Institutional Committees • Research Investigators and Co-Investigators • Study Coordinators and Research Staff • Everyone Else Involved in the Research Enterprise

30. Roles and Responsibilities:Authorized Institutional Official • Legal Signatory for Institution (e.g., Assurance) • Overall organizational responsibility • Ensure adequate placement of IRB within institutional structure • Ensure adequate resources for IRB (staff, computers, office space, etc.) • Inspire and enforce institutional culture of respect and compliance (e.g., oversight and monitoring of research)

31. Roles and Responsibilities:Institutional Review Board (IRB) • Review and Approve Proposed Research • Risks Minimized through Sound Research Design • Risks Reasonable Relative to Benefits • Subject Selection Equitable • Informed Consent Obtained • Informed Consent Documented • Privacy and Confidentiality Protections Adequate • Safety Monitoring is Adequate • Protections for Vulnerable Subjects are Adequate • Exercise Continuing Oversight of Research

32. Roles and Responsibilities:Institutional Review Board (IRB) • IRBs are also required to review HHS grants to ensure that the protocol submitted to the IRB is consistent with the grant application

33. Risks Minimized Through Sound Research Design • Family of Subject who died in Gene Therapy Trial sponsored by Targeted Genetics is suing the company, the IRB and the principal investigator. • The basis of the lawsuit is not so much objections to the informed consent document as the contention that “someone with a mild case of rheumatoid arthritis should not be enrolled in a gene therapy trial.” • The science of the protocol could not justify enrollment of this type of subject in the research.

34. Roles and Responsibilities:Principal Investigators • Accept responsibility for all aspects of the research • Ensure adequate training for entire research team • Ensure adequate supervision of entire research team • Know and ensure compliance with • All regulatory requirements • All IRB requirements • All protocol requirements • Ensure adherence to enrollment criteria • Monitor and report unanticipated problems and adverse events to sponsor and IRB

35. Applying the Regulations to Research Involving Human Subjects

36. Definition of Research:HHS, Federal Policy (Common Rule) • “Research” means: • A systematic investigation • Designed to develop or contribute to • Generalizable knowledge • Includes: • Research development • Testing • Evaluation • Pilot Studies

37. Definition of Research • “Research” means: • A systematic investigation designed to develop or contribute to generalizable knowledge • What does “Systematic” mean? • Carried out according to a plan • Permitting logical conclusions to be drawn • What does “Generalizable” mean? • Beyond the immediate situation • Beyond the institution

38. Manhattan Eye, Ear and Throat Hospital Incident

39. Definition of Human Subject: • “Human Subject” means: • a living individual • about whom an investigator…conducting research obtains: • data through intervention or interaction with the individual, or • identifiable private information -- 45 CFR 46.102(f)

40. Definition of Human Subject:helicobater pylori discovery • Boston Globe, Thursday Oct. 6, 2005 • Madeline Drexler, “A Triumph for Scientific Freedom” • Article on Nobel prize winners Barry J. Marshall, J. Robin Warren

41. Definition of Human Subject:helicobater pylori discovery (cont.) • “At first, Marshall couldn’t produce the crowning scientific proof of his claim: inducing ulcers in animals by feeding them the bacterium. So in 1984, as he later reported in the Medical Journal of Australia, “a 32 year old man, a light smoker and social drinker who had no known gastrointestinal disease or family history of peptic ulceration”-a superb test subject, in other words… swallowed the growth from a flourishing three-day culture of the isolate.”

42. Definition of Human Subject:helicobater pylori discovery (cont.) • The volunteer was Marshall himself. • Five days later, and for seven mornings in a row, he experienced the classic and unpretty symptoms of severe gastritis.

43. VCU Twin Study

44. Definition of Human Subject: • “Private Information” means: • Information about behavior in a context in which an individual can reasonably expect that no observation or recording is taking place • Information, provided for specific purposes, that the individual can reasonably expect will not be made public (e.g., a medical record) -- 45 CFR 46.102(f)

45. Definition of Minimal Risk • Definition impacts: • Pediatric Studies • Important for determining whether a research protocol or change in research can be expedited or must go to the full board. • Waiver of Consent • Document of Consent

46. Definition of Minimal Risk:FDA, HHS, Federal Policy • “Minimal Risk”means: • The probability and magnitude of harm or discomfort • Are not greater than those ordinarily encountered in daily life; or • During the performance of routine physical or psychological examinations or tests.

47. IRB Requirements and Procedures

48. Institutional Review Board (IRB):Mission, Duties, Authorities • Mission To protect the rights and welfare of individuals participating in research involving human subjects • Duties To approve, disapprove, modify, suspend research as necessary to ensure protections for human subjects in research • Authority To exercise final authority within the institution for ensuring adequate protections for subjects. Officials of the institution may not approve research if it has not been approved by an IRB. • Institutional Authority Beyond Regulations Delegated to IRB • Ethical Issues on behalf of institution • Sanctioning Investigators for noncompliance • Use of “tainted” data

49. Institutional Review Board (IRB):Composition • Minimum of 5 members • Diverse in gender and racial background • Sufficiently qualified in experience and expertise • (e.g., pediatric expertise required to review research involving children) • One scientific member • Non-scientific member • One member not otherwise affiliated with the institution • Expertise in vulnerable populations for regular review of such research

50. IRB Review and Approval • Routine oversight mechanisms: • Initial Review • Continuing Review • Review of Adverse Events • Review of Unanticipated Problems • Special oversight mechanisms • Data & Safety Monitoring Boards (DSMBs) • Consent Monitors • Random Audits of Research • Continuing Education