Ernest D. Prentice, Ph.D. University of Nebraska Medical Center

1. BUILDING & SUSTAINING A TRIBAL IRBGUIDING PRINCIPLES OF THE BELMONT REPORT ARE THE CORNERSTONES OF HUMAN SUBJECT PROTECTION RESEARCH Ernest D. Prentice, Ph.D.University of Nebraska Medical Center Rapid City, SDJuly 11, 2005

2. Lecture Outline • Genesis of the Belmont Report • The Principles of the Belmont Report • Application of the Belmont Principles • Role and Responsibilities of the IRB

3. GENESIS OF THE BELMONT REPORT

4. Henry Beecher’s Exposé • 22 examples of unethical research • Highly funded investigators • Prestigious institutions • Declaration of Helsinki violated • Indictment of moral complacency NEJM 274:1354-60, 1966

5. “What seem to be breeches of ethical conduct in experimentation are by no means rare, but are almost, one fears, universal . . . Whoever gave the investigator the god-like right of choosing martyrs?” Henry Beecher, 1966

6. Exposés of Unethical Research(cont’d)1966 - 1972 • Willowbrook Hepatitis Study* • Jewish Hospital Cancer Study* • Tearoom Trade Study • Wichita Jury Study • Milgram Obedience Study • San Antonio Contraceptive Study • PHS Syphilis Study * cited by Beecher

7. The PHSSyphilis Study 1932 - 1972 The infamous study that was not supposed to die until the last of its subjects did.

8. PHS Syphilis Study 1932 - 1972 Purpose: Study natural history of untreated latent syphilis African-American men with syphilis (n=412; controls (n=204) Subjects: Design: No treatment, monitoring, follow-up tests, e.g. spinal taps, blood sampling, x-ray exams Harms: No treatment even when penicillin came online in the 1940’s. Subjects suffered adverse effects and early death

9. Question Did the medical community know about the PHS syphilis study?

10. Question What events led to the halting of the PHS syphilis study?

11. Buxton v. PHS • 1966 CDC is petitioned • 1967 Petition denied • 1969 CDC Panel Appointed • 1969 Panel Endorses Study • 1972 Heller Writes Exposé • 1972 Study Halted

12. Question What was the response of the U.S. Congress to Tuskegee and other unethical studies?

13. THE NATIONAL COMMISSION FOR THE PROTECTION OF HUMAN SUBJECTS OF BIOMEDICAL AND BEHAVIORAL RESEARCH Public Law 93-348 July 1974

14. Charge to the National Commission “Conduct a comprehensive investigation…to identify the basic ethical principles which should underlie the conduct of…research involving human subjects…” Public Law 93-348, Sec. 202(a)(1)(a)

15. National Commission Reports • Research on the fetus; DHEW No. (0S) 76-128, 1975 • Research involving prisoners; DHEW No. (0S) 76-131, 1976 • Research involving children; DHEW No. (0S) 77-0004, 1977 • Institutional Review Boards; DHEW No.(0S) 78-0008, 1978 • Delivery of Health Services; DHEW No. (0S) 78-0010,1978 • Research Involving…Mentally Infirm; DHEW No. (0S) 78-0006, 1978 • The Belmont Report; DHEW No. (0S) 78-0012,1979

16. 45 CFR 46 21 CFR 50, 56 The Belmont Report Justice Respect Beneficence The Common Rule

17. Protections of Vulnerable Human Subjects • 45 CFR 46, Subpart A (vulnerable subjects in general) • 45 CFR 46, Subpart B (pregnant women, fetuses) • 45 CFR 46, Subpart C (prisoners) • 45 CFR 46, Subpart D (children) • 21 CFR 56 (vulnerable subjects in general) • 21 CFR 50, Subpart D (children)

18. THE BELMONT PRINCIPLES & THEIR APPLICATION IN RESEARCH INVOLVING HUMAN SUBJECTS

19. Justice Recruit subjects fairly without discrimination, bias, or undue influence in order to distribute the burdens and benefits of research equitably for individual and Tribal/AI/AN good.

20. The Do’s & Don’ts of Applying “Justice” • Don’t target, or exclude, a subject population based upon convenience or availability. • Use less vulnerable subjects in research without direct benefit before using vulnerable subjects. • Guard against positional influence (e.g., physician and patient) during recruitment.

21. Respect for Persons Respect the autonomy of individuals by obtaining their informed consent or, in the case of persons with diminished or developing autonomy, obtain proxy consent from their legally authorized representative (LAR).

22. The Do’s & Don’ts of Applying“Respect for Persons” • Identify prospective subjects without violating their right to privacy. • Utilize a continuous, on-going consent process in consideration of the nature and duration of the research. • Obtain informed consent from subjects using the “reasonable volunteer standard” in an environment conducive to rational decision making. • Emphasize the process of informed consent as opposed to the consent document.

23. “RESPECT FOR PERSONS”(cont’d) • Ensure the subject understands all the elements of consent necessary to make an informed decision. • Involve the subject’s relatives and counselors in the consent process. • Minimize any risk that the subject may develop a therapeutic misconception about the research.

24. “RESPECT FOR PERSONS”(cont’d) • Obtain assent to the degree possible from persons with diminished autonomy and developing autonomy. • Honor a cognitively impaired person’s dissent to participate in research, except under compelling clinical circumstances. • Honor a child’s dissent to participate in research, except under compelling clinical circumstances in consideration of the age and cognitive ability of the child. • Treat every human subject with dignity and respect.

25. Beneficence Minimize all risks (i.e., potential harms) and maximize potential benefit(s) to the subject which are associated with research participation as well as potential benefit to society.

26. The Do’s & Don’ts of Applying “Beneficence” Minimize all potential harms to the greatest extent possible by ensuring the following: • All study personnel are qualified and kept up to date • Additional protections are in place for vulnerable subjects • Procedures with less associated risks are substituted whenever possible • Procedures are used that would normally be performed for treatment or diagnosis • Subjects are appropriately monitored in accordance with the nature and risk level of the research • Adverse events are promptly reported to the IRB • The subject withdrawal criteria are appropriate • A timely treatment plan is in place

27. “Beneficence”(cont’d) • Maximize the potential benefit(s) of the research by ensuring there is a sound research design, protocol compliance, and timely publication of results. • Ensure that the risks of the research are outweighed, or balanced, by potential benefit(s) to the subjects and/or to the Tribe/AI/AN. • Ensure there is a favorable risk/benefit relationship of the research compared with the available alternative(s) which offer the subject the prospect of direct benefit.

28. “BENEFICENCE”(cont’d) • Ensure upon conclusion of the research that every subject who was on study is provided access to the best available care in consideration of their clinical needs. • Ensure that every subject who withdraws from the study is provided access to the best available care in consideration of their clinical needs. • Ensure that study results are provided to the subjects and the Tribe. • Ensure that the rights and welfare of the subject always take precedence over the needs of science.

29. Question What is the role and responsibilities of the IRB?

30. IRB: “Gate Keeper” of the Belmont Principles “Investigators should not have sole responsibility for determining whether research involving human subjects fulfills ethical standards. Others who are independent of the research must share this responsibility. ” National Commission Report on Institutional Review Boards, 1978

31. Responsibilities of the IRB • Approve, disapprove, or modify research proposals and amendments • Conduct continuing review of IRB approved research • Observe/monitor/audit on-going research • Suspend or terminate approval of research 45 CFR 46.109; 21 CFR 56.109

32. Question From where does the IRB derive it’s authority?

33. Authority of the IRB • Common Rule • 45 CFR 46 • 21 CFR 56, 50 • 21 CFR 312 • 21 CFR 812 • Institutional policies • Federal Wide Assurance

34. Question What is the HHS definition of human subject research?

35. Answer Human subject research means a systematic investigation involving a human subject (living individual), including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. 45 CFR 46.102(e)(f)

36. Question What are the criteria for IRB approval of research?

37. Criteria for IRB Approval • The risks to the subjects are minimized (B) • The risk-benefit relationship of the research is acceptable (B) • The selection of subjects is equitable (J) • An appropriate study monitoring plan is in place (B) • The process of informed consent and the ICF are appropriate (R) • Obtainment of informed consent will be appropriately documented (R) • Privacy of subjects and confidentiality of data are appropriately protected (B) • Appropriate additional protections are in place for vulnerable subjects (R, B) 45 CFR 46.111; 21 CFR 56.111Beneficence (B), Justice (J), Respect for Persons (R)

38. THE RISK-BENEFIT RELATIONSHIP OF RESEARCH

39. Requirement The investigator and the IRB should minimize the risks to the subjects, maximize potential benefits, and ensure achievement of the most favorable risk – benefit relationship in the research as possible in consideration of available alternatives that may be advantageous to the subjects. (Beneficence)

40. Question What is the definition of a risk?

41. Definition of Risk A potential harm, discomfort or inconvenience, which can affect either the subject and/or the Tribe, which is considered significant in deciding whether or not to participate in the research. This is based on what the investigator knows or should know to be the subject’s position and the position of the Tribe.

42. Research Risk Umbrella Harm Individual Subject Discomfort Physical Psychological Social Economic Legal Inconvenience Tribal Community

43. Question How can the risk(s) of the research be minimized to the greatest extent possible to ensure subject safety and prevent harm to the Tribe?

44. Minimization of Risk • Initial and on-going consultation with the Tribal Council and feedback to subjects • All study personnel should be qualified and kept up to date • Additional protections should be in place for vulnerable subjects • Procedures with less associated risks should be substituted whenever possible • Procedures should be used that will already be performed for treatment or diagnosis • Subjects should be appropriately monitored to ensure their safety • Unanticipated adverse events and problems should be promptly reported to the IRB, OHRP, FDA, and the sponsor • Appropriate subject withdrawal criteria should be in place • A timely treatment plan should be in place

45. Question What is the definition of a benefit to be derived from research?

46. Benefit A benefit is a value that may be derived from the research. Benefit(s) may accrue to the subject directly (e.g., health improvement) and/or to the Tribe (e.g., development of disease prevention programs).

47. Question How does an investigator (and the IRB) perform a risk-benefit assessment?

48. Research Risk and Benefits Compared With the Alternatives Clinical Equipoise Drug A DrugB RCT- Alternative Drug C

49. Clinical Equipoise “Clinical [research] equipoise means a genuine uncertainty on the part of the expert medical community about the comparative therapeutic merits of each arm of a clinical trial. The tenet of clinical equipoise provides a clear moral foundation to the requirement that the health care of subjects not be disadvantaged by research participation.” Canada Tri Council Policy: August 1998

50. Question What is the final take home message?