IRBs and the Practice of Research Ethics

1. IRBs and the Practice of Research Ethics November 7, 2012

2. Objectives • Abbreviated historical context • What is an IRB? • Review criteria • Informed Consent • Confidentiality • Conflicts of Interest • Vulnerable Populations • Challenges for faith-based care

3. The technological imperative • “When you see something that is technologically sweet, you go ahead and do it and you argue about what to do about it only after you have had your technological success. That is the way it was with the atomic bomb.” ---J. Robert Oppenheimer

4. Concerns about Baby Fae’s surgery (1984) • Experimental rather than therapeutic nature of the transplant (alternatives were available) • Lack of prior peer review of the research • Hospital’s refusal to release protocol or consent forms • Quality and extent of information conveyed to parents

5. History and Context • Nuremberg Code (1947) • Thalidomide in the US (1960-62) • Declaration of Helsinki (1964) • Henry K. Beecher in NEJM (1966) • Tuskegee Syphilis Study (1932-73) • National Research Act (1974) • Belmont Report (1979) • The Common Rule (1991)

6. The Nuremberg Code (1947) • Voluntary consent is “absolutely essential” • Primacy of individual good over societal benefit (important results do not justify unethical studies) • http://www.hhs.gov/ohrp/archive/nurcode.html

7. Thalidomide in the US(1960-62) • 1962: Dr. Frances Oldham Kelseyreceived the medal for Distinguished Federal Civilian Service from President John F. Kennedy.

8. The Declaration of Helsinki (1964) • Animal welfare (12) • Dependent relationship (23) – “the therapeutic misconception” • Permission and assent (24, 25, 26) • Publication ethics (27) • Controversy over placebo trials (footnote)

9. “Ethics and Clinical Research”Henry K. Beecher, 1966 • Applied principles of Nuremberg and Helsinki to US shores – problems “not uncommon” at top institutions • Consent problem • No ethical distinction between means and ends. • Publication of unethically obtained data requires at a minimum, stern editorial comments, and perhaps should not be published at all.

10. Dr. Beecher • “An experiment is ethical or not at its inception; it does not become ethical posthoc – ends do not justify means. There is no ethical distinction between ends and means.”

11. Tuskegee Syphilis Study (1932-73) • As of May,1980 50 surviving wives and 20 surviving children were receiving full medical care for syphilis that was definitely the result of untreated syphilis in their husbands and fathers. The estimated cost of care for family members of men in the study was $139,000,000. (James H. Jones, Bad Blood: The Tuskegee Syphilis Experiment [New York: Free Press, 1981])

12. National Research Act (1974) • Established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research • Codified the role of IRBs

13. Commission’s charge: • Identify basic ethical principles that should underlie biomedical and behavioral research and develop guidelines for carrying out that research on humans.

14. The Belmont Report (1979) • Boundaries between research and practice • Respect for persons: Nature & definition of informed consent • Beneficence: Assessing risk-benefit in human subject research • Justice: Guidelines for subject selection

15. Dr. Robert J. LevineEthics and Regulation of Clinical Research (1986) • “The behavior-prescribing statements contained in the various codes and regulations on research involving human subjects may be regarded as variants of five general ethical norms. . . In addition, a sixth general ethical norm has begun to appear in some guidelines” (p. 19).

16. The Question: • How do we implement/act upon the foundational ethical principles identified in the Belmont Report? What norms should govern our behavior?

17. Six Ethical Norms for Human Subject Research • Good research design • Competent investigator (scientific training, clinical care, ethical competence) • Favorable balance of harm and benefit • Informed consent • Equitable selection of subjects • Compensation (research-related injuries)

18. The Common Rule (1991) • The laws of sixteen federal agencies regulating HSR in the US were consolidated into one body of law • Note: The FDA rules are contained in a separate code, although insofar as they pertain to IRBs they are quite similar to the Common Law (example: categories for pediatric research – see handout)

19. What is an IRB? “The Commission believes that the rights of subjects should be protected by local review committees operating pursuant to federal regulations located in institutions where research involving human subjects is conducted. Compared to the possible alternatives of a regional or national review process, local committees have the advantage of greater familiarity with the

20. actual conditions surrounding the conduct of research. Such committees can work closely with investigators to assure the rights and welfare of human subjects are protected and, at the same time, that the application of policies is fair to the investigators. They can contribute to the education of the research community and the public regarding the ethical conduct of

21. research. The committees can become resource centers for information concerning ethical standards and federal requirements and can communicate with federal officials with other local committees about matters of common concern.”

22. What is an IRB? • Administrative body (local review pursuant to federal regulations) • Specialized ethics committee • Educational resource for the research community and the public • Points of contact with federal officials and other local committees

23. Role & Function of IRBs • Ensure that the IRB functions with as much organizational independence as possible • Independent from the research enterprise (funding, collaborations with industry, etc.) • Mark Yessian (OIG): “IRBs are the only ones in the research process that exist solely to protect human subjects.”

24. Avoid actual and apparent/potential conflicts of interest, not only as a matter of institutional integrity, but also in preservation of the public trust • Work collegially with other institutional offices that play an important role in human subject research

25. Regulatory Requirements • Must have at least five members • Varying backgrounds • Diversity of gender and professions • At least one non-scientific member • At least one community member • Avoid conflicts of interest • Ad hoc members as need to review particular protocols

26. Review, Approve, Monitor • Initial review (protocol, recruitment materials, and consent/HIPAA) • Approval (Board has found project to be ethically and scientifically sound) • Post-approval: • Amendments (risk and no risk) • Deviations • Adverse events / unanticipated problems • Continuing review (at least annually)

27. Levels of Review(categories of risk) • Full (more than minimal risk)– must be reviewed by entire board • Expedited (no more than minimal risk) – may be approved by chair or designee; may only be refused by entire board • Exempt (educational & truly anonymous research– IRB review not required (but IRB may choose to review) IRB ultimately determines level of risk. Retrospective review is forbidden by law.

28. Risk • Risk: The probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study. Both the probability and magnitude of possible harm may vary from minimal to significant. Federal regulations define only "minimal risk."

29. Minimal Risk (OHRP) • Minimal Risk: A risk is minimal where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests [Federal Policy §___.102(i)]. For example, the risk of drawing a small amount of blood from a healthy individual for research purposes is no greater than the risk of doing so as part of routine physical examination.

30. Note • The definition of minimal risk for research involving prisoners differs somewhat from that given for noninstitutionalized adults. [See 45 CFR 303(d) and Guidebook Chapter 6, Section E, "Prisoners."]

31. Risk includes • Physical • Psychological • Social • Economic

32. Risk Assessment and Disclosure • Nature of risks • Severity • Frequency Note: Specific review criteria are provided by law (FDA and DHHS) with exceptions and/or additional rules for particular categories of research

33. Informed Consent • A process, not an event • Elements: • Information (not “data”) – see handout • Decisional capacity ( legal competence) • Voluntariness – no coercion, manipulation, undue influence • Special considerations, e.g. vulnerable populations

34. Informed Consent(required by law) • Study involves research • Purpose of research • Duration of participation • Procedures to be followed • Which procedures are investigational or performed for research purposes only • Foreseeable risks/discomforts

35. Informed Consent(required by law) • Benefits to subjects (direct) or others (indirect) – payment for participation is not a benefit • Alternatives, if any • Extent to which confidentiality of records will be maintained

36. Informed Consent(required by law) • For research involving more than minimal risk: • Is compensation available • Are medical treatments available if injury occurs • What are those treatments /OR/ where further information may be obtained Note: “Each IRB needs to articulate its own financial reasonableness standards for research-related costs in order to evaluate whether subjects are adequately protected” (KM Hunt in Amdur & Bankert).

37. Informed Consent(required by law) • Contact info for questions about: • Research procedures, side effects, etc. • Rights as a research subject • Occurrence of research-related injury • Participation is voluntary therefore refusal to participate will involve no penalty or loss of benefits • Right to withdraw at any time

38. Informed Consent (required by law “when appropriate”) • Disclosure of unforeseeable risks to subject, embryo, or fetus • Anticipated circumstances under which subject may be withdrawn by investigator without regard to consent • Additional costs that may result from participation in research

39. Informed Consent (required by law “when appropriate”) • Consequences of withdrawal and procedures for “orderly termination” • Approximate number of subjects in the study • Significant new findings arising during the research which may relate to subject’s consent for continued participation will be provided Note: This includes negative results and “gag orders” Sponsors may want in contracts

40. Pediatric Consent • Only the research subject can consent • Therefore: • Parents give permission • Children provide assent when appropriate

41. Assent • Assent = “a child’s affirmative agreement to participate in research.” • Note: passive resignation to submit ≠ assent • Federal regs do not define “informed assent” and do not specify an age

42. Ethical Guidelines • Just as we should conduct research on adults before children when possible, research should be conducted on children who can provide assent before those who cannot (when possible)

43. Remember this distinction: • Protecting confidentiality ≠ anonymity • If there is any LINK that identifies research subjects the research is not truly anonymous (though it may qualify for expedited review). • Generally it is difficult (though not impossible) to conduct medical research that is truly anonymous. • You need a consent OR a HIPAA waiver.

44. Definition • Any conflict between research or other professional scientific judgments and financial or personal interests where acting with disregard tot hat conflict by placing one’s personal or financial interests ahead of professional interests compromises or detrimentally influences professional judgment in conducting or reporting research.

45. Conflicts • Recognize and avoid • Recognize and Disclose (avoid the appearance of a conflict) • Recognize, Disclose, and Remedy (end if necessary) • Remember: each interest may in itself be legitimate, but the interests cannot co-exist without conflict.

46. Conflicts of Interest and Commitment • Financial or Service (consultant, peer reviewer, etc.) • Role (PI or entrepreneur?) • Time (multiple responsibilities) • Institutional (endowments, patents, etc.)

47. Vulnerable Subjects OHRP lists these: • Embryos (in vitro vertilization) • Fetuses • Children • Women • Cognitively impaired • Prisoners

48. Vulnerable Subjects OHRP list continued: • Traumatized and comatose • Terminally ill • Elderly and aged • Minorities • Students, employees and normal volunteers • Subjects in international research

49. NOTE: • It is not inherently unethical to conduct research on vulnerable subjects. • The ethical requirement is to protect those subjects from being coerced or exploited. • Therefore your research plan (IRB application) should explain what protections you will have in place. • Women of CBP are considered vulnerable but should not be routinely excluded.

50. Jay Katz • The central issue in HSR = “the morality with which the invitation to participation in research is extended so that the rights of subjects to be secure in their person and body remain sacrosanct.”