Human Research Ethics

1. Human Research Ethics Roger L. Bertholf, Ph.D. Associate Professor of Pathology Chief of Clinical Chemistry & Toxicology University of Florida Health Science Center/Jacksonville

3. The Nuremberg Trials • The International Military Tribunal (1945) • The Doctors Trial (1946) • The Nuremberg Code (August, 1947)

4. Defendants and Defense Counsel 15 of 23 guilty, 7 hanged, 5 life sentences

5. The Nuremberg Code • Established necessity of informed consent • Introduced concept of beneficence • Introduced the notion of proportionality between risk and benefit

6. “Before IRBs, the only consent required was that of a researcher's department head. The Nuremberg Code was ignored in practice. As I look back on it, the interpretation of these codes was that they were necessary for barbarians, but not for fine upstanding people . . .” Dr. William Silverman, Columbia pediatrician, on the postwar mentality

7. Jewish Chronic Disease Hospital Brooklyn, 1963 • Elderly debilitated patients injected with live cancer cells to study immunologic response (per transplant rejection) • Patients not informed of cancer cells • investigators did not wish to frighten unnecessarily • a priori hypothesis that cells would be readily rejected

8. “ . . . the judgment of the investigator is not sufficient as a basis for reaching a conclusion concerning the ethical . . . set of questions.” NIH panel that investigated studies at Jewish Chronic Disease Hospital “The investigator’s judgment must be subject to prior peer review to ensure an independent determination of risks and benefits and . . .voluntary informed consent.” NIH Director James Shannon, endorsed by Surgeon General William Steward, Feb 1966

9. The Declaration of Helsinki • Adopted by the World Medical Association in 1964 • Provided guidelines for the conduct of human subjects research • Institutional Review Boards • “generally accepted scientific principles” • Distinction between clinical and basic research • Placebo controversy

10. The Tuskegee Syphilis Study • PHS initiated syphilis treatment program in 1928 • Discovered 35 – 40% infection rate in Macon County, AL • Revised study to observation only • Enlisted help of the Tuskegee Institute • Terminated in 1972

11. Philadelphia Enquirer, 1972

12. “Ethical lapses are almost never cases of bad people, doing bad things, for no good reason. Rather, they are good people, doing bad things, for good reasons.” Loosely quoting Marcia Angell, MD former Editor-in-Chief, NEJM

13. US National Research Act (1974) • Established National Commission for Protection of Human Subjects • The Belmont Report, 1979 • Code of Federal Regulations, 1974, 1981 • Institutional Review Boards (IRBs) • Common Rule, 1991

14. The Belmont Report • Drafted by the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research • Final version adopted in 1979 • Three sections: • Clinical practice vs. research • Three guiding principles of ethical research • Application of the three principles

15. Clinical practice vs. research • What is the purpose of the activity? • Are results generalizable? • Example

16. Three Guiding Principles of Ethical Research • Respect for Individuals • Beneficence • Justice

17. Respect for Individuals • Individuals act as autonomous agents • Individuals who are not capable of acting as autonomous agents are entitled to special protections • Minors • Mentally incapacitated persons • Prisoners

18. Beneficence • Guided by two basic principles: • Do no harm • Maximize benefits and minimize potential harms • Risks should be in proportion to potential benefits • Research design should ensure valid results

19. Justice • Benefits and risks of human research should be fairly distributed • Social vs. individual justice

20. Federal Regulations • 45 CFR 46 • The Common Rule (Part A) • Subparts B, C, and D • 21 CFR 50 and 56 • 50 includes rules for clinical trials • 56 describes IRB responsibilities

21. Oversight of human research GAO, OIG, OHRP, DHHS, NIH, FDA, AAMC, AAU, NBAC, Congress, media…

22. Univ of Minnesota UCLA Univ of Rochester Rush Presbyterian West LA, VA Hosp Duke Univ Univ of Ill - Chicago U Colorado VCU/MCV UA-Birmingham Univ of Pennsylvania Univ of Oklahoma UTMB-Galveston Johns Hopkins INSTITUTIONS SANCTIONED BY FEDERAL AGENCIES

23. Case #1:The Academic Pathologist A pathologist submits a protocol that would involve saving surgical specimens submitted from prostate surgeries for future studies using a new immunohistochemical method that may help predict the long term survival of prostate cancer patients. She believes her research is exempt from IRB review, since it does not put subjects at any risk, and involves tissues that would be discarded anyway.

24. Case #1 Questions • Does this protocol need to be submitted for IRB review? • YES! All research involving human subjects must be submitted for IRB review. • What criteria must be met in order for research to be exempted from IRB review?

25. Criteria for Exemption from IRB review • “Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.” 45 CFR 46.101(b)(4)

26. Exemption from IRB review • One of the key words in the statute is “existing.” Why does it make a difference if the data already exists or not? • Does the existence of the research protocol affect the collection of the specimen (the intervention)? • Can the project be carried out without identifying the subjects? • Protocols that do not record any subject identifiers can often be exempted from IRB review

27. Assessing Risk • Do you agree that the project does not put the subjects at any risk whatsoever? • If not, then what is the risk to subjects? • Risk of discovering a prognostic marker • Violation of of a subject’s autonomy, by including them in a research project without their knowledge or consent

28. Expedited Review • If this project is not exempted from IRB review, can its review be expedited? • What are the criteria that must be met for expedited review? • “Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for non-research purposes (such as medical treatment or diagnosis).” 63 FR 60364-60367, November 9, 1998.

29. Case #2:A Deal You Can’t Refuse A local biotechnology company is developing a test for genetic markers of asthma. As part of their validation protocol, the company needs to correlate the presence of the markers with asthma. They have offered your lab $150 for each blood specimen from a patient with the diagnosis of asthma. To protect themselves in case their records are audited, the company will require you to maintain a “key” that can be used to identify the source of each specimen, if necessary.

30. Questions for Case #2: • Does this protocol need to be submitted for IRB review? • Does this research involve any risk for the subjects? • Is payment for research specimens (or subjects) legal and/or ethical? • What are the principal concerns an IRB should have with this protocol?

31. Is the research exempt from review, or eligible for expedited review? • It is not exempt • Because patient identifiers will be maintained, it does not qualify for exemption • It may qualify for expedited review • Only if the risk is deemed minimal

32. Does the research involve risk for the subjects? • A genetic predisposition to asthma may affect a subject’s insurability • Does it make any difference that the patients have already been diagnosed with asthma?

33. Is payment for research subjects legal and/or ethical? • In some cases, it would be unethical not to pay subjects • The principle of justice requires that burdens and benefits of research are fairly distributed • However, money should not be used as an incentive to participate • Are patients entitled to be informed when their blood is sold to private research companies?

34. Summary of IRB concerns • Is there a potential for future harm to subjects based on the information produced by the research? • Is the method for obtaining specimens fair and ethical? • Can the research be carried out if informed consent is required?

35. Case #3:Who’s the research subject? The manufacturer of a new birth control device wants to determine whether use of the device causes any side effects in women. Previous studies have demonstrated that the device is about 85% effective. Subjects must be fertile, discontinue any other form of birth control, and be involved in a monogamous sexual relationship. The purpose of the study and potential risks are adequately explained in the consent form, which the subject must sign to enroll. The device is free to participants, but no other payment is offered.

36. Questions for Case #3: • What are the risks and potential benefits of this study? • The IRB must ensure that any risks associated with participation in research are balanced by potential benefit • Should the sexual partner be considered a research subject also, and sign a consent?

37. Does the study have a favorable risk/benefit ratio? • How does a 15% failure rate compare to standard birth control methods? • What are the benefits of the new birth control device?

38. Should the sexual partner’s consent be required? • Is the sexual partner considered a “research subject?” • The statutes define human subject as: “. . .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.” • Intervention is further clarified as including: “. . .both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes.”

39. Human Protections Rubrick • Does the research involve human subjects? • Does the research involve risk to participating human subjects? • Do the potential benefits of the research justify the risk involved? • Has the protocol been designed to minimize risk to participants?

40. Case #4: Heroic Measures An ED physician wants to determine whether massive doses of TPA can help revive patients who have not responded to conventional resuscitative measures. He will only use this therapy in patients who otherwise would be pronounced dead. He submits a protocol that defines explicitly the circumstances under which a patient will become a candidate for the protocol, and requests a waiver of informed consent.

41. Case #4 Questions • What are the risks to subjects in this project? • Should informed consent be required? • Do you think the IRB should approve this protocol? • If so, should a signed informed consent be required?