History, Ethics, and Regulations of Human Subjects Research

1. History, Ethics, and Regulations of Human Subjects Research Michael Mahoney Coordinator, IRB-01 University of Florida mmahoney@ufl.edu http://irb.ufl.edu/irb01/

2. Overview • “Where are we?” • Historical review • Violations • Guidance documents • Regulations • Apply regs & ethics • Where do we go from here?

3. PART I: Historical Context • Army Yellow Fever 1900 • Nazi Experiments1942-1946 • US Scandals1960s • Tuskegee Syphilis Study 1932-1972

4. Yellow Fever – 1900 • Expose volunteers to infected mosquitos • Consented subjects • Warned of death • Paid $100, +$100 if infected • 2 experimenters • Some spanish immigrants • Mostly soldiers • Could contract illness anyway, would get immediate medical attention in research.

5. Yellow Fever – 1900 “The undersigned understands perfectly well that in case of the development of yellow fever in him, that he endangers his life to a certain extent but it being entirely impossible for him to avoid the infection during his stay in this island, he prefers to take the chance of contracting it intentionally in the belief that he will receive from the said Commission the greatest care and the most skillful medical service.” “The undersigned binds himself not to leave the bounds of this camp during the period of the experiments and will forfeit all right to the benefits named in this contract if he breaks this agreement. And to bind himself he signs this paper in duplicate, in the Experimental Camp, near Quemados, Cuba, on the 26th day of November nineteen hundred. The contracting party,…”

6. High Altitude Freezing Malaria Epidemic jaundice Vaccination Sterilization Seawater LOST gas Sulfonamide Regeneration Poison Incendiary bomb Nazi Medical Experiments1942 – 1946

7. Nuremberg Code • Voluntary Consent of subjects. • Subject is free to stop. • PRIOR knowledge of disease/problem and/or animal experiments. • Experiment should have scientific benefits to society. • Benefits outweigh risks.

8. Nuremberg Code • Avoid all unnecessary suffering and injury (physical or mental). • No intentional death or disability. • Protect against injury, disability, and death. • Investigator to stop if injury, disability, or death likely. • Only qualified investigators.

9. GuidelinesDeclaration of Helsinki1964 • 32 Principals in three parts: • Basic Principles • Clinical Research • Non-therapeutic Research http://www.opt.auckland.ac.nz/public/staffpgs/myap/helsinki.html

10. GuidelinesDeclaration of Helsinki1964 • Clinical • Can use experimental treatment in emergencies. • Compare benefits and risks of research to best current standard methods. • All subjects, even controls, get best treatment. • The refusal of the patient to participate in a study must never interfere with the physician-patient relationship. • Must explain waivers of consent. • Research and medicine can be combined so long as there is potential benefit to the subject. http://www.opt.auckland.ac.nz/public/staffpgs/myap/helsinki.html

11. GuidelinesDeclaration of Helsinki1964 • Non Therapeutic • Researcher protects subjects. • The subjects should be volunteers. • The research should stop if continuing the research could be harmful to the subject. • The interest of science and society should never take precedence over the well-being of the subject. http://www.opt.auckland.ac.nz/public/staffpgs/myap/helsinki.html

12. U.S. First Action • 1966 NIH creates Office for Protection of Research Subjects (OPRR) • OPRR issues “Policies for Protection of Human Subjects” • First call for ethic board review

13. US Scandals 1960s Jewish Chronic Disease Hospital 1962 Milgram’s Obedience Study 1962 Willowbrook 1956 -1972 Radiation experiments Prisoner research

14. Tuskegee Syphilis Study1932-1972 • Federally Funded • 400 low-income African-American males • 40 years • Actively denied proven cure • At least 28 died of syphilis • 100 more suffered blindness and insanity • Death the ultimate outcome

15. U.S. Second Action • 1974 National Research Act • 1975 “Policies for Protection of Human Subjects” raised to regulatory status • 45 CFR 46 • Requires IRBs

16. 1978 National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research Belmont Report 1979

17. Belmont Report Cornerstones • Respect for Persons • Informed Consent process • Privacy and Confidentiality http://ohrp.osophs.dhhs.gov/humansubjects/guidance/belmont.htm

18. Belmont Report Cornerstones • Beneficence • Risk/Benefit Analysis • Scientific Merit http://ohrp.osophs.dhhs.gov/humansubjects/guidance/belmont.htm

19. Belmont Report Cornerstones • Justice • Review of subject selection http://ohrp.osophs.dhhs.gov/humansubjects/guidance/belmont.htm

20. 7 Ethical requirementsJAMA, Volume 283(20), May 24/31, 2000, 2701-2711 1. Value • Leads to improvements • Generate important knowledge • Disseminated 2. Informed consent • Does not ensure ethical research by itself

21. Ethical Requirements 3. Scientific validity • Good research questions • Answered by good research techniques 4. Fair subject selection • Scientific goals determines the subject base

22. Ethical Requirements 5. Favorable risk/benefit ratio • Risks identified • Minimized by research design • Potential benefits delineated • No formula 6. Independent review • Assures society that no misuse of humans will occur

23. Ethical Requirements 7. Respect for potential and enrolled subjects • Privacy/confidentiality • Permitting subjects to withdraw • New information shared with participants • Welfare carefully monitored • Recognize participant contribution – inform them of what was learned

24. Federal Regulations • DHHS Regulations for the Protection of Research Subjects • 45 CFR 46 (1976) • Federal Policy adopted in 1981 • Common Rule (1991) • FDA regulations • 21 CFR 50, 54, 56, 312, 812 (first in 1980) • OCR - HIPAA (2003)

25. OHRP: who, what? • Office of Human Research Protections • Department of Health and Human Services (DHHS) • Responsible for oversight of 45 CFR 46 • 45 CFR 46: covers ALL federally funded human subjects research • Assurance http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm

26. Assurance: what, who? • Assurance needed to receive federal funds for research • Institution “assures” OHRP that research will be conducted under 45 CFR 46 • Obligates institution, its officials, and researchers • UF FWA (FWA00005790) • Shands • VA • Outside locations?

27. Dept. of Agriculture Dept. of Energy Dept. of Commerce Dept. of HUD Dept. of Justice Dept. of Defense Dept. of Education Dept. of Veterans Affairs Dept. of HHS Dept. of Transportation NSF NASA EPA CIA Common Rule: Who is Covered?

28. FDA: who, what? • Food & Drug Administration • Separate set of regulations governing human subjects research when research involves an investigational drug or device. • The basic requirements for IRBs and for Informed Consent are congruent between OHRP and FDA. • However, FDA regs have some additional requirements.

29. FDA: who, what? • 21 CFR 50: Protect Human Subjects • 21 CFR 54: Financial Disclosure by Investigators • 21 CFR 56: Institutional Review Boards • 21 CFR 312: IND • 21 CFR 812: IDE Plus MANY more!

30. FDA: who, what? • NOT tied to OHRP’s federal assurance. • Applicable to any food or drugs transported across state lines, regardless of whether or not federal funding is received.

31. Federal Regulations vs. Guidance • Both OHRP and FDA publish Guidance about the Regulations. • Guidance ≠ Guidelines (Nuremberg Code, etc) • Guidance = government interpretation or implementation of regulations • MUST comply with regulations.

32. OCR: who, what? • Office of Civil Rights • Oversight of HIPAA – Health Insurance Portability and Accountability Act of 1996 • Protect Patient Privacy • Went into effect April 14, 2003

33. Why Ethics, Guidance, and IRBs? • Oct 30, 2003: “A former cancer researcher … was indicted by a federal grand jury … on charges of criminally negligent homicide, manslaughter, and fraud for allegedly falsifying medical records … in order to enroll [patients] in drug studies.”

34. Application to current research • What is a human subject? • What is human subjects research? • Examples of research • Examples that don’t need IRB approval • Examples of non-human research that need IRB approval

35. What is a human subject? • Human subjectmeans a living individual about whom an investigator (whether professional or student) conducting research obtains • data through intervention or interaction with the individual, or • identifiable private information. • 45 CFR 46.102.(f)

36. What is human subjects research? • “Researchmeans a systematic investigation, including research development, testing and evaluation, designedto develop or contribute to generalizable knowledge.” • 45 CFR 46.102.(d)

37. Examples of research • Retrospective review of medical records • Research involving tissue • Either with identifiable data • Direct collection from subjects • Therapeutic Research • Banking of tissue or data IRB APPROVAL REQUIRED.

38. Research? • Need IRB approval: • Anonymous tissue previously collected • Exempt research • Research involving decedent tissue/data (HIPAA)

39. Some examples that are not research • Do not need IRB approval: • Case reports • Designed to contribute to generalizable knowledge, but NOT a systematic investigation • Quality Assurance • Systematic investigation, but NOT to contribute to generalizable knowledge • NOTE: intent to publish = contribute to knowledge = research = IRB approval required!

40. Tissue Quality Assurance (no publication) Case Reports No IRB Approval Required IRB Approval Required Exempt Therapeutic / Clinical Research Chart review Surveys Decedent Research (HIPAA) Quality Assurance (publication)

41. Quality Assurance (no publication) Case Reports No IRB Approval Required IRB Approval Required Exempt Therapeutic / Clinical Research Chart review Surveys Tissue Decedent Research (HIPAA) Quality Assurance (publication) Under what authority do you have access to these subjects and/or their information?

42. IRB • IRB bases requirements on • Ethics • Guidelines • Regulations • Federal Guidance • Findings at other institutions • University policies

43. Institution HURRC IBC GCRC VA SCI R&D Accreditation Consent monitor / patient advocate CRO Research Sponsor(s) Other Protections

45. Where do we go from here?? • Mandatory Accreditation for HRPP • Mandatory education for researchers • Certification of researchers • Conflict of Interest (COI) • Additional protections for vulnerable populations • More litigation

46. Where do we go from here?? • Harmonization between committees • Streamlined electronic processing • Better Adverse Event Reporting

47. Links • Guidance, Regulations, UF Assurance, and IRB-01 Policy and Procedureshttp://irb.ufl.edu/ethics/ethicsregs.pdf • OHRP Web Site: http://ohrp.osophs.dhhs.gov/ • FDA Web Site: http://www.fda.gov/ • FDA Regs: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm • OCR Web site: http://www.hhs.gov/ocr/ • IRB-01 Web Site: http://irb.ufl.edu/irb01/ • UF FWA: http://irb.ufl.edu/FWA.htm • IRB-01 Policy & Procedures: http://irb.ufl.edu/docs/irb01ppmanual%20100603.doc

48. Recommended Reading Beauchamp, Tom L., and Childress, James F. Principals of Biomedical Ethics, 3d ed. New York; Oxford University Press, 1989 Beecher, Henry K. “Ethics and Clinical Research.” New England Journal of Medicine, 274 (1966): 1354-1360 Rothman, David J. Strangers at the Bedside; A History of How Law and Bioethics Transformed Medical Decision Making. New York: Basic Books, 1991 Rothman, David J. “Ethics and Human Experimentation: Henry Beecher Revisited.” New England Journal of Medicine, 317 (No. 19, November 5, 1987): 1195-1199. Sieber, Joan E. Planning Ethically Responsible Research: A Guide for Students and Internal Review Boards, Applied Social Research Methods Series, vol. 31. Newbury Park, CA: Sage Publications, 1992. U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. A complete list of the National Commission’s reports and recommendations is provided in Appendix 1.