IRB Workshops

1. IRB Workshops Initially will be given in three parts 1. Human subject research ethics History of research ethics History of unethical research 2. Regulatory IRB responsibilities Investigator responsibilities Informed consent requirements 3. Logistics Office contacts Completion of forms and reports

2. What Do These Institutions Have in Common? -Rush Presbyterian - St. Luke’s Medical Center -West Los Angeles VA Medical Center -Duke University -The University of Illinois at Chicago -The City University of New York -Mt. Sinai School of Medicine -University of South Florida -University of Colorado

3. Origins of Human Subject Research Ethics  Hippocrates (~400 B.C.) -medical practice and medical ethics -physicians should “abstain from whatever is deleterious and mischievous.” -does not deal with research or experimentation with human subjects -does not mention the principle of informed consent

4. Origins of Human Subject Research Ethics (Cont.) Thomas Percival (1803) -code of medical ethics -”…and new methods of chirurgical treatment should be devised but … should be scrupulously and conscientiously governed by sound reason, just analogy, or well-authenticated facts … previous consultation of the physicians or surgeons to the nature of the case.” -must have good methods and competent investigators -no mention of consent

5. Origins of Human Subject Research Ethics (Cont.) William Beaumont (1833) -Oldest American document dealing with research -Experimentation is needed; information cannot be otherwise obtained -Investigator must be conscientious and responsible; methodological approach; no random studies -Voluntary consent is necessary -Discontinuation of experiment when it causes distress to the subject or the subject objects or becomes dissatisfied

6. Origins of Human Subject Research Ethics (Cont.) Claude Bernard (1865) -Textbook - “An Introduction to the Study of Experimental Medicine” -Permissible to save, cure, or gain personal benefit for the subject -Can’t be harmful to the subject in the name of science -”Those [experiments] that can only harm are forbidden. Those that are innocent are permissible, and those that may do good are obligatory.”

7. Origins of Human Subject Research Ethics (Cont.) The 1900 Prussian Directive -Response to public debate on human subject experimentation -Prohibited experiments in minors and those not fully competent -Unequivocal consent required after explanation of the experiment and possible adverse consequences -Only certain people were allowed to do the research and they must keep written records -Did not apply to medical treatment for diagnosis, therapy, or immunization

8. Origins of Human Subject Research Ethics (Cont.) Reich Health Council Regulations (1931) -14 points which demanded complete responsibility of the medical profession for carrying out human experimentation -General, technical, and ethical standards -Informed consent necessary -Documented justification of protocol deviation -Risk - benefit analysis required -Justification for studying vulnerable populations -Necessity for written records

9. Problems With Human Subject Experimentation: Relationship to codes of research ethics From Hippocrates to Percival -Uncontrolled, unscientific human experiments; Purely empirical -Vivisection was common -Experiments on Condemned Criminals --Newgate Prison (1721) - offered pardons for participation in “inoculations” -Jenner (1776) inoculated an 8 yr old boy with cowpox material

10. Problems With Human Subject Experimentation: Relationship to codes of research ethics Beaumont -Gunshot wound; open fistula tract; physiology of the stomach -Consent was needed and obtained Bernard -Supported using dying patients in experiments that caused no suffering -Endorsed giving intestinal parasites to a condemned woman to be examined at autopsy -Practice what he preached?

11. Problems With Human Subject Experimentation: Relationship to codes of research ethics 1900 Prussian Directive -Response to “Case of Neisser” -Dr Neisser studied immunization of healthy persons against syphilis by inoculating them with serum from syphilitic patients -3 prostitutes inoculated; all contracted syphilis -No consent obtained Reich Health Council -75 children died in experiments with tuberculosis vaccinations

12. Problems With Human Subject Experimentation: Nazi Germany Dr. Mengele’s Experiments -Infected one twin with a “germ”. When he/she died, the other twin was killed and their organs compared at autopsy. “No one ever attempted to explain anything to us. There was never an attempt to minimize our risks…we were there for one reason: to be used as experimental object and then to be killed.”

13. Problems With Human Subject Experimentation: Nazi Germany Dr. Mengele’s Experiments (Cont.) -Sewed twins together to create a Siamese twin -Studied subjects with genetic defects and genetic traits so as to better “purify the Aryan superrace” -performed cross transfusions to “make boys into girls and girls into boys”

14. Nazi Military Experiments

15. Problems With Human Subject Experimentation: Nazi Germany Experiments with Military Relevance -High altitude simulation -Malaria pathogenesis and treatment -Bone, muscle and nerve regeneration and bone transplantation -Rendering sea water drinkable -Endemic jaundice -Chemical sterilization -Typhus pathogenesis and treatment

16. Nuremberg Doctor’s Trial

17. Post War Response “The Case Against the Nazi Physicians” Nuremberg Doctor’s Trial - 1946-47 -23 defendants; 3 non-physicians -15 found guilty -7 were hanged (4 physicians) -5 sentenced to life in prison -4 sentenced to 10-20 yrs in prison -7 were acquitted and freed Separate Trial -31 “underlings” were also found guilty; 22 of them were hanged

18. Post War Response Nuremberg Code of Medical Ethics - “first authoritative , most stringent pronouncement on the rights of research subjects” (Annas, 1992) -adopted by the World Medical Association in 1948 -True informed consent; freely given; prior to experimental procedures -Truly necessary, well thought out experiments in which the expected benefits justify the risks and there is no unnecessary physical or mental suffering or injury

19. Post War Response: Nuremberg Code -The person performing the task is qualified ` -No experiment shall be undertaken where death or disabling injury will likely occur (except that experimental physicians can serve as subjects) -Proper preparation and adequate facilities to protect subjects must be present to prevent further injury -Subjects should be allowed to discontinue participation at any time -Upon observing the likely risk of injury, disability or death, the researcher should terminate the experiment

20. Acceptance of the Nuremberg Code: International World Medical Association (WMA) -Helsinki Declaration (1964) --praised the Code --rejected it for widespread use --modified the code -Further modifications --Tokyo (1975) --Hong Kong (1989)

21. Acceptance of the Nuremberg Code: U.S. Dr. Henry Beecher - NEJM (1966) -Criticized the lack of sincerity in implementing the basic concepts of informed consent -Cited 50 episodes of potential “Code” violations which were published in peer-reviewed scientific journals in the U.S. -Suggested that journal editors reject articles based on violations of patient rights

22. Reaction to Beecher’s Comments Feb. 1966 -NIH required establishment of IRBs for institutions receiving $ for medical research -Medical, nursing and lay-public members -Review & approve research protocols prior to conducting experiments July 1966 -UTMB policy accepted by PHS May 1967 -UTMB extended the policy to all research

23. Reactions (cont.) 1969, 1971, 1973 -PHS policy modified *May 1974 -National Research Act: IRB review and approval of all research involving human subjects *Apr 1979 - Belmont Report Jan 1981 -HHS amended the policy to provide a framework within which IRBs would function 1985- Act amended -Codification (45 CFR Part 46)

24. Belmont Report  Principles -Respect for person’s autonomy (informed consent) -Beneficence - protect research subjects from harm (assessment of risks/benefits) -Justice - who bears the burden? Who receives the benefits (selection of subjects equitable and unbiased) Basis of all U.S. human research regulation

25. Research Regulations DHHS - 45 CFR Part 46  FDA - 21 CFR (First developed and promulgated 1962-1966) Part 50 (Informed Consent) Part 56 (IRBs) Part 312 (Drugs) Part 812 (Devices)  Department of Education 34 CFR Part 97 (All are reasonably harmonized)

26. DHHS (45 CFR 46): Special Protections  Fetuses, Pregnant Women, and Human In Vitro Fertilization - Minimal risks to fetus/mother - Must meet health needs of fetus/mother  Prisoners - Minimal risk/minor inconvenience - More than Minimal Risk with potential for benefit  Children - Anticipated benefit - Solicit assent of the child -Consent of the parents

27. Major Problems With Research Ethics in the U.S. ?

28. Major Problems With Research Ethics in the U.S. 1932-1972 -PHS study of the effects of untreated syphilis on black men in Macon County Alabama (“Tuskegee Study”) -399 men who already were in the late stages of syphilis -201Negative Controls -Treatment was available but not used

29. Major Problems With Research Ethics in the U.S.: Tuskegee Study -No formal protocol located; “procedures evolved” -Not a treatment study -Studied the effects of spontaneous evolution of syphilis on black males -Few of the physicians and none of the subjects really knew what the study involved -The men were told they had “bad blood”

30. Tuskegee “Round-up”

31. Major Problems With Research Ethics in the U.S.: Tuskegee Study Why participate? -Poor and illiterate; most had never seen a doctor before -Free physical exams -Free rides to the clinic -Hot meals on exam days -Free treatment for minor ailments -Burial stipends -Nurse Eunice Rivers

32. Nurse Rivers and the Tuskegee Study

33. Major Problems With Research Ethics in the U.S.: Tuskegee Study Nurse Rivers -Black Nurse, employed by the PHS who tracked participants -Spoke with the men and their families -Advised doctors not to treat them; “under study” -Subjects told that, if treated, they would be dropped from the study PHS Response - “mildly uncomfortable” Press later labeled it “racial medicine”

34. Major Problems With Research Ethics in the U.S.: Radiation Experiments Report from the Advisory Committee on Human Radiation Experiments (ACHRE) -81 examples of pediatric research projects --non-therapeutic nutritional studies at a school for retarded children --consent was sought without telling parents that radiation would be used --children “induced” to participate even if they refused

35. Major Problems With Research Ethics in the U.S.: Radiation Experiments Others -plutonium injections to study the effects of radiation -radioactive iodine given to mentally retarded children -total body irradiation on cancer patients (as research) -atomic bomb exposure (military) -several thousand government sponsored human radiation experiments and hundreds of intentional releases of radioactive material

36. Major Problems With Research Ethics in the U.S.: Others -Studies of hepatitis on mentally retarded children (Willowbrook) --inadequate consent --deliberately infected -Studies on prisoners --coercive inducements --cash --early release -Not limited to the above and still occur today; even with IRB oversight -Important to know what is acceptable and what is permissible in research