1. Phil/Mbiol 7570, Fall 2007 Bryan Benham Ethical Issues in Research with Human Participants 1

2. Outline Why Protections for Human Participants? Ethical Principles: Belmont Report Additional Considerations

3. Human Subjects? Any “living individual(s) about whom an investigator conducting research obtains: (1) data through intervention or interaction with the individual; or (2) identifiable private information” Exemptions include research involving established educational settings, use of educational tests, involving use of existing data if unidentifiable or publicly available, conducted by department heads, or taste and food quality evaluation. See article in The Chronicle of Higher Education (Nov. 10, 2006) about possible changes in these exemptions: Oral History Under Review (http://chronicle.com/weekly/v53/i12/12a01401.htm)http://chronicle.com/weekly/v53/i12/12a01401.htm 45 CFR 46.102(f)

4. Human Subject Research? If it qualifies under the definition of human subject research, then –Federally funded research requires review and approval by IRB. –At U of U, regardless of funding, requires review and approval by IRB. Bottom Line: All research involving human subjects requires IRB review and approval; exemptions are determined by IRB, not individual researchers.

5. Why Protections? ‘Greater Good’ Argument A Little History

6. For the Greater Good General Argument: –If research may contribute to the greater good of human society, then it outweighs the interests of individual subjects involved. A Persistent Argument –Edward Jenner (small pox vaccine, 18th cent.) –American Eugenics Movement and Sterilization Laws (Indiana, 1907) –Testing Chemical (& Biological) agents, WWI. –1966: H. K. Beecher paper ( Ethics and clinical research. Beecher HK NEJM 1966;274:1354-60.) See more: In the Name of Science, Andrew Goliszek, St. Martin’s Press (2003).

7. Nuremberg Trials The Doctors Trial (1945-46): 23 physicians/scientists who participated in experiments on concentration camp prisoners. 16 found guilty; 7 executed. –Included experiments about: high-altitude, freezing, malaria, mustard gas, sulfanilamide, tissue (bone, muscle, nerve) regeneration and transplantation, epidemic jaundice, sterilization, spotted fever, poison, incendiary bombs, etc. The trials at Nuremberg was the most forceful confrontation of “greater good” argument. Resulted in “Nuremberg Code” (1947); first international standard for protections of human subjects; and basis for most protections that followed.

8. Nuremberg Code, 1947 (excerpts) Voluntary consent of the human subject is absolutely essential. The experiment should be such as to yield fruitful results for the good of society. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. During the course of the experiment the human subject should be at liberty to bring the experiment to an end. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

9. Tuskegee Syphilis Study 1932-1972, Federally funded research designed to track the natural history of syphilis in mostly black males in rural Alabama. The subjects were told they had “bad blood” and provided with warm meals and funeral arrangements when necessary. Subjects believed that they were receiving proper medical treatment when, in fact, they received either inadequate treatment or no treatment. Even after effective antibiotic treatment (penicillin) for syphilis was discovered (1940/50s), subjects were not offered treatment so that research could track course of the disease. At least 40 of these subjects died during the study. Presidential apology by Clinton. http://www.cnn.com/HEALTH/9705/16/nfm.tuskegee/index.html

10. Willowbrook Hepatitis Study Research at Willowbrook State School (Staten Island, NY) during the 1960s on mentally retarded children to better understand the natural history of the highly infectious hepatitis virus. Subjects intentionally injected with hepatitis virus. Only parents who agreed to the research were able to enroll their children into Willowbrook. Consent form did not mention risks.

11. Other Cases US Plutonium Study (1947) Jewish Chronic Disease Hospital Study (1963) The Cincinnati Radiation Project (1966) Oregon and Washington State Prisons X-ray Studies (1963-71) West Los Angeles Veterans Administration (1999) Johns Hopkins Lead Paint Study (2001) S. Korean Stem Cell Scandal (Hwang; 2005)

12. What have we learned? Protections for Human participants needed –Nuremberg Code (1947) –Helsinki Declaration (1964, 2002) –“Common Rule” (~1974/1991: 45 CFR 46, subpart A) –Formation of IRBs Institutional Review Board (IRB) –Institutional Oversight and Review –Implementing the Common Rule and other subparts... –U of U: www.research.utah.edu/irb/www.research.utah.edu/irb/

13. Ethical Frame for Protections Belmont Principles (1979) Respect for Persons Beneficience Justice Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. From US Department of Health, Education, and Welfare, 1979 (Now DHHS): www.hhs.gov/ohrp/humansubjects/guidance/belmont.htmlwww.hhs.gov/ohrp/humansubjects/guidance/belmont.html

14. Respect for Persons Requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy. –Individuals have the right to make their own decisions for and about themselves… –With all relevant information… –And without undue influence or coercion… Key mechanisms: –Informed Consent Procedure –Right to Withdrawal –Privacy and Confidentiality

15. Beneficience An obligation to maximize benefits and reduction of risk for the participant. –Determining allowable risks… –Demonstrate some benefit, direct or indirect? Key mechanism: –IRB process: risk/benefit analysis feasibility of study

16. Justice Fair distribution of risks and benefits in population. –Those who take the risk, do not do so without some expectation of benefit –Representative population for which the benefit is expected Key mechanism –Selection criteria –International guidelines

17. Balancing Act Respect for Persons Beneficience Justice Greater Good Argument

18. Additional Concerns Vulnerable Subjects Extended Responsibilities Emerging Issues

19. Vulnerable Subjects Pregnant women, fetuses, neonates. (subpart B) Prisoners (subpart C)* Children (subpart D) People with diminished or absent capacity Identifiable Populations –subject to stigma, exclusion, or other harms –Individuals vs. Group protections, consent, etc.

20. Extended Responsibilities Follow-up report on research? Surreptitious findings –HIV or other indicator for disease/risk –Implications for relatives or offspring Sensitive research areas –Privacy and confidentiality –Other social responsibilities?

21. Emerging Issues Less-that-complete-informed consent –ER research –Research with children or diminished capacity (e.g., Alzheimer’s patients) Risk/Benefit Assessment –$$$ for egg donation? –Research on prisoners? –Conflicts of Interest in Recent Gene Therapy Deaths? Jesse Gelsinger (Sep., 1999) and Jolee Mohr (July, 2007) Justice –International drug research and distribution of benefits –Genetic Information: HIPAA and GINA, others