1. Recruitment of Healthy Volunteers: Research Ethics under Pressure Recruitment of Healthy Volunteers: Research Ethics under Pressure INSIGHT Toronto October 24 2006 Michael Goodyear Department of Medicine, Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax NS

3. Learning Objectives I: A Culture of Safety I: A Culture of Safety II: What Motivates Volunteers? II: What Motivates Volunteers? III: Why Volunteers are Vulnerable III: Why Volunteers are Vulnerable IV: Role of Financial Incentives IV: Role of Financial Incentives V: Adverse Risk-Benefit Ratio V: Adverse Risk-Benefit Ratio VI: Defining the Ethical Problem VI: Defining the Ethical ProblemSummary

4. Part I A Culture of Safety

5. A Healthy Volunteer Died Ellen Roche

6. “What's the worst that can happen to me? … I die, and it's for the babies.“ New York Times, 28 Nov 1999 Jesse Gelsinger

7. TGN1412

8. Hell of human guinea pigs How the drug trial horror unfolded By MICHAEL SEAMARK, Daily Mail 17th March 2006 We saw human guinea pigs explode Victims tearing at shirts By NICK PARKER, EMMA MORTON and JACQUI THORNTON 16th March 2006

9. Ryan, Gangrene Khan, Eyewitness Placebo Elephant Man and Girlfriend Oedema

10. A Culture of Safety “The demand for human subjects is at an all time high, and the competition for human subjects for research participation is equally great. Investigators must take care to not respond to this competitive environment … The temptation to entice subjects with a large amount of money is a natural reaction to such conditions; however, the protection of human subjects must come first” Tishler CL, Bartholomae S: The recruitment of normal healthy volunteers: A review of the literature on the use of financial incentives J Clin Pharmacol 2002; 42: 365-375

11. Part II What Motivates Volunteers?

12. Altruism Altruism –Disease –Society Curiosity Curiosity Medical Care (where not available) Medical Care (where not available) Money Money Other incentives Other incentives

13. Walter Reed Experimenting on Yellow Fever Cuba, 1898 $100 in Gold Additional $100 in Case of Death Research related injury Informed Consent re risk

14. Allied Research International is always recruiting for normal healthy study participants for our phase I and bioequivalence studies. We conduct our studies in a cheerful, safe, and respectful environment. Our meals are second to none and …now with 100% more pool tables! $950

16. Part III Why Volunteers are Vulnerable

17. Economically Disadvantaged Economically Disadvantaged High Incidence of Psychopathology High Incidence of Psychopathology –Up to 50%

18. Part IV Role of Financial Incentives

20. Difficult to assess –Subjective and Relational –Degree of risk –Risk taking behaviour –Personal values –Amount of money

21. Role of Financial Incentives Incentives compromise autonomy Incentives compromise autonomy Unpaid volunteers believe there should not be payments Unpaid volunteers believe there should not be payments Voluntariness becomes occupation Voluntariness becomes occupation Repeat or professional volunteers Repeat or professional volunteers Problems of Justice, Generalisability Problems of Justice, Generalisability

22. Part V Adverse Risk-Benefit Ratio

23. Essentially no benefit Essentially no benefit (Social obligation) (Social obligation)

24. Part VI Defining the Ethical Problem

25. DisadvantagedPopulationsRequireSpecialProtection Belmont CFR FDA, OHRP

26. Healthy Research Volunteers OHRP – IRB Guidebook Chapter VI: Special Classes of Subjects: Chapter VI: Special Classes of Subjects: –“Volunteers for whom no therapeutic benefit can result from participation in research should, therefore, be exposed to risks that are minimized to the greatest extent possible.” –“…IRBs must ensure that any monetary payments to subjects are not so great as to constitute an undue inducement. …Payments should be commensurate with time, discomfort, and risk involved.”

27. Vulnerable Populations 21 CFR 56.111 (b) Criteria for IRB Approval of Research: Criteria for IRB Approval of Research: “When some or all of the subjects, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons, are likely to be vulnerable to coercion or undue influence additional safeguards have been included in the study to protect the rights and welfare of these subjects." “When some or all of the subjects, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons, are likely to be vulnerable to coercion or undue influence additional safeguards have been included in the study to protect the rights and welfare of these subjects."

28. Defining the Ethical Problem Risk/Benefit Vulnerability

29. Summary

30. Summary I/II Volunteers are Harmed Volunteers are Harmed Are largely Motivated by Financial Incentive Are largely Motivated by Financial Incentive Are Economically Disadvantaged Are Economically Disadvantaged Have Increased Vulnerability Have Increased Vulnerability Have Compromised Voluntariness Have Compromised Voluntariness Have Adverse Risk-benefit Considerations Have Adverse Risk-benefit Considerations

31. Summary II/II Experimentation with Normal Healthy Volunteers Requires A High Degree of Review and Oversight

32. Acknowledgements Dr Janice Parente, Ethica Clinical Research