1 Ethical issues in international clinical trials Bernard Lo, M.D. University of California San Francisco May 28, 2009

3 HIV prevention in Cambodia  RCT of daily tenofovir as pre-exposure prophylaxis (PrEP)

5 PrEP protests  Should receive standard interventions  Prevention services Needle exchange, methadone for IDUs  Dialysis for renal failure  ART for seroconverters

6 PrEP protests  Access to drug after trial  Manufacturer offered to sell at cost  Still unaffordable  Lack of informed consent

7 Questions for audience  State of art prevention services?  Access to study drug after trial?

8 Need research in developing countries  Some conditions primarily in South  Uncertainty over best Rx  Optimal therapies not feasible

9 Drug company interest in developing countries  Trials cheaper and quicker  Many “naive” patients  Simultaneous licensing in many countries  Most clinical trials now offshore

10 Tenofovir study  Trials halted, delayed  Results expected 2009

11 Issues to discuss 1. Interventions for control group  Placebo controls 2. Informed consent 3. Benefits to participants and communities

12 Fundamental ethical principles 1. Beneficence  Acceptable risk/benefit balance  Withholding beneficial interventions criticized as unethical 2. Respect for participants  Informed and voluntary consent

13 Fundamental ethical principles 3. Justice  Criticized for exploitation, double standard

14 1. Interventions for control group

15 Interventions for control group: Helsinki #29 (2000)  Interventions must be tested against “best current prophylactic, diagnostic, and therapeutic methods”  Rejected “highest attainable and sustainable”

16 Interventions for control group: NBAC report (2001)  Studies must address priorities of host country  Pertinent research question may be: is a limited intervention better than current (no) care?

17 Interventions for control group: Helsinki (2008)  Placebo necessary to determine safety and efficacy  Compelling and scientifically sound methodological reasons  No serious and irreversible harm

18 2. Informed consent

19 RCT of prenatal folate  Prevent birth defects?  Unethical to useplacebo control in U.S.

21 Prenatal folate trial in China  Subjects illiterate women in rural areas  One child policy  Misinformation about trial  Concerns that birth defects ascribed to drug  Seek permission from mother-in-law

22 What is culturally appropriate?  Respect for persons is universal  Tailor consent procedures and documentation to particular situation  Not longer consent form  Participant may seek permission from third party

23 Innovations in informed consent  Consult with community representatives  What are participants’ concerns about study?  What will be difficult to understand?  How best to explain study?

26 Innovations in informed consent  Assess participant comprehension  Disclosing information is necessary but not sufficient  Shift emphasis away from consent form

28 3. Benefits to participants and communities  In return for helping researchers and sponsors, what benefits should participants and communities receive?  Should not take unfair advantage

29 Benefitsto participants during trial  Physical exam, laboratory tests  Short-term medical care  Clinical significance?  If no care for diagnosed problems  If no ongoing care for chronic condition

30 Post-trial access  “Reasonable” availability of study drug  Few positive pivotal trials

31 Fair benefits  To community where trial carried out, not just participants  Education, training  Volunteer clinical care  Equipment after trial

32 Summary  Ethical issues in any clinical trial  Particularly complex in global setting  Adverse publicity from allegations of unethical behavior

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