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Ethical issues in international clinical trials

Ethical issues in international clinical trials. Bernard Lo, M.D. bernie@medicine.ucsf.edu September 17, 2009. Tenofovir. Nucleoside RT inhibitor Generally fewer side effects than other HAART Proximal tubular damage, ATN Reverses on discontinuation. PrEP protests.

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Ethical issues in international clinical trials

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  1. Ethical issues in international clinical trials Bernard Lo, M.D. bernie@medicine.ucsf.edu September 17, 2009

  2. Tenofovir • Nucleoside RT inhibitor • Generally fewer side effects than other HAART • Proximal tubular damage, ATN • Reverses on discontinuation

  3. PrEP protests • Should receive standard interventions • Prevention services • Needle exchange, methadone for IDUs • Dialysis for renal failure • ART for seroconverters

  4. PrEP protests • Access to drug after trial • Manufacturer offered to sell at cost • Still unaffordable • Lack of informed consent

  5. PrEP protests • Cultural / political context • Poor care at government clinics • Involvement in planning • New advocacy groups refuse to meet • Charges of exploitation

  6. Questions?

  7. Need research in developing countries • Burden of disease • Some conditions primarily in South • Uncertainty over best Rx • Optimal therapies not feasible

  8. Drug company interest in developing countries • Cheaper and quicker • Many “naive” patients • Simultaneous licensing in many countries • Most clinical trials now offshore

  9. Ethical issues also salient in US • Is background care appropriate? • Is consent adequate? • Will patients have post-trial access?

  10. Disclosure • NBAC • CAPS • HPTN • Gates

  11. Perinatal HIV studies • AZT standard of care in U.S. • Starting 3rd trimester • IV during labor and delivery • Not feasible in South

  12. Perinatal HIV studies (1996) • Shorter course AZT vs. placebo in Thailand, Africa • Criticized as exploitation, double standard • Proposed equivalency trial

  13. Tuskegee Revisited “Those offended by the comparison of the African research with Tuskegee have yet to show how these studies differ in their fundamental failure to protect the welfare of human subjects.”. Wall Street Journal. Oct 29, 1997

  14. Interventions for control group: Helsinki #29 (2000) • Interventions must be tested against “best current prophylactic, diagnostic, and therapeutic methods” • Rejected “highest attainable and sustainable” www.wma.net

  15. 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? http://bioethics.georgetown.edu/nbac/

  16. Interventions for control group: Helsinki (2008) • Placebo necessary to determine safety and efficacy • Compelling and scientifically sound methodological reasons • No serious and irreversible harm www.wma.net

  17. Perinatal HIV study • Placebo established proof of principle and efficacy • Efforts to make drugs more available • Additional funding • Lawsuits against manufacturers • Price reductions

  18. RCT of prenatal folate • Does folate during pregnancy prevent birth defects? • Unethical to do placebo control in U.S.

  19. Prenatal folate trial in China • Subjects illiterate women in rural areas • Unethical to give folate in China? • One child policy • Government plot for sterilization • Concerns that birth defects ascribed to drug

  20. Prenatal folate trial in China • Seek permission from mother-in-law • Supplement, not replace patient consent

  21. Challenges in informed consent • In clinical care • Not disclose diagnosis • Not discuss uncertainty • Not obtain consent • Defer to village leader, husband

  22. Challenges in informed consent • Different model of disease • Blood draws = spell • Phlebotomy not minimal risk? • Rumors, misinformation

  23. Challenges in informed consent • Detailed consent form counterproductive • Low health literacy • Suspicion of signature or thumbprint

  24. What is culturally appropriate? • Respect for persons is universal • Tailor consent procedures to particular situation

  25. Innovations in informed consent • Consult with community representatives • What are participants’ concerns? • What will be difficult to understand? • How best to explain study?

  26. Innovations in informed consent • Community-based education • Street theater, group meetings • Imaginative explanations • Randomization • Independent witness rather than signature

  27. Innovations in informed consent • Participant may seek approval from others • Final choice by individual participant

  28. Innovations in informed consent • Questionnaire to assess participant comprehension • Disclosing information is necessary but not sufficient

  29. Similar innovations in U.S. • Consult community representatives • Check understanding of participants

  30. Oral antibiotic for meningitis • Intravenous antibiotics not feasible in developing nations • RCT oral trovaflaxacin vs. ceftriaxone

  31. RCT during epidemic • Nigerian collaborators had no input into study design • Need for care vs. research? • Study team flew in, flew out

  32. Ethical problems • No prior oral use in children • Not told that clinic nearby • No repeat LP • Failures not switched

  33. Ethical problems • Control drug given IM, lower doses • IRB consent forged

  34. Study outcomes • Mortality in both arms 6%, comparable to US and local care • Later international multicenter study, including US sites • Trovaflaxacin causes liver damage, use restricted

  35. Research oversight • IRB review at UCSF and in host country • Informed consent

  36. IRB challenges in international studies • U.S. IRB lacks expertise about host country • Host country IRB lacks resources and experience

  37. Challenges in international studies • IRB approval not ensure ethical issues adequately addressed • Greater responsibility on investigator • If something goes wrong, IRB approval is no defense

  38. Context of international research • Vast disparities in wealth • Limited resources in host country • History of “exploitation”

  39. Partnerships in international research • Partnership with host country • Scientists, officials, community leaders • Start in design phase • Not just present draft protocol BMJ 2003; 327: 337

  40. Partnerships in international research • Capacity building • Training host country staff and collaborators • Leave behind equipment • Involve in data analysis and writing

  41. Ethical obligations of researcher • Good intentions not enough • Act as advocate, not guarantee change • Set high but not unrealistic standard • Make good-faith, reasonable efforts

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