IRBs and Ethics in Emerging Markets

1. IRBs and Ethics in Emerging Markets ACPU October 19, 2010 John Isidor, J.D. Sr. Director and Co- Founder, Institutional Official Schulman Associates IRB jisidor@sairb.com

2. OUTLINE Overview of Research in Developing Countries Ethics Committees in DCs Placebo Issue Informed Consent AZT Trial Issues

3. OIG REPORT, JUNE 2010 FDA’S ABILITY TO MONITOR AND INSPECT FOREIGN TRIALS (JUNE 2010) 80% of marketing applications for drugs and biologics in FY08 contain data from ex/U.S. studies Over 50% of trial sites in FY08 were ex/U.S. 78% of all subjects in FY08 were enrolled ex/U.S. 87% of all subjects in biologics trials in FY08 were enrolled ex/U.S.

4. OIG REPORT: FDA’S ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS (JUNE 2010) Although sponsors can submit data from trials not conducted under an IND, sponsors must follow FDA’s GCP regulations FDA is allowed to inspect for adherence to IND or GCP regulations FDA inspects 1.2% of all U.S. based sites, but only 0.7% of ex/U.S. sites

5. OIG REPORT: FDA’S ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS (JUNE 2010) Western Europe accounted for the most sites and subjects outside of the U.S. but large numbers of sites and subjects also were in the developing world Central and South America have highest average of subjects per site Large and growing numbers of sites and subjects from Peru, Colombia, Chile, Panama, Venezuela, Nicaragua, Argentina, Brazil, Costa Rica Other large numbers from South Africa, Russia, Poland

6. REASONS FOR DOING TRIALS IN DCs Better address neglected diseases Countries such as Nigeria, South Korea, China and India require significant local data for product approval Target diseases that disproportionately affect DCs such as HIV/Aids, Malaria and TB May help assess the relevance and applicability of the treatment with the local healthcare system Include a more diverse range of patients/participants Access untapped PIs and treatment naïve patients Develop broader base of qualified PIs Increase health/medical infrastructure in low resource countries

7. WHY MOVE CLINICAL TRIALS INTO THE DEVELOPING WORLD? • Lower site costs • Fewer competitive trials • Treatment-naïve subjects • Motivated subjects and investigators • Disease-specific study needs • Countries trying to attract clinical research • e.g., Singapore, India, Malaysia, China, Eastern Europe, Brazil

8. TRIALS IN THE DEVELOPING WORLD

9. LAWS, REGULATIONS, ETHICAL PRINCIPLES GOVERNING CLINICAL RESEARCH IN DCs Nuremberg Code Declaration of Helsinki ICH/GCPs CIOMS Belmont Principles FDA GCPs

10. LAWS, REGULATIONS, ETHICAL PRINCIPLES GOVERNING CLINICAL RESEARCH IN DCs • Many DCs have national laws governing research • Costa Rica • Peru • India • Brazil • Argentina

11. INDEPENDENT/LOCAL ETHICS COMMITTEES (IECs) • Ask the PI for information about local IECs • Review Policies & Procedures • Inquire whether the IEC is government required or independent IECs exist • Ask the Public Health Minister about IECs

12. CONCERNS ABOUT IECs IN DCs Inadequate Training Inadequate Resources Inadequate SOPs Inadequate Understanding of Informed Consent issues Lack of Understanding of Ethical Issues such as Placebo Control

13. TRAINING RESOURCES FOR IECs Internet Programs such as CITI PRIM&R Offers Training such as IRB 101 & 102 Hiring a Consultant Partnering with a University or Government IEC

14. TRAINING RESOURCES FOR IECs • International Bioethics organizations that provide training and information • FERCAP • SIDCER • ICMR • PABIN

15. CONFRONTING A SUBSTANDARD LOCAL IEC Discuss with Local PI Discuss with Ministry of Health Possible Second Layer Review with a recognized Ethics Committee GCP Compliant IEC

16. CONCERNS ABOUT INFORMED CONSENT IN DCs • Basic Principles • Identify proper subject for consent • Written or verbal consent • Provide appropriate information about the research • Adequately understand the information • Voluntarily decide to participate • Explicitly consent to participate

17. IDENTIFYING PARTY TO CONSENT • In addition to research subject may need to • Discuss with local government or Principal Investigator • Involve community person such as community or tribal leader • Involve domestic and/or sexual partner • Involve family member or grandparent • Be multiple levels of consent

18. CONCERNS ABOUT WRITTEN CONSENT Consent form can be threatening Too long Breach of trust relationship Provide identification of subject Take something from subject

19. APPROPRIATELY INFORM ABOUT THE RESEARCH Difficult concepts to explain such as randomization and placebo Concerns about alternative treatment Concerns about risks and compensation for injury Payment to participant/coercive

20. ADEQUATE UNDERSTANDING What is adequate understanding? How is understanding measured? Understanding the study as a whole or every detail?

21. VOLUNTARINESS Does consent = freedom to refuse? What if study treatment is only available healthcare option?

22. EXPLICIT CONSENT Intertwined with voluntariness Freedom to refuse due to differing social status with physician/PI/healthcare workers Great deference to physicians/conflict of interest Signature of participant/witness and possibly family member or community member Use of independent witness where there are literacy problems

23. ETHICAL ISSUES FOR PHARMA SPONSORS CONDUCTING RESEARCH IN DCs Trials should only be conducted where the medicines will likely be suitable and available for widespread use after the trial ends Is local healthcare system able to provide continued post trial care for participants Will licensed and or investigational medicines be made available post trial to participants with a chronic disease where there is no suitable alternative treatment

24. ETHICAL ISSUES FOR PHRMA SPONSORS CONDUCTING RESEARCH IN DCS Is the standard of care for the host country measured by a worldwide standard or the standard that exists in the host country Can we use placebo as a control when no standard treatment exists in the host country or must you use the best available treatment in the world Some arguments for using local standard of care Research can determine if a new treatment is better than one currently used in the host country It ensures continued post trial treatment to the same standard in the host country In many therapeutic areas there is no consensus on the best available treatment In some cases the best treatment may be a surgery not available in the host country

25. JUSTIFICATION OF THE SHORT COURSE AZT TRIAL

26. A QUESTION OF JUSTICE IN THE SHORT COURSE AZT TRIAL

27. There was never any intent to exploit a vulnerable population The Short Course AZT Trial could not be conducted in the U.S. The health ministries of the host countries endorsed the study Health care justice in Sub Sahara Africa did not exist Justice in U.S. clinical research is a myth despite the Belmont Report POINTS TO CONSIDER

28. A QUESTION OF BENEFICENCE IN THE SHORT COURSE AZT TRIAL

29. The standard of practice in Sub Sahara Africa was no treatment for the prevention of perinatal HIV A placebo control did not place mothers or infants at increased risk compared to no treatment Subjects randomized to AZT incurred only a minor risk of toxicity The potential benefit of assignment to AZT was prevention of perinatal HIV POINTS TO CONSIDER

30. All subjects could potentially benefit by better prenatal care provided by the study If the Short Course AZT proved to be efficacious, other HIV infected women in the 3rd world may benefit HIV infected women in developed countries will not benefit unless the Short Course AZT is as effective (highly unlikely) as the 076 Regimen It is unrealistic to demand that every subject receive the best proven therapy available anywhere in the world POINTS TO CONSIDER CONT’D

31. A QUESTION OF RESPECT FOR PERSONS IN THE SHORT COURSE AZT TRIAL

32. Consent was obtained by local physicians familiar with the culture POINT TO CONSIDER

33. A QUESTION OF PRACTICALITY, ECONOMIC REALITY AND CULTURAL LIMITATIONS IN THE SHORT COURSE AZT TRIAL

34. The 076 Regimen was not affordable and a cheaper treatment was needed The 076 Regimen was too complicated to implement in undeveloped countries POINTS TO CONSIDER WHY?

35. Most women in Sub Sahara Africa do not seek prenatal care Most women breast-feed, which is the cultural norm Formula is not affordable or culturally acceptable The necessary medical infrastructure to support the 076 Regimen was non-existent BECAUSE…

36. Use of the 076 Regimen as an active control instead of placebo would extend the trial The Short Course AZT regimen is relatively simple and “inexpensive” Scarce resources in Sub Sahara Africa are invariably devoted to economic needs Drug companies and/or developed countries will not assume the cost of expensive treatments for 3rd world countries POINTS TO CONSIDER CONT’D

37. WHAT’S THE BOTTOM LINE?

38. Unqualified and rigorous application of the principles of The Belmont Report to 3rd world clinical research may ultimately prove to be harmful and, therefore, unethical. THE BOTTOM LINE

39. Epilogue The Short Course AZT Trial was shown to reduce perinatal HIV transmission by approximately 50%.

40. CONCLUSION Research will continue to grow in DCs Many important reasons to conduct research in DCs Many ethical challenges remain such as identifying qualified researchers, IECs and ongoing informed consent challenges Ethical research offers the potential for great benefits for the host country and its citizens as well as world healthcare