1. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 1 Praphan Phanuphak, M.D., Ph.D. Faculty of Medicine, Chulalongkorn University & The Thai Red Cross AIDS Research Centre Bangkok, Thailand Ethical considerations of HIV research in Thailand: the HIV-NAT as a case study

2. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 2 104 Rajdumri Road Pathumwan Bangkok 10330 Thailand Tel: +66 2 255 7334/5 Fax: +66 2 252 5779 www.hivnat.org HIV-NAT The HIV Netherlands Australia Thailand Research Collaboration

3. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 3 Thai Red Cross AIDS Research Centre (TRC ARC) Bangkok, Thailand Prof. Praphan Phanuphak National Centre in HIV Epidemiology and Clinical Research (NCHECR) University of New South Wales, Sydney, Australia Prof. David A. Cooper International AIDS Therapy Evaluation Centre (IATEC) University of Amsterdam, The Netherlands Prof. Joep. M.A. Lange Collaborating organizations

4. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 4 Conduct multi-centre HIV-related clinical studies according to good clinical practice (GCP) and good laboratory practice (GLP) guidelines in Thailand and the region Provide access to antiretroviral therapy for HIV-infected people in Thailand Educate healthcare workers in Thailand and the region on GCP, GLP and HIV medicine Mission and Objectives

5. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 5 1995HIV-NAT concept 1996start of operations first patients enrolled on study 1997first presentations at international meetings 1998Bangkok symposium in HIV medicine UNAIDS collaborating centre 1999UNAIDS Best Practice 2000first pK study of NLV in newborn 2003 approximately 1,500 patients on studies Milestones

6. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 6 001 001.1 001.2 002 002.1 003 003.1 003.2 004 IL-2 Vanguard 005 007 001.3 002.2 extension 001.4* BMS PI D4T ER Decadurabolin 002.2 ESPRIT 2NN Mid 1996 1997 1998 1999 2000 2001 HIV-NAT STUDY TIMELINES 009* * 2 new studies started June 2001

7. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 7 Ethical considerations n Biased ethical approval: authoritative or political n Unethical conduct or deviation of the approved protocol without 3rd party supervision n Ineffective consent process or not telling the whole true story n Subjects do not have much choice n What to offer to those who cannot enroll or fail the inclusion criteria? n End of trial medications n Research colonialism

8. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 8 Ethics n Ethical approval, protocols and consent form are just arbitrary processes. n Integrity of researchers is most crucial. It is inherent within individuals but can be shaped up if they know that someone is looking after them. n Research watchdog is useful to guarantee international standards but sometimes can be a stumble block. n Voice of the local affected people should be listened. n We need to help them to get the best possible options.

9. Quantitative studies of the quality of the informed consent given by the Thai researchers in the ESPRIT study Christine Pace, Ezekiel J. Emanuel, et al Department of Clinical Bioethics NIH

10. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 10 ESPRIT n A phase III international study of SC IL-2 n 4000 subjects worldwide, 368 from Thailand n Randomized 1:1 with ARV alone, a 5-year study n 141 patients immediately after signing the informed consent to join ESPRIT were invited to participate in in-person interview before learning of their randomization assignments n The survey was administered by Thai personnel trained by NORC who had no affiliation with ESPRIT n ESPRIT staff had no access to the completed Q&A

11. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 11 The informed consent process n Initial information given by M.D. or VCT counselor n Group discussion of the protocol led by a nurse coordinator (20-30 min) n Thai version of the informed consent document provided with 20 minutes to read n Q & A session before signing the 2600 words long standard NIH informed consent The survey used a 67-question questionnaires, developed by NORC, Univ. Chicago, with an average of 33 minutes long in-person interview

12. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 12 Main findings of the survey n High level of knowledge about the study (over 93% vs 28% in US study) including the side-effects n 21% felt that the discussion was more useful than the written materials n None had pressure from the ESPRIT research team to join the study n 30% had pressure from their health-related circumstances to join n Understanding treatment randomization was a problem, only 31%

13. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 13 Conclusion The results challenge the claim that research participants in developing countries cannot give voluntary and fully informed consent. However, independent monitoring such as this is essential. Of note: 48% of the subjects had completed college or graduate schools.

14. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 14 End of trial medications: strategies of HIV-NAT n Try to negotiate for at least 2 years of ARV supply or life-long if possible n If patients do not yet need ARV, for example, in a pK study, 2 years guarantee of ARV when ARV is needed in the future. Grant is given for future ARV. n Request ARV support from the MOPH, some success n Roll-over protocols n HIV-NAT Drug Fund

15. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 15 HIV-NAT 001 series n 001 : Half-dose vs. full-dose ZDV/ddC n 001.1: d4T/ddI/SQV-SGC vs. ZDV/3TC/SQV-SGC (1400 mg bid) n 001.2: 001.1 +/- itraconazole 100 or 200 mg OD to look for SQV plasma level n 001.3: SQV-SGC 1600 mg + RTV 100 mg OD (for undetectable VL) vs. SQV-SGC 1400 mg bid (for detectable VL) n 001.4: Continuous OD SQV/RTV vs. week on-week off vs. CD4-guided (STI)

16. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 16 HIV-NAT drug fund n Initiated in November 2001 n Subsidize antiretroviral drugs based on “a Co-Pay and a Sliding Scale System” for post-trial patients and patients in trials with intolerance or resistance n Rule: patient pays at least 1500 Baht and HIVNAT at most 5000 Baht n Funding of 2 million baht (first year) and 1 million baht (subsequent years)

17. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 17 Progress report (End of year 2002) n 868 in-trial, 278 post-trial n 83 patients requested assistance n 62 patients received assistance n Budget used: 413,321 Baht

19. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 19 Future plans n Re-evaluate patients’ financial status every 12 months n Patient questionnaire to assess –Benefits –Problems –Suggestions for improvement

20. HIVNAT The HIV Netherlands Australia Thailand Research Collaboration 20 Summary n Ethics in performing HIV research is a real concern in Thailand but can be improved. n Good and ethical HIV research can be done but it should be closely monitored. n Ethical standardization is ideal but should not be a barrier for doing research in developing countries and should be tailored to fit each country, taking into the consideration of all stakeholders in the country, not only from the North or the funding agencies.