African perspective on ethical guidelines Salim S Abdool Karim CAPRISA: Center for the AIDS Program of Research in South Africa, University of Natal and Columbia University, October 15-17, 2003. Santiago, Chile

Overview of Presentation Global Context Ethical Oversight Choice of appropriate controls in trials (Guideline 11) Case Study of exclusive breastfeeding

Global Context World population: wealthiest 20% vs poorest 20% Start of 20th century : 9X 1960 : 30X 1990 : 60X 1997 : >70X Life Expectancy: Industrialized countries : >70 years Poor countries : <50 years

Global Context Annual per capita health expenditure US : $4000 African countries: <$5 Patterns of diseases 52 million deaths per year 18 million : infectious and parasitic diseases 10 million: diseases of circulatory system 6 million : malignant tumors Poor countries : 80% of global burden of diseases in DALYs

Global Context Early 21st century World characterized by widening economic and health disparities between rich and poor countries Increase in absolute poverty - >50% of world population live on <$2/day Emergence of new diseases afflicting those predominantly marginalized by poverty

Research Ethics Committees Evaluate research proposals with special attention to: Equity in distribution of benefits and burdens Risk/Benefit ratios Conflicts of interests Adequacy of information provided for participants Protection of freedom – within consent freedom; for subjects to withdraw without prejudice to care; investigators to publish Educate and assist researchers and community in understanding and appreciating ethics of research Monitor and audit research and provide public accountability

Research Ethics Committees - Developing countries Ethics receives patchy attention Little uniformity in structure and function Some instances – self-appointed private ethics committees Little accountability Conflict of interest – eg. Drug company payments, carers vs researchers

of scientific evidence Trials - Benchmark of scientific evidence Need for more clinical trials to find solutions to the many problems in developing countries Care in Africa is so under-developed that even slight improvements will raise standards substantially Choice of control group in trials: If developed country Standard of Care is applied, will the study results be useful?

Exclusive Breastfeeding vs Formula feeding Perinatal transmission rate in Africa: 25-30% of babies are HIV+ Best proven therapeutic method = ACTG 076 (AZT + formula feeding) = 64% lower Current standard of care is Nevirapine + mixed feeding – 52% lower In South Africa: NVP + mixed feeding = 14-18% of babies are HIV+

Exclusive Breastfeeding vs Formula feeding Vitamin A trial found that exclusive b/feeding lowers HIV infection rate in baby Is it ethical to do a trial on exclusive b/feeding with control as NVP + mixed feeding? NVP + formula feeding? AZT + formula feeding (ACTG 076)?

Case study: Breastfeeding At issue is that formula theoretically protects fully from breastfeeding transmission Formula Feeding : possible 0% HIV Risk Breastfeeding : up to 14% HIV Risk Is a trial to assess efficacy of exclusive breastfeeding ethical? Exclusive b/f is unlikely to be as good as f/f Exclusive b/f is likely to be worse than f/f Exclusive b/f may or may not be better mixed feeding

Case study: Scenarios A) Exclusive b/feeding vs Exclusive formula feeding 12% vs 8% = 50% worse B) Exclusive breastfeeding vs Current mixed feeding 12% vs 18% = 50% better Some argue that A is unethical as the study intervention is not thought a priori to be equivalent to formula feeding, which is best proven therapeutic method Some argue that only A is ethical, this will prevent the discovery of a cheap practical solution to reduce HIV infection in those babies who cannot be formula fed?

Should potential low efficacy HIV vaccines be tested in high HIV prevalence countries? Based on mathematical models it is unlikely that low efficacy vaccines will be useful in low prevalence countries Is it ethical to do phase III efficacy trials of low efficacy vaccines only in high risk countries when it may not be ethical to conduct these trials in low risk countries?

Conclusion Research in developing countries depends on local ethics committees to serve as custodians to determine if the research is warranted and whether it is exploiting the poor and vulnerable (ala Capron) Capacity building for ethics committees Ethically important to encourage research aimed at finding low efficacy but feasible solutions for the developing world

Acknowledgements Solly Benatar, University of Cape Town, South Africa Cynthia Woodsong, Family Health International, North Carolina Cheryl Baxter, CAPRISA