Ethics in international Research

1. Ethics in international Research Justice across national boundaries

3. Clinical Trials Group (ACTG) 076: Vertical Perinatal HIV Transmission • Antiretroviral drug zidovudine administered orally in the prenatal period, intravenously during labor, and administered orally to the newborn reduced HIV infection in the newborn by two-thirds • Study terminated at first interim analysis • Within two months the Public Health Service announced that HIV positive women should receive this treatment.

4. Post-ACTG 076: USA • zidovudine was estimated to have reduced neonatal HIV death by 50% in the US and Europe.

5. Post ACTG-076: Africa • In Africa, accounting for 70% of the global HIV burden, therapy played no role because of cost • Therapeutic regimens as effective but less expensive than zidovudine needed for developing countries

6. Research design to search for a less expensive regimen? June, 1994, WHO convened expert panel to advise research agenda for perinatal HIV transmission “Placebo-controlled trials offer the best option for a rapid and scientifically valid assessment of alternative antiretroviral drug regiments to prevent [perinatal] transmission of HIV.” (WHO 1994)

7. 18 trials to explore alternative interventions * In trials conducted in the US, subjects in all study groups had full access to zidovudine or other antiretroviral drugs. • In 15 of the 16 trials in developing countries, some or all of the patients were not provided with antiretroviral drugs. • 9/15 studies conducted in other countries were funded by the US government through the CDC or NIH.

8. Declaration of Helsinki • First written in 1962; rewritten in 1975; modified three times since its rewrite. • All versions placed the benefit and well-being of the subject as the pre-eminent concern

9. Debate over Declaration Revisions • establishment of general rather than local ethical review committees • a more liberal view towards the use of placebos; and • allowing for local determination of access to health care

10. Polarization “Some argued that the proposed revision established a model for human biomedical research ethics that encouraged utility and efficiency at the expense of patient autonomy and well-being. Those who defended the amendments said they were more in line with contemporary ethical thinking ….” Deutsch Edinburgh 2000 633-641

11. Declaration of Helsinki (2000) • Significant rewrite • Emphasizing again that the rights of the individual should take precedence over the interests of science and society • Emphasizes the protection of vulnerable populations. • Local versus international rule unclear

12. Modification of Helsinki (2001) • Para 29: “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current …methods. This does not exclude the use of placebo, or no treatment in studies where no proven…method exists” • Amendment: “a placebo-controlled trial may be ethically acceptable, even if a proven therapy is available”(2001 revision)

13. Issues behind the Declaration • Local versus global standards of care • Informed Consent • Equipose • Placebo controlled studies versus no placebo (“Science versus Ethics”) • Shared Burden of Risk/Equity

14. Standard of care: local versus global • “A global view of justice, which endorses international equity, cannot be squared with international research guidelines that allow ‘local conditions’ to define the scope of duty to the control group” de Zulueta P Bioethics 2001 289-311

15. Standard of care: local versus global (con) • Should the standard be the standard of the host country, the standard of the sponsoring country or some global standard? • Is it appropriate to assume that a standard set by industrialized countries can be/should be applied to developing countries? • Should standards of care differ based on the sponsoring country ?

16. Standard of care: local versus global (con) • Many instances of possibly “unethical exploitation” occur in a two-tiered system * Local scientists and physicians argue that only because of the two-tiered system did their country have any access to these studies. • An argument has been made that even if the funding is external, if the researchers are local, local standards can be used.

17. Standard of care: local versus global (con) • Are local investigators, who have much to gain both financially and by reputation, by receiving funding from the US, in the position to take an appropriate ethical stance? • “,,,[A] local standard may benefit participants and non-participants alike in impoverished countries, but it comes at the cost of using a double standard for what is considered ethical human experimentation.”Rothman BMJ 2000 442-444 • “...[t]he heated debate reflects a tension, if not an outright war, between two conflicting meta-ethical systems, or incommensurable paradigms, that underpin scientific research involving human subjects…” de Zulueta P Bioethics 2001 289-311

18. Informed Consent: • What constitutes “informed consent”---especially among those who are vulnerable because of age, mental or physical disability, level of education, or degree of poverty? • Is it appropriate to ask a potential subject in a developing country who lives under an entirely different legal system to complete an informed consent that is consistent with the legal expectations of the sponsoring country • Can we explain concepts of risk and protection to persons with little education?

19. Informed Consent, con. Study in the Gambia of 137 acceptors and 52 refusors of Hemophilus influenza type B conjugate: * 90% knew purpose of vaccine was to prevent disease * 93% of acceptors did so to receive the vaccine * “placebo control” was understood by only 10% Leach et al Soc Sci Med 1999: 139-48

20. Informed Consent, con. • What does a vaccine that may have fifty percent efficacy mean to an illiterate woman? • How do we establish that we have explained something clearly? • Are some populations so vulnerable, so dependent that the concept of “informed, voluntary consent” may be unachievable? • Are genuinely consensual relations possible between the research community and participants who otherwise have little or no access to healthcare or other basic rights and liberties?....

21. Equipoise • The state in which we have no reason to believe that one experimental condition or intervention is superior to another • “The necessity for investigators to be in this state of equipoise applies to placebo-controlled trials, as well. Only when there is no known effective treatment is it ethical to compare a potential new treatment with a placebo”. Angell NEJM 1997 847-849

22. Placebo Control versus no control (“Science versus ethics”) • Equipoise: the gateway to and the foundation for a placebo-controlled trial. • The randomized, placebo-controlled trial is upheld as the paradigm of the excellence in science • If there is not equipoise, there is not a basis for genuine scientific query • Is the overarching need for a placebo-controlled trial “placing science ahead of ethics”?

23. Placebo Control versus no control (“Science versus ethics”) (con.) • Placebo group provides the benchmark • Placebo-controlled trials withhold existing therapy in order to further observe the natural course of infection and disease • Placebo=a fixed and reliable reference point ? • At times already approved medications can be ineffective

24. Reasonable risk • Central component of justice: individual or group should neither shoulder a disproportionate percentage of risk nor receive more than “fair share” of benefits • ~90% of medical research conducted on diseases that cause only 10% of the global burden of disease

26. Reasonable Risk, con. • Is this a fair sharing of the burden of risk? Of the possible benefit? If he were to receive a higher sum, would this make the study more ethical—or less ethical? Would offering him a lower stipend for participation make it more ethical? Is there a different way that he could be compensated? Would the “ethics” change if the disease prevalence remained the same in his country, but relative to other diseases, it was more prominent?

27. Reasonable Risk, con. • Would it change if his education level were higher? Are we concerned that he cannot understand the concept of a vaccine that is 65% efficacious? Would it change if he were not a peasant farmer but were a US soldier stationed abroad would the situation be more ethical? If the sponsoring agency were not the US but his own country, would this change the ethics of the situation?

28. “Fair Benefits": An ethical solution or a utilitarian compromise? • Benefits to Participants During the Research • Improvements to health and health care • Collateral health services unnecessary for research stud • Benefits to Population During the Research • Collateral health services unnecessary for research • Public health measures • Employment and economic activity • Benefits to Population After the Research • Reasonable availability of effective Research and medical care capacity development • Public health measures • Long-term research • Sharing of financial rewards from research results

29. Supplemental components to “Fair Benefits * Collaborative Partnership Community involvement at all stages Free, uncoerced decision-making by population bearing the burdens of the research * Transparency Central, publicly accessible repository of benefit agreements Process of community consultations Ethical aspects of Research in Developing Countries Science 2002 21