Should research ethics change at the border?

The use of placebos in HIV drug trials has raised concerns about research ethics in developing countries

MJA 1998; 169: 509-510

Research on mothers with HIV in poor countries has attracted vehement criticism. The researchers (largely funded from the West) are accused of changing their ethics "at the customs desk."1 In defence of their own position researchers (and their sponsoring bodies) claim that ethical standards are unrealistic and that local conditions require studies "that might not be found ethically acceptable in developed countries."2 They argue for achievable standards that depend on local circumstances.2-4 The controversy concerns the use of placebos in zidovudine drug trials on mothers with HIV in Thailand, Africa and the Caribbean. The trials aimed to test the effectiveness of a short course of low-dose zidovudine in preventing transmission of HIV from mothers to infants by comparing transmission rates of mothers given zidovudine with those offered only a placebo. The short course is an alternative to a more expensive regimen of treatment with zidovudine for both mother and infant previously demonstrated to be effective in the trial known as ACTG 076.5 Although the ACTG 076 regimen has been effective in reducing transmission rates by almost 70%, it is not available in resource-poor countries because of the cost and lack of necessary facilities and support.3 Placebo trials in Thailand have recently shown that a simplified regimen of zidovudine was effective in reducing the transmission of HIV between infected mothers and their infants by 51%. This finding is from studies with women who did not breastfeed and who were given zidovudine orally for three to four weeks before birth. No zidovudine was given to their infants.6 This result now makes it clear that placebo comparisons are no longer ethical in mother-to-child HIV transmission studies, even in poorer countries. However, it does not answer the charge that they were unethical in the first place. It is an issue that is still current because there are other diseases for which treatments are available in the West, but not in resource-poor countries. Could placebo trials be justified to test cheaper alternative treatments for these diseases? Furthermore, to continue the logic of the Thai HIV transmission trials, is it ethical to test an even cheaper (shorter course and lower dose) zidovudine regimen? In broad terms the issue is whether ethical standards in research apply across borders, irrespective of poverty and lack of supporting health care systems. The concern with "ethical relativism" in HIV research1,7 is an instance of a long-standing debate between universalism and relativity in ethics, with the universalists arguing for an "irreducible set of ethical standards" that apply internationally.8 These include requirements that the interests of participants in research be given priority over potential benefits for science and society;9 that there be "genuine doubt" as to whether an alternative is as good as standard accepted treatment;10 that studies be approved by an independent committee;9 and that no study be conducted in a foreign country unless it meets the standards of the sponsoring country.11 Failure to accept these minimal conditions, it is argued, is an invitation to unscrupulous researchers and companies to exploit poorer countries.11 Lurie and Wolfe ask ". . . why not select the approach that minimizes loss of life?"11 Although these authors opposed the placebo studies, the answer to their question may well support the placebo trials in Thailand, in that they were quicker and their results support immediate implementation of an effective treatment program (albeit one not as effective as the ACTG 076 regimen). The indications are that in the long run these particular placebo trials will save more lives. Does this end result justify research that withheld effective treatment from HIV-infected mothers and their infants? I admit to being caught between the arguments: on the one hand it is abhorrent to accept that mothers were recruited for studies in which some of them were deprived of a treatment that might have protected their child from contracting HIV. On the other hand, a great many more (future) lives may have been saved. The pragmatic argument is that we must do what we can to test and find effective treatments which can be made available in conditions of poverty. The inequity lies, not in researchers withholding effective treatment, but in a callous world that tolerates gross disparities between rich and poor countries. Researchers are trying to reduce (where they can) some of those inequities. Could there be a middle way between the extremes of universalism and relativity? Nussbaum, while supporting a universalist approach to ethics, argued for "a delicate balancing between general rules and a keen awareness of particulars, in which process . . . the particular takes priority . . . in the sense that a good rule is a good summary of wise particular choices, and not a court of last resort."12 From this perspective, the rule that research must meet the standards of the sponsoring country may need "modification in the light of new circumstances".12 If we take this lead, there may be no simple answer. Each situation would require a careful analysis, guided by internationally accepted rules, and applied with a keen sense for the most humane decision in those circumstances. Certainly, we should be on our guard and block research which simply exploits those in poverty. However, the "wise choice"12 that most benefits people in poor countries may not always conform to Western standards. In this issue of the MJA Studdert and Brennan13 call for "dialogue about whether a universal standard of care is applicable." Although this debate may no longer be relevant to studies of mother-to-child HIV transmission, it remains an important ethical question in responding to dire health needs of those in poor countries. Paul M McNeill Associate Professor in Ethics and Law Faculty of Medicine, University of New South Wales Sydney, NSW Acknowledgement: My thanks to Gregory J Dore, National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, for information on recent developments and his many helpful comments. Cohen J. Ethics of AZT studies in poorer countries attacked. Science 1997; 276: 1022. Varmus H, Satcher D. Ethical complexities of conducting research in developing countries. N Engl J Med 1997; 337: 1003-1005. Levine RJ. The "best proven therapeutic method" standard in clinical trials in technologically developing countries. IRB -- A Review of Human Subjects Research 1998; 20(1): 5-9. Merson MH. Ethics of placebo-controlled trials of zidovudine to prevent the perinatal transmission of HIV in the third world [letter]. N Engl J Med 1998; 338: 836. Centers for Disease Control and Prevention. Administration of zidovudine during late pregnancy and delivery to prevent perinatal HIV transmission -- Thailand, 1996-1998. JAMA 1998; 279: 1061-1062; also in MMWR - Morbid Mortal Wkly Rep 1998; 47(8):151-154. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994; 331: 1173-1180. Angell M. The ethics of clinical research in the third world. N Engl J Med 1997; 337: 847-849. Angell M. Ethical imperialism? Ethics in international collaborative clinical research. N Engl J Med 1988; 319: 1081-1083. McNeill PM. The ethics and politics of human experimentation. Sydney and London: Cambridge University Press, 1993: 165-183. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987; 317: 141-145. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. N Engl J Med 1997; 337: 853-856. Nussbaum N. Non-relative virtues: an Aristotelian approach. In: Nussbaum N, Sen A, editors. The quality of life, Oxford University Press, 1993: 242-269, at 257. Studdert DM, Brennan TA. Clinical trials in developing countries: scientific and ethical issues. Med J Aust 1998; 169: 545-547.