The articles on the ethics of clinical research in developing countries [1,2] published in the New England Journal of Medicine raise important points. However, the central ethical question should be: why hasn't the successful intervention that is currently used as a matter of course in Western countries become the standard of care worldwide? Ideally, we shouldn't be conducting more trials but rather implementing a proven prevention intervention. However, the reality is that in most of the world, perinatal HIV transmission continues unchecked largely because of the expense of zidovudine. In addition, in many developing countries women often deliver without prior medical care or outside a health care setting and, when they do go to hospitals, medications are scarce and, therefore, de facto no prevention of perinatal HIV transmission is the 'standardofcare' in most developing countries.
Furthermore, the international patent regime makes currently available drugs in Western countries unaffordable to most. [3] International pharmaceutical companies hold monopolies on virtually all drugs proven to be beneficial in AIDS treatment. This allows them to charge prices the fragile health care systems existent in many developing countries are unable to pay. It has been calculated recently by Hogg et al that treatment with the currently available drugs would cost Africa approximately 8.3 per cent of the region's GDP in 1995 and would exceed 50 per cent of GDP in Malawi, Mozambique, Uganda and Tanzania. [4]
It makes little sense then to use Western standards as the benchmark for the design of trials. Under such circumstances, it is ethically justifiable to test a drug which may be expected to be less effective than zidovudine, as long as it can be expected to be more effective than the de facto standard of care (no prevention) in a given developing country. After all, a drug that is less effective than the standard of care in Western countries, but more effective than the standard of care in a given developing country, would lead to an overall larger number of HIV negative newborns in this developing country. A consequentialist approach to ethics would therefore consider scientific research designed to test such cheaper drugs as defensible. This approach would certainly violate international research ethics guidelines such as those of the Council for International Organizations of Medical Sciences and the WHO. [5]
However, research ethics guidelines are not something with a value of their own; rather, they are tools designed to protect the interests of vulnerable people. Given that we live in a less than ideal world, is it so unreasonable to suggest that the interests of people with AIDS in developing countries are better served by clinical researchers studying affordable drugs than by those who uphold international ethical research guidelines which could effectively prevent research in those countries? We think that this type of ethical principlism is a luxury people with AIDS in developing countries cannot afford.
The comparison to Tuskegee [1] is clearly inappropriate. Patients there were deceived, told that they were receiving therapy when in fact they were not and therapy was available in the USA, while antiretrovirals are not available to most HIV infected women. Furthermore, participants in the studies scrutinised by Lurie et al [2] gave voluntary informed consent while patients in Tuskegee did not. It would be of interest, however, to see if the participants indeed understood what informed consent and placebocontrolled trial meant. Patient comprehension of the content of informed consent forms has been questioned even in the United States. For example, Williams et al at Grady Memorial Hospital in Atlanta, Georgia found that a standardised, informed consent was beyond the reading level of 40 per cent to 74.7 per cent of all patients. [6] Furthermore, it has been demonstrated that there is good reason to believe that a large percentage of trial participants in preventive AIDS vaccine trials in Brazil have a therapeutic misconception, and mistakenly assume that they have received a successfully working drug capable of preventing an HIV infection. [7]
Quite another matter is, of course, whether placebo controls are ethically acceptable. After all, we clearly know from the trials that have led to the status quo in Western societies what zero treatment means for HIVinfected pregnant women. It can be argued that it is ethically problematic to subject these women to a placebo control based on current understanding of perinatal transmission. On the other hand, one can argue that historical controls are inappropriate and, since the standardofcare is no treatment, then that should be the control arm. Additionally, zidovudine has anaemia as a major side effect, and it is possible that it could be detrimental in a population where malaria and chronic anaemia are already endemic. [8]
As new treatment guidelines are published [9,10] a 'Berlin Wall' is inexorably separating persons living with HIV/AIDS in developed and developing nations. More than ever, high quality research is needed in developing nations that does more than attempt to mimic the trials and results of developed nations. Such research must have relevance for and applicability to the specific contexts of developing countries. We believe the time has come for a renewed debate about research ethics guidelines appropriate for developing countries. What is clear, however, is that the research conducted in developing countries ought to heed at least one of the requirements of the CIOMS/WHO research ethics guidelines: that is to guarantee that those communities where these new drugs have been tested will be given affordable access to the newly developed and approved drugs. Otherwise, one might rightly argue that people in developing countries have yet again been exploited by Western researchers without benefiting from the positive results their risktaking has yielded.
1. Angell M. The ethics of clinical research in the Third World. New England Journal of Medicine. 1997; 337:84749.
2. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. New England Journal of Medicine. 1997; 337:85356.
3. Schuklenk U, del Rio C, Magis C, Chokevivat V. AIDS in the Developing World. In: Chadwick R. (Ed). Encyclopedia of Applied Ethics. Academic Press 1998, San Diego, CA (Vol 1, pp. 123127).
4. Hogg RS, Anis A, Weber AE, O+Shaughnessy, Schechter MT. Triplecombination antiretroviral therapy in subSaharan Africa. Lancet 1997; 350: 9088
5. CIOMS/WHO. International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS 1993.
6. Williams MV, Parker RM, Baker DW, Parikh NS, et al. Inadequate Functional Health Literacy Among Patients at Two Public Hospitals. JAMA 1995; 274:16771682.
7. Queiroz de Fonseca, O, Lie, RK. Informed consent to preventive AIDS vaccine trials in Brazil. AIDS and Public Policy Journal 1995; 10: 2226.
8. DeCock K, Shaffer N, Wiktor S, Simonds RJ, Rogers M. Ethics of HIV trials. Lancet 1997; 350:154647.
9. BHIVA Guidelines Coordinating Committee. British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. Lancet 1997; 349:108692.
10. Carpenter CC, Fischl MA, Hammer SM, et al. Antiretroviral
Therapy for HIV Infection in 1997. Updated Recommendations of
the International AIDS Society USA Panel. JAMA 1997;277(24):19629.