Ethics in clinical research: searching for absolutes.

The ethics of contemporary research practice, especially with respect to the design and conduct of clinical trials, has been subjected to considerable scrutiny in recent years. Issues related to informed consent, the use of placebo controls and the tension between the requirement for scientific evidence on the one hand and for patient autonomy on the other have all generated heated debate. In this editorial I review some recent controversies that highlight the fractious nature of the debate and point to the watershed we are approaching in clinical research ethics. Although there are no obvious solutions, it is clear that there is a need for increased patient participation in any attempt to achieve consensus on the ethical conduct of medical research. Several months ago the British Medical Journal published 2 research studies involving several hundred patients from whom informed consent had not been obtained. Both studies had been approved by local ethics committees. Moreover, both studies complied with the Declaration of Helsinki, which permits physicians to waive the requirement for informed consent as long as an independent ethics committee has deemed the waiver to be justified. Divergent opinions on the ethics (and publication) of the studies were expressed in accompanying commentaries and in the unprecedented wave of letters to the journal that followed. More recently, 2 articles in the New England Journal of Medicine that questioned the ethics of placebo use in certain clinical trials generated strong criticism from members of that journal’s editorial board. At issue were several placebocontrolled trials of antiretroviral treatment (to reduce perinatal HIV transmission) being carried out in developing countries. An objection to the use of placebo controls in contexts where effective treatment exists was previously raised by Rothman and Michels, who documented several examples. Reaction from researchers and regulators (including members of Health Canada’s drugs directorate) has been equivocal, however. Those favouring the use of placebo controls put forward pragmatic (it is quicker and cheaper), statistical (it requires smaller sample sizes) and other counterarguments. In the case of the HIV transmission trials, for instance, it has been argued that, given the cost of antiretroviral drugs, patients from developing countries would not have received such treatment under the local health care system. Moreover, imposing Western standards on all clinical trials conducted in developing countries would have prevented the development of many interventions such as oral rehydration, micronutrient supplementation (e.g., vitamin A) and low-cost surgical procedures (e.g., cataract surgery). Finally, if the placebo arm were replaced by known effective treatment, study results might be difficult to interpret. A clear consensus on the issue has yet to emerge: in at least 2 of the HIV transmission trials, the investigators have decided to drop the placebo arms, while the Lancet has reversed its previous editorial opposition to the use of placebo controls. Other issues relating to placebo use, namely, the updating of informed consent and the premature termination of randomized trials, were recently highlighted in relation to the TRACE trial (on the effects of ACE [angiotensin-converting enzyme] inhibitors in patients with left-ventricular dysfunction after myocardial infarction). The results of 2 other randomized trials (demonstrating a benefit for ACE inhibitors) were published before the planned termination of the TRACE trial. Brophy and Joseph pointed out that the informed consent of participants Editorial