This paper analyzes statistical decisions during the interim analyses of clinical trials. After some general remarks about the ethical and scientific demands of clinical trials, I introduce the notion of a hard-case clinical trial, explain the basic idea behind it, and provide a real example involving the interim analyses of zidovudine in asymptomatic HIV-infected patients. The example leads me to propose a decision analytic framework for handling ethical conflicts that might arise during the monitoring of hard-case clinical trials. I (...) use computer simulations to show how the framework can assist in reconciling certain ethical conflicts. The framework is partial, lacking the precision of a complete systematization of statistical monitoring procedures in practice. (shrink)

Placebo-trials on HIV-infected pregnant women in developing countries like Thailand and Uganda have provoked recent controversy. Such experiments aim to find a treatment that will cut the rate of vertical transmission more efficiently than existing treatments like zidovudine. This scenario is first stated as generally as possible, before three ethical principles found in the Belmont Report, itself a sharpening of the Helsinki Declaration, are stated. These three principles are the Principle of Utility, the Principle of Autonomy and the Principle (...) of Justice. These are taken as voices of moral imperative. But although each has intuitive appeal, it can be shown that there are possible scenarios in which they give conflicting prescriptions. To achieve consistency, one must be subordinate to the others. The voice of utility is taken as subordinate to those of justice and autonomy and it is shown that given plausible assumptions about the level of poverty and education in the developing country targeted, the experiment is ruled morally wrong in the name of both justice and autonomy. Moreover, it is argued that no justification can be found for the inclusion of a placebo group, when strictly defined. By contrast, a ‘no- treatment’ control arm might be justified, but only when the demands of autonomy are satisfied, demands that are more stringent than they might appear. A utilitarian defence of the experiment is examined, namely that the would-be participants are in a no-loss situation, and it is shown that this defence is seriously flawed. Finally, it is concluded that there is no justification for amending the Declaration of Helsinki. (shrink)

Records the papers and commentaries, with an edited discussion, presented at an international consultation convened by the Council for International Organizations of Medical Sciences (CIOMS) to guide revision of the CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects. The Guidelines, first issued in 1982 and then revised in 1993, are being updated and expanded to address a number of new and especially challenging ethical issues. These include issues raised by international collaborative trials of drugs in developing countries, especially (...) expensive drugs, and the use of placebo controls in randomized clinical trials. Others arise from the complexity of research in human genetics, including stem-cell research, and in reproductive biology. Throughout, particular attention is given to the difficult questions that arose during the heated debate over trials in developing countries, of short-duration zidovudine (AZT) therapy to reduce perinatal transmission of HIV. The International Ethical Guidelines for Biomedical Research Involving Human Subjects set out a code of research ethics that is widely used by ethical review committees and other bodies responsible for reviewing and overseeing the ethical design of studies and conduct of research. The revision of the Guidelines is being coordinated by CIOMS, in collaboration with WHO. The consultation centered on seven specially commissioned papers, authored by international experts that explore some of the more difficult issues in depth. Each is followed by an invited commentary, often expressing opposing views, and a summary of the issues or conclusions that emerged during the subsequent debate. The first paper, on justice in international research, deals with the question of whether proposals for research to be conducted in a developing country should make provision for future access of the population involved to the interventions under investigation. Also considered are questions that arise when research uses populations in developing countries to investigate interventions that will be of exclusive benefit to the industrialized world. Case studies of recent drug trials and their research protocols are discussed to illustrate circumstances in which use of populations in developing countries is justified or constitutes exploitation. Ethical challenges of the randomized controlled trial are considered in the second paper, which includes a discussion on the equitable distribution of benefits and risks, the use of placebo for controls, and the obligation to ensure that the participation of controls does not compromise their medical care or endanger their health. A paper on informed consent in international health research considers how cultural factors influence communication and language in the informed-consent process and respect for privacy and confidentiality in the research. Subsequent papers address issues in genetics research and reproductive biology, including the moral status of fetuses and the use of embryos in research, and examine the contribution which international human rights instruments can make in the application of the general principles of ethics to research involving human subjects. The final paper gives an overview of capacity building and the role of communities in international biomedical research. (shrink)

The maternal‐fetal HIV transmission trials, conducted in developing countries in the 1990s, undoubtedly generated one of the most intense, high profile controversies in international research ethics. They sparked off a prolonged acrimonious and public debate and deeply divided the scientific community. They also provided an impetus for the revision of the Declaration of Helsinki – the most widely known guideline for international research. In this paper, I provide a brief summary of the context, outline the arguments for and against the (...) controversial use of placebo controls, and focus on particular areas that I believe merit further discussion or clarification. On balance, I argue that the researchers failed in their duties to protect the best interests of their research subjects, and to promote distributive justice. I discuss the difficulties of obtaining valid consent in this research context, and argue that it is unethical to inform women of their HIV status without at least offering them prophylactic treatment for their unborn children. 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. Finally, I suggest that the 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. (shrink)