Some recent developments in the international guidelines on the ethics of research involving human subjects

We are in a period of reconsideration and revision of international ethical guidelines for the conduct of biomedical research involving human subjects. The proximate cause of much of this activity is the recent controversy over the ethics of the use of a placebo control in the clinical trials of the short-duration regimen of zidovudine for prevention of perinatal transmission of HIV infection, trials that were carried out in several so-called technologically developing countries. Critics of these trials claimed that they were in violation of Article II.3 of the Declaration of Helsinki, which states: "In any medical study, every patient--including those of a control group, if any--should be assured of the best proven diagnostic and therapeutic method. This does not exclude the use of inert placebo in studies where no proven diagnostic or therapeutic method exists." The critics claimed that since the "best proven ... method" is the 076 regimen, this is what must be provided to members of the control groups. Failure to do so, they asserted, was a serious breach of ethics. In response to this allegation, several major international and national agencies convened multidisciplinary groups to consider the ethics of multinational clinical research. The first thing they realized was that Article II.3 was in error in that it did not reflect contemporary ethical thinking. Moreover, it was routinely violated in research conducted in developed as well as in developing countries. What replaces this standard? The 1993 CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects include several criteria for justification of research carried out in developing countries. Most importantly, the research must be responsive to the health needs and priorities of the host country. They also require that any therapeutic products developed in such research must be made "reasonably available" to residents of the host country. A new standard is emerging for selecting therapies to be administered to participants in multinational clinical trials and for use as the control "treatment" in such trials. It is called the "highest attainable and sustainable" therapeutic method. Application of this standard differs from application of the "best proven method" standard in that it permits the evaluation of new therapies that are responsive to the health needs and priorities of resource-poor countries. It has long been recognized that the Declaration of Helsinki is a flawed document in that it relies on the illogical distinction between therapeutic and nontherapeutic research. This distinction has been removed from the most recent draft revisions of the Helsinki and the CIOMS documents.