A new look at international research ethics

British Medical Journal, Sept 30, 2000 by Solomon R Benatar, Peter A Singer

The normal "standard of care" against which new interventions are tested in medical research has not been formally defined. It is usually taken to mean the "best proved treatment" for any condition under investigation in a trial. We reject the arbitrariness of this notion of the standard of care and offer a more comprehensive alternative. Use of this new standard invokes a new approach to international research ethics that focuses on reducing inequalities in global health.

The debate on what constitutes a fair and reasonable standard of care for subjects in developing countries who participate in clinical trials has been rekindled by critics of studies on the transmission of HIV.[1-3] They argued that placebo controlled trials of new regimens to prevent the vertical transmission of HIV were unethical because they included a placebo arm rather than "the best proven treatment" available in developed countries. Some commentators considered the criticisms to be unfounded[4-6] and associated with imperialistic attitudes.[7]

The debate made it clear that the high standards of research aspired to have not been adequately defined. It was also marred by simplistic notions of ethics. Although there was justified concern that pressure from the US Food and Drug Administration could "dilute" the Declaration of Helsinki, critics also presumed that whether a trial was ethical could simply be deduced from the text of a declaration. But declarations--such as the Declaration of Helsinki, governing international research ethics--are like constitutions, needing interpretation. Determining what is ethical goes beyond merely following prescriptions and requires moral reasoning: consideration of all relevant aspects of the case in its context, weighing and balancing competing moral requirements, and developing justifiable conclusions.

Although more mature insight is gradually emerging into the complexity associated with the ethics of research in developing countries, the debate remains incomplete for several reasons.[8-12] Firstly, there has been a failure to define adequately the "standard of care." Secondly, it has been incorrectly assumed that the standard set by developed countries can be considered the norm. Thirdly, few commentators on research ethics have taken into consideration the injustice of 90% of all medical research being undertaken on those diseases that cause 10% of the global burden of disease.[13]

How do we define "standard of care" for research subjects?

Equal standards of medical care during research, reflecting equal respect for the dignity of subjects, could be taken to mean any one or a combination of several requirements (box 1). It is arbitrary and not justifiable to select only one of these--for example, which drugs are used--to compare the standard of care in developed and developing countries.

In the context of the disputed studies on HIV transmission, the vehement emphasis on the "best proven drugs" eclipsed considerations of whether the drug regimen could be safely applied in different settings. Little attention was paid to the fact that there were many differences between pregnant women in developing countries and those in countries where the "best proven" treatment had been established. Pregnant women in developing countries present to antenatal clinics much later in pregnancy than the women in the original studies; they are often anaemic and malnourished, and they live within a context in which breast feeding has different implications for newborn infants. Moreover, advice not to breast feed would contradict years of intensive education by the World Health Organization.

Concerning the use of placebos, the approach has also been simplistic. Whether a placebo arm is justified in a trial requires careful consideration of potential harms and benefits in specific contexts and cannot be simply deduced from a general declaration.[7] Of course it is necessary to acknowledge that many placebo trials are unethical because they are undertaken largely for marketing purposes--to show that "me too" drugs have actions greater than placebo, rather than to study whether they are better than existing similar, and often cheaper, drugs. Not only should nothing be done to make it easier to do such trials, but also every effort should be made to reduce wasting time and money on "promotional studies" In those situations where there are good reasons for placebo controlled trials, these should be considered on their merits rather than be precluded by a bluntly designed exclusive clause in a declaration.

Considerations of context are required aspects of moral reasoning in the application of universal principles in specific situations and do not entail moral relativism. Failure to distinguish moral relativism from the morally relevant considerations of context that are necessary for the specification of universal principles shows a lack of knowledge of the ethical decision making process.[14]

Is the blanket application of a universal standard of care achievable?