Standard of care: an evolution in ethical thinking

Abstract

The phrase “standard of care” has been applied in different multinational research contexts, perhaps unwisely because of its ambiguity. It is little more than a decade since ethical controversy erupted over placebo-controlled clinical trials of mother-to-child HIV transmission in developing countries. One side argued that an ethical obligation to members of the control group is limited to whatever is the “standard of care” in the community or country where the research is carried out. Their opponents contended that when a proven intervention exists anywhere in the world, it should be provided to the control group, even if that intervention would not be available outside the clinical trial in the developing country. Moreover, if no preventive or therapeutic method exists in the country, it is a mistake to consider no care a “standard” of care. The advent of HIV biomedical prevention trials of candidate vaccines and microbicides added a new dimension to ethical debates about standard of care. The ongoing urgency to develop an effective method to prevent the acquisition and transmission of HIV has led to a steady increase in these clinical trials, despite recent disappointing trial results. A controversial question arose when preventive vaccine trials were just beginning: what level of care and treatment should be provided to participants in vaccine trials in developing countries who become infected with HIV during the trial? Should they be provided the standard of care that is prevalent in their country or community? Or should they receive the highest standard, that is, what is available to participants in the same or similar trials in industrialised countries? How this question has been answered has changed over time, illustrating an evolution in thinking about ethical standards in research. When circumstances change, so can ethical thinking about obligations to research participants. One side in this debate has argued that no obligation exists on the part of anyone to provide antiretroviral treatment to participants in vaccine trials who become infected during the trial; nothing more is owed to participants in HIV prevention trials than to any others whose failure to take proper precautions results in their becoming infected. From the outset, those who defend the provision of antiretroviral treatment have maintained that although it may be difficult to identify the source of an obligation, nevertheless HIV-infected participants should receive state-of-the art treatment after they become medically eligible, perhaps for a lifetime. One justification cites the obligation of researchers to seek to maximise benefits to research participants, as well as to keep the risks of conducting the trial to a minimum. Providing medical treatment to participants who become sick is one way, among others, of maximising health-related benefits. A different justification points to considerations of justice, noting the disparity between what research participants would receive if the trial were undertaken in industrialised countries and what is normally available in developing countries. A multicentre preventive vaccine or microbicide trial done simultaneously in industrialised and developing countries poses this stark contrast. Perhaps based on the merits of these ethical arguments, but also because of changing circumstances, an evolution in ethical thinking has occurred. As recently as 2000, when WHO and UNAIDS were carrying out a series of regional consultations on ethical issues in preventive HIV vaccine research, opinion was sharply divided. In 2003, a WHO consultation began with the premise, “not whether, but how” state-of-the-art antiretroviral treatment should be made available to participants in vaccine trials who become infected. By the end of 2007, an ethical guidance document issued by UNAIDS and WHO called for providing access to treatment regimens from among those internationally recognised as optimal. Although critics continue to maintain that there is no sound ethical justification for this provision, defenders strengthen their principled arguments by pointing to the altered context of HIV treatment. The main factor contributing to this evolution in thinking about what is owed to participants in HIV prevention trials is the increasing availability of antiretroviral therapy in many resource-poor countries. The scale-up began with the establishment of The Global Fund to Fight AIDS, Tuberculosis, and Malaria in 2002, continued with WHO's and UNAIDS's 3 by 5 initiative in 2003, and expanded further with the US Government's $15 billion President's Emergency Plan for AIDS Relief (PEPFAR) that began in 2004, among other efforts to expand access to treatment. Back when access to antiretroviral drugs was available to only a minority in most developing countries, some argued that it would be unjust for vaccine-trial participants to be singled out while other HIV-infected members of the community, including family members of the participants, lacked access. Even then, their opponents claimed that volunteers who place themselves at some risk, enduring discomfort and inconvenience, deserve something in return for their efforts in contributing to a search for an efficacious vaccine. Now that access to antiretrovirals is much more widely available, HIV prevention activities should be able to join in partnership with treatment programmes in developing countries, thereby accomplishing the twin goals of HIV prevention and treatment. Still, not everyone has been convinced that provision of antiretrovirals to those who become infected in HIV prevention trials is justified. In light of the increasing availability of treatment in many of the countries where prevention trials have begun or are proposed, some opponents have abandoned the argument that paying for treatment would be too costly. They turn to a very different claim, hoping to play an ethics trump card. This claim contends that offering antiretroviral treatment would constitute an “undue inducement” to take part in HIV prevention trials, thereby compromising the voluntariness with which individuals agree to enrol. Since voluntary participation in research is one of the bedrock ethical requirements, anything that would constitute undue influence is ethically unacceptable. This change of tactics seeks to place proponents of offering antiretrovirals on the defensive. Now it is not economics, but ethics that militates against providing treatment. But the argument is flawed on two counts. First, participants in HIV prevention trials are healthy volunteers. They do not need treatment at the time of enrolment and most will not become infected during the trial. Surely participants will not deliberately get infected in order to receive the eventual benefit of treatment. Second, a more telling consideration is the possible efficacy of the vaccine or microbicide being tested. If anything could count as an inducement for individuals who engage in risky behaviour to enrol in a phase III HIV prevention trial, it is the prospect that the product could actually work. Despite cautions stated in the informed consent process and document, volunteers are likely to hold out hope for the product's efficacy. Thus, the experimental product itself could be viewed as an undue inducement to take part in the study—a result that reduces the argument to an absurdity. A new ethical concept for biomedical prevention trials has already prompted controversy. The 2007 UNAIDS/WHO ethical guidance document uses the term “standard of prevention” in calling for provision of state-of-the-art risk reduction methods for the intervention and control groups in HIV prevention trials. But researchers contend that the more that participants in prevention trials have access to effective ways of reducing their risk of acquiring HIV, the more difficult it becomes for scientists to determine the efficacy of the preventive method being studied. From the time HIV preventive vaccine trials began, there was wide agreement that counselling on risk reduction should attain the highest existing standards, that condoms should be available free of charge to participants, and that where legal, clean needles should be distributed to injection drug users. But as more efficacious preventive methods loom on the horizon, researchers worry that requiring a prevention package containing state-of-the art methods will thwart their ability to obtain meaningful results of trials. The demonstrated efficacy of male circumcision in lowering the likelihood of acquiring HIV infection has prompted the question of what should be offered or provided to participants in prevention trials. Is it sufficient for researchers to refer potential participants for circumcision but without paying for the procedure? Is referral with payment for the procedure ethically obligatory? Should researchers go even further by arranging for direct provision of circumcision at trial sites? Irrespective of who pays, once the first efficacious HIV vaccine or microbicide is licensed, subsequent trials will have to incorporate those methods in a prevention package unless evidence exists that the population for the new trials is significantly different from that in which the method has been found efficacious. Determining the proper criteria for “significant difference” will itself be a daunting task. A growing consensus is emerging on the ethics of providing a state-of-the art prevention package to participants in biomedical prevention trials. Yet the question of who should pay remains unanswered and controversial. It is clear that the burden should not fall entirely on sponsors or researchers. And governments in low-resource countries still could not afford to shoulder the entire burden alone. But with the current array of international donors and the emergence of ever more public-private partnerships, it is entirely possible to incorporate these modest additional costs into the budgets of prevention trials. What would be needed to accomplish this? One approach might be to include skilled negotiators with the requisite skills to broker such arrangements among the array of existing clinical trial personnel. Such a negotiator could help to ensure that participants receive a state-of-the art prevention package, as well as access to treatment, when needed, if they become HIV infected during the trial. The ethical conduct of biomedical prevention trials demands nothing less. Ruth Macklin is an adviser to WHO and UNAIDS and an elected member of the US Institute of Medicine