Ethics of Cancer Clinical Trials in Low-Resource Settings

Debates surrounding the appropriate design and conduct of clinical research in low-resource settings have bedeviled the scientific, policy, and bioethics communities for decades. Historically, controversies primarily involved trials related to infectious disease. With the growing globalization of cancer clinical trials and the recognition of cancer as a public health threat in developing as well as developed countries, these debates will increasingly engage the cancer research community. The paradigmatic case that sparked discussion of the ethics of international clinical trials concerned the development of antiretroviral therapies to prevent vertical transmission of HIV from pregnant women to their newborn infants. In 1994, the AIDS Clinical Trials Group published results of the Pediatric AIDS Clinical Trials Group Protocol 076 trial (hereafter, 076), a study conducted in the United States and France that compared an intensive and prolonged regimen of perinatal zidovudine to placebo.1 The 076 regimen reduced the risk of vertical transmission from 25.5% to 8.3%, and it rapidly became the standard of care for HIV-infected pregnant women in developed nations. Most of the world's burden of HIV, however, resided in low-resource areas such as sub-Saharan Africa, areas in which the 076 regimen was infeasible for financial and logistical reasons. Thus, numerous research teams set out to identify less expensive, less logistically demanding approaches to the problem of perinatal transmission. Because standards of care in low-resource countries after the publication of the 076 study did not include zidovudine, most teams compared potentially feasible new interventions against placebo controls. In 1997, Lurie and Wolfe2 and Angell3 ignited a firestorm with the charge that placebo-controlled trials of perinatal short-course zidovudine, one of the regimens under study as a feasible alternative to the 076 regimen, unethically denied proven effective therapy to control-group participants. Pointing out that placebo-controlled studies of interventions to reduce the incidence of vertical HIV transmission were no longer acceptable in developed countries, they claimed that the use of placebos in developing-world trials represented an unethical double standard. Angell, invoking the memory of the infamous Tuskegee syphilis study, claimed that “acceptance of this ethical relativism could result in widespread exploitation of vulnerable Third World populations for research programs that could not be carried out in the sponsoring country.”3 Study sponsors and other commentators disputed this position, arguing that placebo controls were necessary to assess the efficacy and feasibility of the short-course regimen as compared with the absence of antiretroviral treatment and that no patients were made worse off by trial participation relative to the local standard of care.4,5 Cancer, too, is increasingly a disease of the developing world. According to the American Cancer Society, 56% of cancer cases and 64% of cancer deaths in 2008 occurred in the economically developing world.6 Such statistics highlight a pressing need for high-quality research to identify feasible, evidence-based therapeutic strategies appropriate for low-resource settings. Despite the public health urgency of cancer in the developing world, along with the globalization of industry-sponsored clinical research, the ethics of cancer clinical trials in low-resource settings have received little attention.7,8 However, recent controversies suggest that these trials may come under increased scrutiny.9–13 What are the appropriate standards for the design and conduct of such trials? Ethical criteria for clinical research are generally held to universally.14 Differences in health service priorities and wide disparities in background conditions, however, raise the possibility that the questions asked and the methods used to answer them might justifiably vary across regions. Two questions relevant to clinical trials in low-resource settings are particularly vexing. First, what is the proper control group for evaluating investigational treatments in this setting? As with HIV, investigators conducting cancer trials—especially those based at developed-world institutions or funded by developed-world sources—must decide whether trials should compare novel interventions to the developed-world standard of care, or if it is acceptable, or even preferable, to evaluate them against locally available treatments. Second, must these trials have the potential to benefit the host population? These questions, which encompass what sponsors and investigators owe both to study participants and to host communities, remain unsettled to this day.15