Clinical development of new prophylactic antimalarial drugs after the 5th Amendment to the Declaration of Helsinki

Abstract

Malaria is of continuing concern in nonimmune traveling populations. Traditionally, antimalarial drugs have been developed as agents for dual indications (treatment and prophylaxis). However, since 2000, when the 5th Amendment to the Declaration of Helsinki (DH2000) was adopted, development of new malaria prophylaxis drugs in this manner has ceased. As a consequence, there may not be any new drugs licensed for this indication in the foreseeable future. Major pharmaceutical companies have interpreted DH2000 to mean that the traditional development paradigm may be considered unethical because of doubt over the likelihood of benefit to endemic populations participating in clinical studies, the use of placebo, and the sustainability of post-trial access to study medications. In this article, we explore the basis of these concerns and suggest that the traditional development paradigm remains ethical under certain circumstances. We also consider alternative approaches that may be more attractive to sponsors as they either do not use placebo, or utilize populations in endemic countries who may unambiguously benefit. These approaches represent the way forward in the future, but are at present unproven in clinical practice, and face numerous regulatory, logistical and technical challenges. Consequently, in the short term, we argue that the traditional clinical development paradigm remains the most feasible approach and is ethical and consistent with the spirit of DH2000 under the appropriate circumstances.

Keywords: DH2000; Declaration of Helsinki; ethics; malaria; prophylaxis; treatment.

Figure 1

Clinical development of new drugs for malaria prevention. Note: Antimalarial drugs have traditionally been developed for both malaria treatment and prophylaxis as outlined in the panel on the left. Malarone, the last drug approved in the United States, and developed prior to the adoption of the 5th Amendment of the Declaration of Helsinki (DH2000), is used as an example. Major pharmaceutical companies now consider this approach to be unethical because placebos must be used and the Phase III prophylaxis studies utilize semi-immune individuals in malaria-endemic countries who would not normally benefit from malaria prophylaxis. The development of Malarone^™ (atovaquone-proguanil) has also been criticized because the high cost of treatment made sustainable post-trial access to the drug difficult. Our perspective is that the traditional approach remains ethical and consistent with DH2000 for the reasons stated at the bottom of the left panel and discussed in the accompanying text. The three panels to the right outline potential alternative clinical development pathways based on studies conducted in the traditional target population for prophylaxis (Western travelers), mixed populations of endemic country and nonendemic country immunes or focused on novel forms of prophylaxis. These resolve some of the DH2000 ethical concerns but have varying degrees of feasibility as indicated in the figure and discussed in the accompanying text.