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:

• malaria
• prophylaxis
• treatment
• Declaration of Helsinki
• DH2000
• ethics

Acknowledgements

This manuscript was reviewed by Walter Reed Army Institute of Research (WRAIR) and US Army Medical Research and Material Command (MRMC), and there is no objection to its publication or dissemination. The opinions expressed herein are those of the authors and do not reflect the views or opinions of the Department of the Army or the Department of Defense. We thank Dr Wilbur K. Milhous for helpful comments on the manuscript.

Disclosure

The authors are actively engaged in new drug development for antimalaria chemoprophylaxis at the WRAIR and have a professional interest in identifying a pathway forward for clinical development of new drugs for the prophylaxis indication. The authors are or in the past have been members of the joint GlaxoSmithKline-US Army tafenoquine clinical development team. None of the authors have a financial conflict of interest.