Comparing Highly Efficacious Antimalarial Drugs

Perspective I t is almost ten years since a clarion call was sounded to malaria researchers, funding agencies, governments, and international organisations to help avert " a malaria disaster " [1]. At that time, infrastructure in malaria control programmes across Africa was deteriorating. This deterioration was exacerbated by an alarmingly high prevalence of parasites resistant to the two affordable treatments being used across the continent: chloroquine and sulphadoxine-pyrimethamine. The plea was to speed up the introduction of combination therapies in which one of the component drugs was from a highly effective antimalarial class, the artemisinins, derived from the Chinese herbal remedy qinghaosu. Subsequent investment in research and clinical trials, and new drug procurement arrangements through the Global Fund to Fight AIDS, Tuberculosis and Malaria, have achieved much to be proud of. Many African countries have now implemented new malaria treatment policies centred around artemisinin combination therapy (ACT) as the front-line treatment for malaria. There is now an urgent need to bring new combination therapies into the malaria drug development pipeline, to provide endemic country governments with alternative regimens suited to malaria transmission in their setting, and to minimise the global impact of resistance to ACTs, should it arise. However, in order to be granted licensure, such new combinations must be tested against current ACT-based regimens of high efficacy. Therefore the previously established phase III clinical trial designs, which test for superiority of the investigational product against a failing drug such as chloroquine or sulphadoxine-pyrimethamine, can no longer apply. There are now important questions about the design and standardisation of such pre-licensure phase III antimalarial treatment trials. In a new Policy Forum on this topic, Steffen Borrmann and colleagues make important recommendations for such trials [2]. In particular, they advocate the use of a non-inferiority study design when deciding if a new regimen has an acceptable level of performance. In such a design, a new therapy is deemed acceptable for further investigation or licensure if it performs " at least as well as " a current therapy of good efficacy. The precise meaning of this phrase must be widely agreed before this approach can be adopted, and before future standardisation of such studies can be established. Borrmann and colleagues throw this debate open, but themselves advocate a " delta margin " (see Glossary) of 5%, with a fixed benchmark of at least 90% cure rate. Thus the efficacy of any new …