Over 90% of deaths attributable to
malaria are in African children under 5 years old. Yet, new treatments are often tested primarily in adult patients and extrapolations have proven to be sometimes invalid, especially in dosing regimens. For studies in severe
malaria an additional complication is that the decline in severe
malaria in adult patients precludes sufficiently powered trials in adults, before the intervention can be tested in the ultimate target group, paediatric severe
malaria. In this paper we propose an alternative pathway to the development of drugs for use in paediatric severe
malaria. We argue that following the classical phase I and II studies, small safety and efficacy studies using well-chosen
surrogate endpoints in adult severe
malaria be conducted, instead of larger mortality endpoint trials. If the
drug appears safe and promising small pilot studies in paediatric severe
malaria using the same endpoints can follow. Finally, with carefully observed safeguards in place to ensure high ethical standards, promising candidate interventions can be taken forward into mortality endpoint, well-powered, large paediatric studies in African children with severe
malaria. Given the available research capacity, limited numbers of prudently selected interventions can be studied in phase III trials, and adaptive designs should be considered.