Development of drugs for severe malaria in children.
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.
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd, Bangkok, 10400, Thailand Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK phaikyeong@tropmedres.ac.
Phaik Yeong
PY
Cheah
The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Michael
M
Parker
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd, Bangkok, 10400, Thailand Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Arjen M
AM
Dondorp
D000293:Adolescent; D000349:Africa; D000962:Antimalarials / Q000592:standards* / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D017277:Drug Approval / Q000379:methods*; D015507:Drugs, Investigational / Q000592:standards* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008288:Malaria / Q000188:drug therapy*; D008297:Male
D000962:Antimalarials; D015507:Drugs, Investigational
Children; Clinical trial; Ethics; Mortality; Paediatrics; Severe malaria