Revisiting the Design of Phase III Clinical Trials of Antimalarial Drugs for Uncomplicated Plasmodium falciparum Malaria

In 2002, Plasmodium falciparum caused at least 0.5 billion uncomplicated clinical attacks of malaria worldwide, particularly in non-immune young children living in Africa [1]. Because inadequately treated uncomplicated P. falciparum malaria can progress rapidly to life-threatening severe malaria [2,3], mortality from P. falciparum in Africa doubled during the 1990s against a rising frequency of resistance to commonly used drugs, such as chloroquine and sulfadoxine-pyrimethamine [4]. In recent years, the deployment of highly efficacious oral three-day regimens of artemisinin-based combination therapies (ACTs) with parasitological cure rates of 95% or greater in more than 40 endemic countries has radically changed antimalarial treatment [5–8]. This success demands a new approach to the ways in which we assess new antimalarial drugs during clinical development and judge their potential utility for the public health deployment [9]. For example, the ability of slowly eliminated new drugs to delay re-infections and thus secondary malaria episodes for several weeks by suppressing the growth of P. falciparum provides additional public health benefits, especially in high-transmission areas where re-infection rates can exceed 50% in less than six weeks [10,11]. In turn, new drugs with comparatively higher efficacy against primary blood stage infections and/or a shorter elimination half-life minimise morbidity from recrudescent primary infections and may reduce the rate of spread of resistance [9,12], and are thus particularly valuable in situations of low or decreasing transmission rates [13] where the likelihood of re-infection during the relatively short post-treatment prophylactic period is lower (Figure 1A and ​and1B).1B). There is already a general consensus on the design and interpretation of clinical trials used for monitoring antimalarial drug efficacy by national malaria control programmes [14]. The objective of this paper is to reflect on the design and interpretation of phase III trials. Figure 1 Simulated Plots of Weekly Incidence Rates and Cumulative Proportions for Recrudescent Primary Infections and Re-Infections Following Treatment of Uncomplicated P. falciparum Malaria with a Slowly Eliminated (Partner) Drug (Half-Life of ~1 Week) Summary Points Curing malaria episodes is the key priority for antimalarial treatment; its measurement as primary endpoint in phase III trials provides consistent estimates of the antiparasitic effect of a new regimen. The delay of secondary malaria episodes by slowly eliminated new drugs provides additional public health benefits in high-transmission areas; it should therefore be measured as key secondary or, preferably, co-primary endpoint. WHO suggests aiming to achieve parasitological cure rates of ≥95%; if adopted for drug development this sets a high bar and may lead to the premature rejection of potentially valuable new drugs. Since small differences in cure rates of ≥95% may be outweighed by advantages in cost, dosing, or tolerability, new drugs can be examined in non-inferiority trials with a proposed difference margin of ≤5%. We recommend survival analysis of the primary endpoint.