Revisiting the Design of Phase III Clinical Trials of Antimalarial Drugs for Uncomplicated Plasmodium falciparum Malaria
Authors: Steffen Borrmann, Tim Peto, Robert W Snow, Win Gutteridge, Nicholas J White
Journal: PLoS Medicine (2008)

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.