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

Date Published: November 18, 2008

Publisher: Public Library of Science

Author(s): Steffen Borrmann, Tim Peto, Robert W Snow, Win Gutteridge, Nicholas J White

Abstract: Steffen Borrmann and colleagues discuss appropriate endpoints and their measurement during phase III trials of new antimalarial drugs.

Partial Text: 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 the era of highly efficacious ACTs there is considerable debate among experts on what, exactly, constitutes the most relevant property of a new antimalarial drug [9,15]. In other words, in phase III trials, should we ask:
How efficacious is the new drug in curing primary blood stage infections (chemotherapeutic efficacy)?orHow efficacious is the new regimen in curing primary infections and in preventing secondary infections (composite chemotherapeutic and post-treatment prophylactic efficacy)?orHow efficacious is the new drug in reducing the post-treatment incidence of malaria and its complications (clinical risk reduction)?

Optimal target profiles for new antimalarial drugs have been described elsewhere and used as guiding principles from early discovery through clinical development [39,40]. In an ideal world, antimalarial treatments would be 100% efficacious; in the real world, WHO suggests aiming to achieve parasitological cure rate point estimates of at least 95% (excluding re-infections) [41]. To establish with 95% confidence that a new treatment can demonstrate a cure rate of at least 95% in a phase III trial with 500 patients per group, the true (unknown) cure rate would have to be at least 97%. This sets a high bar for evaluating new candidate drugs and might lead to the premature rejection of new products because of suboptimal dosing, formulation, or the play of chance. A greater than 90% parasitological cure rate (lower boundary of the 95% confidence interval) represents an alternative, more realistic initial target for new treatments (requiring only a true cure rate of at least 93% under the same sample size assumption).

Figure 1A illustrates how trailing plasma drug concentrations of slowly eliminated antimalarial drugs delay detectable recrudescent primary and secondary blood stage infections alike. These effects fade during follow-up beyond day 28.

In phase III, the new candidate drug is compared in a randomised controlled trial [44] to a standard treatment that retains the desired “control effect size” [44], e.g., the targeted more than 90% parasitological cure rate (excluding reinfections). Historically, when existing recommended treatments were failing, antimalarial phase III drug trials have been designed as superiority trials [9,45], but there is a dramatic increase in the sample sizes required to demonstrate superiority of a potential future replacement for a drug with currently very high parasitological cure rates [9].

The interpretation of a non-inferiority trial with a survival estimate of recrudescent infections can be based on two criteria: (1) the hypothesis test result, e.g., the 95% CI of the proportional hazard ratio test/control remains below the non-inferiority limit on the hazard ratio to support claims of efficacy [51]; and (2) the day 28 and later survival rate estimate in the test drug arm. Table 1 lists possible combinations of trial results and recommendations for their interpretation. The standardised reporting of key baseline and outcome variables of antimalarial trials using a hierarchical system will greatly facilitate further detailed post-hoc analyses and interpretations [18].

Consensus-agreed regulatory guidelines on how phase III trials of antimalarial drugs for uncomplicated P. falciparum malaria are designed and interpreted are only now being developed [52]. This review intends to stimulate an informed discussion on the utility of the different primary endpoints in future phase III antimalarial trials and proposes a comparative framework for the interpretation of results from ongoing trials. We hope that consensus between academia, public health professionals, industry, and regulators on the design and particularly the primary endpoint of phase III trials allows earlier appraisal of the potential advantages or equivalence of a new treatment in comparison with existing therapies ahead of more extensive phase IV programmes.