Improved efficiency for cross-arm comparisons via platform designs

Abstract

Though platform trials have been touted for their flexibility and streamlined use of trial resources, their statistical efficiency is not well understood. We fill this gap by establishing their greater efficiency for comparing the relative efficacy of multiple interventions over using several separate, 2-arm trials, where the relative efficacy of an arbitrary pair of interventions is evaluated by contrasting their relative risks as compared to control. In theoretical and numerical studies, we demonstrate that the inference of such a contrast using data from a platform trial enjoys identical or better precision than using data from separate trials, even when the former enrolls substantially fewer participants. This benefit is attributed to the sharing of controls among interventions under contemporaneous randomization. We further provide a novel procedure for establishing the noninferiority of a given intervention relative to the most efficacious of the other interventions under evaluation, where this procedure is adaptive in the sense that it need not be a priori known which of these other interventions is most efficacious. Our numerical studies show that this testing procedure can attain substantially better power when the data arise from a platform trial rather than multiple separate trials. Our results are illustrated using data from two monoclonal antibody trials for the prevention of HIV.

Keywords: COVID-19; Efficiency gain; Noninferiority test; Platform designs; Survival analysis; Vaccine efficacy.

Fig. 1

The empirical rejection rates of the intersection test and the likelihood ratio type test for different preselected active interventions based on data from the platform trial and separate trials, evaluated at (in months postenrollment) with varying margin values, the significance level of and the efficacy threshold , when all the observations are censored at 6 calendar months post-trial initiation and subject to moderate loss to follow-up.

Fig. 2

The confidence interval widths of the relative efficacy (on an additive scale) of the low-dose intervention relative to the high-dose intervention in HVTN 703 and HVTN 704, evaluated at week 80.