Online control of the False Discovery Rate in group-sequential platform trials

Abstract: When testing multiple hypotheses, a suitable error rate should be controlled even in exploratory trials. Conventional methods to control the False Discovery Rate (FDR) assume that all p-values are available at the time point of test decision. In platform trials, however, treatment arms enter and leave the trial at any time during its conduct. Therefore, the number of treatments and hypothesis tests is not fixed in advance and hypotheses are not tested at once, but sequentially. Recently, for such a setting the concept of online control of the FDR was introduced. We investigate the LOND procedure to control the online FDR in platform trials and propose an extension to allow for interim analyses with the option of early stopping for efficacy or futility for individual hypotheses. The power depends sensitively on the prior distribution of effect sizes, e.g., whether true alternatives are uniformly distributed over time or not. We consider the choice of design parameters for the LOND procedure to maximize the overall power and compare the OBrien-Fleming group-sequential design with the Pocock approach. Finally we investigate the impact on error rates by including both concurrent and non-concurrent control data.