Decision rules for identifying combination therapies in open-entry, randomized controlled platform trials.

Abstract

Platform trials have become increasingly popular for drug development programs, attracting interest from statisticians, clinicians and regulatory agencies. Many statistical questions related to designing platform trials—such as the impact of decision rules, sharing of information across cohorts, and allocation ratios on operating characteristics and error rates—remain unanswered. In many platform trials, the definition of error rates is not straightforward as classical error rate concepts are not applicable. For an open‐entry, exploratory platform trial design comparing combination therapies to the respective monotherapies and standard‐of‐care, we define a set of error rates and operating characteristics and then use these to compare a set of design parameters under a range of simulation assumptions. When setting up the simulations, we aimed for realistic trial trajectories, such that for example, a priori we do not know the exact number of treatments that will be included over time in a specific simulation run as this follows a stochastic mechanism. Our results indicate that the method of data sharing, exact specification of decision rules and a priori assumptions regarding the treatment efficacy all strongly contribute to the operating characteristics of the platform trial. Furthermore, different operating characteristics might be of importance to different stakeholders. Together with the potential flexibility and complexity of a platform trial, which also impact the achieved operating characteristics via, for example, the degree of efficiency of data sharing this implies that utmost care needs to be given to evaluation of different assumptions and design parameters at the design stage.