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

The design and conduct of 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. In particular, the strict control of the family-wise Type I error rate often seems unreasonably rigid. 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, e.g. in case one compound is found to be superior to standard-of-care, it could become the new standard-of-care in future cohorts. Our results indicate that the method of data sharing, exact specification of decision rules and quality of the biomarker used to make interim decisions all strongly contribute to the operating characteristics of the platform trial. Together with the potential flexibility and complexity of a platform trial, which also impact the achieved operating characteristics, this implies that utmost care needs to be given to evaluation of different assumptions and design parameters at the design stage.