Current statistical considerations and regulatory perspectives on the planning of confirmatory basket, umbrella and platform trials.
- Competence Center for Methodology and Statistics
Master protocols have received a growing interest during the last years. By assigning patients to specific sub-studies, they aim at targeting and accelerating clinical development. Given their complexity, basket, umbrella, and platform designs have raised challenging regulatory and statistical questions, especially the control of multiplicity in confirmatory trials. In basket trials, regulatory assessment of the benefit/risk in pooled populations and choice of the treatment indication is challenging. We provide here our perspectives on these topics. In master protocols, as long as the statistical hypotheses tested between the different sub-studies are independent, no supplementary adjustment for multiplicity over the different sub-studies should be required. Moreover, sharing a control arm within an umbrella or a platform trial investigating different drugs would not require a correction for the Type 1 error rate, whereas the chance of multiple false positive regulatory decisions should be recognised. In basket trials, pooling across sub-studies requires a rationale supporting the intended indication and should be pre-planned. Assessment of the benefit/risk in pooled target populations can be complicated by differences in design or in efficacy /safety signals between the sub-studies. While trials governed by a master protocol can offer logistic and financial advantages, more experience is needed to gain a deeper insight of this novel framework.