Current Statistical Considerations and Regulatory Perspectives on the Planning of Confirmatory Basket, Umbrella, and Platform Trials

Olivier Collignon*, Christian Gartner, Anna Bettina Haidich, Robert James Hemmings, Benjamin Hofner, Frank Pétavy, Martin Posch, Khadija Rantell, Kit Roes, Anja Schiel

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

35 Citations (Scopus)

Abstract

Master protocols have received a growing interest during the last years. By assigning patients to specific substudies, 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 substudies are independent, no supplementary adjustment for multiplicity over the different substudies 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 I error rate, whereas the chance of multiple false positive regulatory decisions should be recognized. In basket trials, pooling across substudies requires a rationale supporting the intended indication and should be preplanned. Assessment of the benefit/risk in pooled target populations can be complicated by differences in design or in efficacy/safety signals between the substudies. While trials governed by a master protocol can offer logistic and financial advantages, more experience is needed to gain a deeper insight into this novel framework.

Original languageEnglish
Pages (from-to)1059-1067
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume107
Issue number5
DOIs
Publication statusPublished - 1 May 2020

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