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Current Statistical Considerations and Regulatory Perspectives on the Planning of Confirmatory Basket, Umbrella, and
Olivier Collignon1, Christian Gartner2, Anna-Bettina Haidich3
1Competence Centre in Methodology and Statistics, Luxembourg Institute of Health, Strassen, Luxembourg.
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.
Insights
Master protocols accelerate clinical development by grouping patients into substudies. Statistical adjustments for multiplicity are not needed if hypotheses are independent, but regulatory review requires careful benefit/risk assessment.
Area of Science:
- Clinical Trials Methodology
- Regulatory Science
- Biostatistics
Background:
- Master protocols, including basket, umbrella, and platform designs, are increasingly used to streamline clinical development.
- These complex designs present unique regulatory and statistical challenges, particularly concerning multiplicity control in confirmatory trials.
Purpose of the Study:
- To provide perspectives on the regulatory and statistical considerations for master protocols.
- To address challenges in multiplicity control, benefit/risk assessment, and treatment indication selection within these complex trial designs.
Main Methods:
- The study offers expert perspectives and discusses statistical principles related to master protocols.
- It examines the implications of shared control arms and pooled analyses across substudies.
Main Results:
- Independent statistical hypotheses across substudies in master protocols do not necessitate supplementary multiplicity adjustments.
- Sharing control arms in umbrella or platform trials does not require Type I error rate correction, though the risk of false positive regulatory decisions must be acknowledged.
- Basket trials require preplanned rationale for pooling substudies and careful benefit/risk assessment due to potential design and signal heterogeneity.
Conclusions:
- Master protocols offer potential logistic and financial advantages for clinical development.
- Further experience and insight are needed to fully understand and optimize this novel trial framework.
- Careful planning and statistical considerations are crucial for the successful implementation and regulatory acceptance of master protocols.
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