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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.

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Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping is a therapeutic approach that aims to induce production of partially functional dystrophins. Recently, an AON targeting exon 51 became the first of its class to be approved by the United States regulators [Food and Drug Administration (FDA)] for the treatment of DMD. A unique aspect of the exon-skipping approach for DMD is that, depending on the size and location of the mutation, different exons need to be skipped. This challenge raises a number of questions regarding the development and regulatory approval of those individual compounds. In this study, we present a perspective on those questions, following a European stakeholder meeting involving academics, regulators, and representatives from industry and patient organizations, and in the light of the most recent scientific and regulatory experience.

Duchenne muscular dystrophy is a rare, progressive, muscle-wasting disease leading to severe disability and premature death. Treatment is currently symptomatic, but several experimental therapies are in development. Implemented care standards, validated outcome measures correlating with clinical benefit, and comprehensive information about the natural history of the disease are essential for regulatory approval of any treatment. However, for Duchenne muscular dystrophy and other rare diseases, these requirements are not always in place when potential therapies enter the clinical trial phase. A cooperative effort of stakeholders in Duchenne muscular dystrophy-including representatives from patients' groups, academia, industry, and regulatory agencies-is aimed at addressing this shortfall by identifying strategies to overcome challenges, developing the tools needed, and collecting relevant data. An open and constructive dialogue among European stakeholders has positively affected development of treatments for Duchenne muscular dystrophy; this approach could serve as a paradigm for development of treatments for rare diseases in general.