On the need to adjust for multiplicity in confirmatory clinical trials with master protocols

Stallard, Nigel; Todd, Susan; Parashar, Deepak; Kimani, Peter K.; Renfro, Lindsay A.

doi:10.1093/annonc/mdz038

Cited by 37 publications

(43 citation statements)

References 17 publications

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“…As mentioned in refs. 32 and 36, we also recognized that this situation is different from the case where the trial arms investigate several doses of the same treatment; in this case strong control of the FWER over the treatment arms would be needed. As regards basket trials, Stallard et al .…”

Section: Discussionmentioning

confidence: 94%

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

Collignon

Gärtner

Haidich

et al. 2020

Clin Pharma and Therapeutics

103

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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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Section: Discussionmentioning

confidence: 94%

“…Importantly, the notion of independence between trials and more specifically between the tests of hypotheses was also mentioned in ref. 36 as being of primary relevance. In this context, we agree with Stallard et al .…”

Section: Discussionmentioning

confidence: 99%

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

Collignon

Gärtner

Haidich

et al. 2020

Clin Pharma and Therapeutics

103

View full text Add to dashboard Cite

show abstract

“…They define new type 1 error rates of interest and give recommendations for which type 1 error rates should be controlled with respect to the nature of the hypothesis tested. Stallard et al 248 classified trials with multiplicity issues that arise from multiple subgroups and multiple treatments as treatment arms within subgroups, subgroups within treatment arms, or subgroups within treatment arms within subgroups and proposed that multiplicity corrections should be used in the second and third settings. Wason et al 249 conducted a literature review of articles published in 2012 and found that there was no consensus on whether multiplicity corrections are needed if in a multi-arm trial the different arms are different treatments and not multiple doses of the same treatment.…”

Section: Multiplicitymentioning

confidence: 99%

The Evolution of Master Protocol Clinical Trial Designs: A Systematic Literature Review

Meyer

Mesenbrink

Dunger-Baldauf

et al. 2020

Clinical Therapeutics

100

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Purpose: Recent years have seen a change in the way that clinical trials are being conducted. There has been a rise of designs more flexible than traditional adaptive and group sequential trials which allow the investigation of multiple substudies with possibly different objectives, interventions, and subgroups conducted within an overall trial structure, summarized by the term master protocol. This review aims to identify existing master protocol studies and summarize their characteristics. The review also identifies articles relevant to the design of master protocol trials, such as proposed trial designs and related methods. Methods: We conducted a comprehensive systematic search to review current literature on master protocol trials from a design and analysis perspective, focusing on platform trials and considering basket and umbrella trials. Articles were included regardless of statistical complexity and classified as reviews related to planned or conducted trials, trial designs, or statistical methods. The results of the literature search are reported, and some features of the identified articles are summarized. Findings: Most of the trials using master protocols were designed as single-arm (n ¼ 29/50), Phase II trials (n ¼ 32/50) in oncology (n ¼ 42/50) using a binary endpoint (n ¼ 26/50) and frequentist decision rules (n ¼ 37/50). We observed an exponential increase in publications in this domain during the last few years in both planned and conducted trials, as well as relevant methods, which we assume has not yet reached its peak. Although many operational and statistical challenges associated with such trials remain, the general consensus seems to be that master protocols provide potentially enormous advantages in efficiency and flexibility of clinical drug development. Implications: Master protocol trials and especially platform trials have the potential to revolutionize clinical drug development if the methodologic and operational challenges can be overcome.

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“…Stallard and colleagues [11] propose a refined classification which replaces ambiguous labels with a more precise visual description, as shown in Figure 2.In each of the six designs, a small square is representative of a cohort of patients. On the left hand side are the basket-type designs, where there is only one new treatment (T) targeting a particular mutation (M), but this mutation occurs across diseases (D 1 , D 2 , … ).…”

Section: Master Protocol Trialsmentioning

confidence: 99%

“…A classification of master protocol designs by Stallard and colleagues[11]. Each square represents a cohort of patients.…”

mentioning

confidence: 99%

Efficacy Evaluation in the Era of Precision Medicine: The Scope for AI

Magirr¹

2020

Artificial Intelligence in Oncology Drug Discovery and Development

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Patient stratification and the use of real-world evidence in regulatory decisionmaking are two key areas where algorithms are having an impact on drug development. The two are linked: increased patient stratification makes it harder to recruit patients into randomized-controlled trials, increasing the pressure on drug developers to find alternative sources of evidence for showing efficacy. In addition to real-world evidence, we are also seeing the emergence of more efficient 'master protocol trials', where multiple targeted agents can be evaluated simultaneously. In this chapter, I will review these developments and investigate the limitations for AI in terms of demonstrating the efficacy of novel targeted agents.

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On the need to adjust for multiplicity in confirmatory clinical trials with master protocols

Cited by 37 publications

References 17 publications

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

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

The Evolution of Master Protocol Clinical Trial Designs: A Systematic Literature Review

Efficacy Evaluation in the Era of Precision Medicine: The Scope for AI

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