Statistical controversies in clinical research: basket trials, umbrella trials, and other master protocols: a review and examples

In oncology, next generation sequencing and comprehensive genomic profiling have enabled the detailed classification of tumors using molecular biology. However, it is unrealistic to conduct phase I–III trials according to each sub-population based on patient molecular subtypes. Common protocols that assess the combination of several molecular markers and their targeted therapies by means of multiple sub-studies are required. These protocols are called “master protocols,” and are drawing attention as a next-generation clinical trial design. Recently, several reviews of clinical trials based on the master protocol design have been published, but their definitions of these such trials, including basket, umbrella, and platform trials, were not consistent. Concurrently, the acceleration of the development of new statistical designs for master protocol trials has been underway. This article provides an overview of recent reviews for master protocols, including their statistical design methodologies in Oncology. We also introduce several examples of previous and on-going master protocol trials along with their classifications by some recent studies.

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“…In this article, we will organize the trial types by definitions given in recent works [[21], [22], [23]]. …”

Section: Basket Umbrella and Platform Trialsmentioning

confidence: 99%

Master protocol trials in oncology: Review and new trial designs

Hirakawa

Asano

Sato

et al. 2018

Contemporary Clinical Trials Communications

103

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“…Protocols begin with dose finding and then enroll patients across multiple histologies (22); sometimes they include a safety run-in for each cancer subtype due to context-dependent toxicity. The goal of these designs is to increase efficiency by allowing the study to add different cancers via protocol amendments instead of developing new protocols.…”

Section: Introductionmentioning

confidence: 99%

Challenges and Opportunities in Adapting Clinical Trial Design for Immunotherapies

Siu

Ivy

Dixon

et al. 2017

Clinical Cancer Research

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Immunotherapy adds an exciting new dimension to the treatment of cancer, joining other approaches as a key pillar in the oncotherapeutics armamentarium. Immuno-oncology agents harbor unique mechanisms of antitumor activity by leveraging the host immune system, which may result in response patterns, resistance kinetics, and toxicity profiles that differ from other systemic therapies. These features have led to many discussions on ways to optimally integrate immunotherapy into cancer clinical trials. This overview provides an introduction to the four CCR Focus articles that ensue, with special thoughts paid to clinical trial endpoints, biomarker development and validation, combination strategies, and limitations that arise with increasing use of these agents. In addition, this overview examines design concepts that may be applied to invigorate clinical trials and to maximize their impact in the immuno-oncology era.

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“…In order for targeted cancer therapies to be adequately assessed for their efficacy, they need to be tested in the appropriate group of patients: those who are predicted to respond. Basket trials, for instance, evaluate the effectiveness of a drug based on its underlying mode of action rather than strictly on the specific form of cancer it was intended to treat 106 . For example, the ongoing CREATE trial evaluates the use of crizotinib in treating patients with a variety of tumour types, all with targetable variants in the hepatocyte growth factor (HGF) receptor (also known as MET) and/or AKT pathways (NCT01524926).…”

Section: Precision Medicine and Drug Developmentmentioning

confidence: 99%

Drug development in the era of precision medicine

Dugger

Platt

Goldstein

2017

Nat Rev Drug Discov

349

243

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For the past three decades, the use of genomics to inform drug discovery and development pipelines has generated both excitement and scepticism. Although earlier efforts successfully identified some new drug targets, the overall clinical efficacy of developed drugs has remained unimpressive, owing in large part to the heterogeneous causes of disease. Recent technological and analytical advances in genomics, however, have now made it possible to rapidly identify and interpret the genetic variation underlying a single patient’s disease, thereby providing a window into patient-specific mechanisms that cause or contribute to disease, which could ultimately enable the ‘precise’ targeting of these mechanisms. Here, we first examine and highlight the successes and limitations of the earlier phases of genomics in drug discovery and development. We then review the current major efforts in precision medicine and discuss the potential broader utility of mechanistically guided treatments going forward.

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Statistical controversies in clinical research: basket trials, umbrella trials, and other master protocols: a review and examples

Cited by 222 publications

References 64 publications

Master protocol trials in oncology: Review and new trial designs

Master protocol trials in oncology: Review and new trial designs

Challenges and Opportunities in Adapting Clinical Trial Design for Immunotherapies

Drug development in the era of precision medicine

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