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

ABSTRACT: In recent years, cancers once viewed as relatively homogeneous in terms of organ location and treatment strategy are now better understood to be increasingly heterogeneous across biomarker and genetically defined patient subgroups. This has produced a shift toward development of biomarker-targeted agents during a time when funding for cancer research has been limited; as a result, the need for improved operational efficiency in studying many agent-and-target combinations in parallel has emerged. Platform trials, basket trials, and umbrella trials are new approaches to clinical research driven by this need for enhanced efficiency in the modern era of increasingly specific cancer subpopulations and decreased resources to study treatments for individual cancer subtypes in a traditional way. In this review, we provide an overview of these new types of clinical trial designs, including discussions of motivation for their use, recommended terminology, examples, and challenges encountered in their application.

SUBMITTER: Renfro LA

PROVIDER: S-EPMC5834138 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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

Renfro L A LA Sargent D J DJ

Annals of oncology : official journal of the European Society for Medical Oncology 20170101 1

In recent years, cancers once viewed as relatively homogeneous in terms of organ location and treatment strategy are now better understood to be increasingly heterogeneous across biomarker and genetically defined patient subgroups. This has produced a shift toward development of biomarker-targeted agents during a time when funding for cancer research has been limited; as a result, the need for improved operational efficiency in studying many agent-and-target combinations in parallel has emerged. ...[more]

PMID: 28177494

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Project description:BACKGROUND:Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial), offering enhanced efficiency and a more ethical approach to trial evaluation. Despite the many advantages of these designs, they are infrequently used. METHODS:We conducted a landscape analysis of master protocols using a systematic literature search to determine what trials have been conducted and proposed for an overall goal of improving the literacy in this emerging concept. On July 8, 2019, English-language studies were identified from MEDLINE, EMBASE, and CENTRAL databases and hand searches of published reviews and registries. RESULTS:We identified 83 master protocols (49 basket, 18 umbrella, and 16 platform trials). The number of master protocols has increased rapidly over the last five years. Most have been conducted in the US (n = 44/83) and investigated experimental drugs (n = 82/83) in the field of oncology (n = 76/83). The majority of basket trials were exploratory (i.e., phase I/II; n = 47/49) and not randomized (n = 44/49), and more than half (n = 28/48) investigated only a single intervention. The median sample size of basket trials was 205 participants (interquartile range, Q3-Q1 [IQR]: 500-90 = 410), and the median study duration was 22.3 (IQR: 74.1-42.9 = 31.1) months. Similar to basket trials, most umbrella trials were exploratory (n = 16/18), but the use of randomization was more common (n = 8/18). The median sample size of umbrella trials was 346 participants (IQR: 565-252 = 313), and the median study duration was 60.9 (IQR: 81.3-46.9 = 34.4) months. The median number of interventions investigated in umbrella trials was 5 (IQR: 6-4 = 2). The majority of platform trials were randomized (n = 15/16), and phase III investigation (n = 7/15; one did not report information on phase) was more common in platform trials with four of them using seamless II/III design. The median sample size was 892 (IQR: 1835-255 = 1580), and the median study duration was 58.9 (IQR: 101.3-36.9 = 64.4) months. CONCLUSIONS:We anticipate that the number of master protocols will continue to increase at a rapid pace over the upcoming decades. More efforts to improve awareness and training are needed to apply these innovative trial design methods to fields outside of oncology.

Project description:BACKGROUND:Novel precision oncology trial designs, such as basket and umbrella trials, are designed to test new anticancer agents in more effective and affordable ways. However, they present some ethical concerns referred to scientific validity, risk-benefit balance and informed consent. Our aim is to discuss these issues in basket and umbrella trials, giving examples of two ongoing cancer trials: NCI-MATCH (National Cancer Institute - Molecular Analysis for Therapy Choice) and Lung-MAP (Lung Cancer Master Protocol) study. MAIN BODY:We discuss three ethical requirements for clinical trials which may be challenged in basket and umbrella trial designs. Firstly, we consider scientific validity. Thanks to the new trial designs, patients with rare malignancies have the opportunity to be enrolled and benefit from the trial, but due to insufficient accrual, the trial may generate clinically insignificant findings. Inadequate sample size in study arms and the use of surrogate endpoints may result in a drug approval without confirmed efficacy. Moreover, complexity, limited quality and availability of tumor samples may not only introduce bias and result in unreliable and unrepresentative findings, but also can potentially harm patients and assign them to an inappropriate therapy arm. Secondly, we refer to benefits and risks. Novel clinical trials can gain important knowledge on the variety of tumors, which can be used in future trials to develop effective therapies. However, they offer limited direct benefits to patients. All potential participants must wait about 2 weeks for the results of the genetic screening, which may be stressful and produce anxiety. The enrollment of patients whose tumors harbor multiple mutations in treatments matching a single mutation may be controversial. As to informed consent - the third requirement we discuss, the excessive use of phrases like "personalized medicine", "tailored therapy" or "precision oncology" might be misleading and cause personal convictions that the study protocol is designed to fulfill the individual health-related needs of participants. CONCLUSIONS:We suggest that further approaches should be implemented to enhance scientific validity, reduce misunderstandings and risks, thus maximizing the benefits to society and to trial participants.

Project description:ObjectivesTo assess the completeness of reporting of sample size determinations in unpublished research protocols and to develop guidance for research ethics committees and for statisticians advising these committees.DesignReview of original research protocols.Study selectionUnpublished research protocols for phase IIb, III, and IV randomised clinical trials of investigational medicinal products submitted to research ethics committees in the United Kingdom during 1 January to 31 December 2009.Main outcome measuresCompleteness of reporting of the sample size determination, including the justification of design assumptions, and disagreement between reported and recalculated sample size.Results446 study protocols were reviewed. Of these, 190 (43%) justified the treatment effect and 213 (48%) justified the population variability or survival experience. Only 55 (12%) discussed the clinical importance of the treatment effect sought. Few protocols provided a reasoned explanation as to why the design assumptions were plausible for the planned study. Sensitivity analyses investigating how the sample size changed under different design assumptions were lacking; six (1%) protocols included a re-estimation of the sample size in the study design. Overall, 188 (42%) protocols reported all of the information to accurately recalculate the sample size; the assumed withdrawal or dropout rate was not given in 177 (40%) studies. Only 134 of the 446 (30%) sample size calculations could be accurately reproduced. Study size tended to be over-estimated rather than under-estimated. Studies with non-commercial sponsors justified the design assumptions used in the calculation more often than studies with commercial sponsors but less often reported all the components needed to reproduce the sample size calculation. Sample sizes for studies with non-commercial sponsors were less often reproduced.ConclusionsMost research protocols did not contain sufficient information to allow the sample size to be reproduced or the plausibility of the design assumptions to be assessed. Greater transparency in the reporting of the determination of the sample size and more focus on study design during the ethical review process would allow deficiencies to be resolved early, before the trial begins. Guidance for research ethics committees and statisticians advising these committees is needed.

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

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

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