Stopping a trial early – and then what?

Wittes, Janet

doi:10.1177/1740774512454600

Cited by 14 publications

(25 citation statements)

References 22 publications

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“…Although there does not exist a unique solution to early stopping correction of statistical bias, various statistical procedures have been proposed [ 67 , 70 – 76 ], and it appears that these methods are rarely implemented by statisticians in routine practice. What is unclear, is the extent of the impact of statistical bias correction, on the results and decision making of these group sequential RCTs, particularly those that are stopped early.…”

Section: Discussionmentioning

confidence: 99%

An Investigation of the Shortcomings of the CONSORT 2010 Statement for the Reporting of Group Sequential Randomised Controlled Trials: A Methodological Systematic Review

et al. 2015

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BackgroundIt can be argued that adaptive designs are underused in clinical research. We have explored concerns related to inadequate reporting of such trials, which may influence their uptake. Through a careful examination of the literature, we evaluated the standards of reporting of group sequential (GS) randomised controlled trials, one form of a confirmatory adaptive design.MethodsWe undertook a systematic review, by searching Ovid MEDLINE from the 1st January 2001 to 23rd September 2014, supplemented with trials from an audit study. We included parallel group, confirmatory, GS trials that were prospectively designed using a Frequentist approach. Eligible trials were examined for compliance in their reporting against the CONSORT 2010 checklist. In addition, as part of our evaluation, we developed a supplementary checklist to explicitly capture group sequential specific reporting aspects, and investigated how these are currently being reported.ResultsOf the 284 screened trials, 68(24%) were eligible. Most trials were published in “high impact” peer-reviewed journals. Examination of trials established that 46(68%) were stopped early, predominantly either for futility or efficacy. Suboptimal reporting compliance was found in general items relating to: access to full trials protocols; methods to generate randomisation list(s); details of randomisation concealment, and its implementation. Benchmarking against the supplementary checklist, GS aspects were largely inadequately reported. Only 3(7%) trials which stopped early reported use of statistical bias correction. Moreover, 52(76%) trials failed to disclose methods used to minimise the risk of operational bias, due to the knowledge or leakage of interim results. Occurrence of changes to trial methods and outcomes could not be determined in most trials, due to inaccessible protocols and amendments.Discussion and ConclusionsThere are issues with the reporting of GS trials, particularly those specific to the conduct of interim analyses. Suboptimal reporting of bias correction methods could potentially imply most GS trials stopping early are giving biased results of treatment effects. As a result, research consumers may question credibility of findings to change practice when trials are stopped early. These issues could be alleviated through a CONSORT extension. Assurance of scientific rigour through transparent adequate reporting is paramount to the credibility of findings from adaptive trials. Our systematic literature search was restricted to one database due to resource constraints.

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Section: Discussionmentioning

confidence: 99%

An Investigation of the Shortcomings of the CONSORT 2010 Statement for the Reporting of Group Sequential Randomised Controlled Trials: A Methodological Systematic Review

et al. 2015

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“…Several statistical issues may arise when using an AD depending on its type and the scope of adaptations, the adaptive decision-making criteria and whether frequentist or Bayesian methods are used to design and analyse the trial 22. Conventional estimates of treatment effect based on fixed design methods may be unreliable when applied to ADs (for example, may exaggerate the patient benefit) 96209210211212213. Precision around the estimated treatment effects may be incorrect (for example, the width of confidence intervals may be incorrect).…”

Section: The Ace Checklistmentioning

confidence: 99%

“…Statistical methods for estimating the treatment effect and its precision exist for some ADs68222223224225226227228229230231 and implementation tools are being developed 82232233234. However, these methods are rarely used or reported and the implications are unclear 49209235. Debate and research on inference for some ADs with complex adaptations is ongoing.…”

Section: The Ace Checklistmentioning

confidence: 99%

The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design

Dimairo

Pallmann

Wason

et al. 2020

BMJ

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Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised.This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process.The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text.The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits.

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“…It has also been suggested that stage wise ordering technique could be used to calculate the statistics [6].…”

Section: Methods Stopping Rule and Its Challengesmentioning

confidence: 99%

“Get Real with Stopping Rule”-Evaluating the Value of being able to Stop Early using the Real Option Framework

2014

J Clin Trials

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Stopping a trial early – and then what?

Cited by 14 publications

References 22 publications

An Investigation of the Shortcomings of the CONSORT 2010 Statement for the Reporting of Group Sequential Randomised Controlled Trials: A Methodological Systematic Review

An Investigation of the Shortcomings of the CONSORT 2010 Statement for the Reporting of Group Sequential Randomised Controlled Trials: A Methodological Systematic Review

The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design

“Get Real with Stopping Rule”-Evaluating the Value of being able to Stop Early using the Real Option Framework

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