Wilson, D.T., Hudson, E. and Brown, S. (2024) Three-outcome designs for external pilot trials with progression criteria. BMC Medical Research Methodology, 24. 226. ISSN 1471-2288
Abstract
Background
Whether or not to progress from a pilot study to a definitive trial is often guided by pre-specified quantitative progression criteria with three possible outcomes. Although the choice of these progression criteria will help to determine the statistical properties of the pilot trial, there is a lack of research examining how they, or the pilot sample size, should be determined.
Methods
We review three-outcome trial designs originally proposed in the phase II oncology setting and extend these to the case of external pilots, proposing a unified framework based on univariate hypothesis tests and the control of frequentist error rates. We apply this framework to an example and compare against a simple two-outcome alternative.
Results
We find that three-outcome designs can be used in the pilot setting, although they are not generally more efficient than simpler two-outcome alternatives. We show that three-outcome designs can help allow for other sources of information or other stakeholders to feed into progression decisions in the event of a borderline result, but this will come at the cost of a larger pilot sample size than the two-outcome case. We also show that three-outcome designs can be used to allow adjustments to be made to the intervention or trial design before commencing the definitive trial, providing the effect of the adjustment can be accurately predicted at the pilot design stage. An R package, tout, is provided to optimise progression criteria and pilot sample size.
Conclusions
The proposed three-outcome framework provides a way to optimise pilot trial progression criteria and sample size in a way that leads to desired operating characteristics. It can be applied whether or not an adjustment following the pilot trial is anticipated, but will generally lead to larger sample size requirements than simpler two-outcome alternatives.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | Pilot trial, Progression criteria, Sample size |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Clinical Trials Research (LICTR) (Leeds) |
Funding Information: | Funder Grant number MRC (Medical Research Council) MR/N015444/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 26 Sep 2024 13:05 |
Last Modified: | 21 Oct 2024 12:54 |
Published Version: | https://bmcmedresmethodol.biomedcentral.com/articl... |
Status: | Published |
Publisher: | BMC |
Identification Number: | 10.1186/s12874-024-02351-x |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:217610 |