Adaptive versus fixed designs in confirmatory clinical trials: centering the choice on ethics

Baas, Stef, Pin, Lukas, Robertson, David S., Bretz, Frank, Cho, Hearn Jay, Flight, Laura, van der Graaf, Rieke, Graham, Mackenzie, Jacko, Peter, Jaki, Thomas, Kimmelman, Jonathan, Manfrin, Andrea, Milne, Richard, Mozgunov, Pavel, Pallmann, Philip ORCID: https://orcid.org/0000-0001-8274-9696, Parke, Tom, Parmar, Mahesh K. B., Pirard, Vinciane, Sahan, Kate, Singh, Jerome, Tom, Brian D. M., Whittaker, John C., Wozniak, Kate, Wright, David, Zheng, Haiyan, London, Alex John, Sheehan, Mark and Villar, Sofia 2025. Adaptive versus fixed designs in confirmatory clinical trials: centering the choice on ethics. SSRN , 5937835.

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Abstract

Importance: Because confirmatory clinical trials are costly, large-scale endeavors, the choice of their design carries significant weight. While the current methodological landscape offers tools to address residual pre-trial uncertainty through pre-specified adaptations to design elements, design choices remain frequently constrained by prevailing orthodoxies. We posit that trial design must transition from a habit-based process to one where pre-trial uncertainties are openly discussed and addressed. Strict adherence to default templates prevents stakeholders from matching the design strategy to the specific complexities of the research question. Observations: We observe that the "gold standard" status of fixed designs often obscures their limitations in handling design uncertainties. A rigid adherence to these conventions can ethically hinder a trial's ability to deliver conclusive results. Conversely, while adaptive designs can offer tools to efficiently reduce uncertainty, we acknowledge that adaptive elements are not without cost; their implementation requires rigorous safeguards to manage specific risks to trial integrity and potential operational biases. Conclusions and Relevance: To better align clinical research with its ethical and scientific mandates, we issue two calls to action. First, trial designers, including statisticians, must clearly articulate how target and design uncertainties impact ethical obligations, promoting an open-minded evaluation of both fixed and adaptive methods. Second, stakeholders must foreground ethical considerations during design selection, requiring explicit justification for the use—or non-use—of adaptive elements. The ethical path forward is not to default to the old or blindly adopt the new, but to explicitly justify the chosen design based on its responsiveness to the specific uncertainties of the trial.

Item Type:	Working paper
Date Type:	Published Online
Status:	Submitted
Schools:	Research Institutes & Centres > Centre for Trials Research (CNTRR)
Last Modified:	21 Jan 2026 12:15
URI:	https://orca.cardiff.ac.uk/id/eprint/183429

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