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Review
. 2025 Aug;44(18-19):e70174.
doi: 10.1002/sim.70174.

Confidence Intervals for Adaptive Trial Designs I: A Methodological Review

David S Robertson  1 , Thomas Burnett  2 , Babak Choodari-Oskooei  3 , Munya Dimairo  4 , Michael Grayling  5 , Philip Pallmann  6 , Thomas Jaki  1   7
Affiliations
Review

Confidence Intervals for Adaptive Trial Designs I: A Methodological Review

David S Robertson et al. Stat Med. 2025 Aug.

Abstract

Regulatory guidance notes the need for caution in the interpretation of confidence intervals (CIs) constructed during and after an adaptive clinical trial. Conventional CIs of the treatment effects are prone to undercoverage (as well as other undesirable properties) in many adaptive designs (ADs) because they do not take into account the potential and realized trial adaptations. This paper is the first in a two-part series that explores CIs for adaptive trials. It provides a comprehensive review of the methods to construct CIs for ADs, while the second paper illustrates how to implement these in practice and proposes a set of guidelines for trial statisticians. We describe several classes of techniques for constructing CIs for adaptive clinical trials before providing a systematic literature review of available methods, classified by the type of AD. As part of this, we assess, through a proposed traffic light system, which of several desirable features of CIs (such as achieving nominal coverage and consistency with the hypothesis test decision) each of these methods holds.

Keywords: adaptive design; bootstrap; coverage; estimation; flexible design; group sequential; interim analyses; repeated analyses.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE A1
FIGURE A1
PRISMA flowchart for the systematic review.
See this image and copyright information in PMC

References

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