SynthesisTrials2026
Investigating estimand considerations in adaptive trials: a systematic review.
Synthesis in Trials, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors.
Funding
Abstract
backgroundRandomised controlled trials (RCTs) are the gold standard for evaluating treatment effects, with the results informing policy and clinical practice. To ensure appropriate methods are utilised and to avoid misinterpretation of the results of a clinical trial, it is vital that we understand the research question a trial aims to answer. However, there is often ambiguity in how trialists define their research questions. In 2019, an addendum to the international trial regulatory guidelines (ICH E9 (R1)) introduced the estimand framework to combat this. A review of protocols published in 2020 investigated the early adoption of the estimand framework and found no uptake as well as a lack of clarity on key items such as the handling of intercurrent events. The aim of this review was to identify the current application of the estimand framework specifically to trials with an adaptive design.
methodsThe search strategy aimed to identify trial protocols and statistical analysis plans that described RCTs published in two journals (BMJ Open and Trials) in 2023. Articles were eligible if they related to phase 2-4 trials with an adaptive design. A pre-piloted data extract form was used to extract data relating to study details, intercurrent events and estimands.
resultsOne thousand five hundred and forty-one articles were identified by the initial search. Following screening, 146 articles were identified as meeting the eligibility criteria. Of the eligible articles, five (3%) stated their primary estimand, and of these, three (2%) stated all five estimand attributes. Ninety-four (64%) articles described one or more intercurrent events; these included a total of two hundred and thirty-two intercurrent events described. Fifty-two (36%) articles did not describe any intercurrent events. No articles specified the estimand for any planned interim analyses or considered the implications of adaptations on the primary estimand.
conclusionsThis review provides evidence that there is still a lack of uptake of the estimand framework in RCTs. Wider application of the estimand framework would ensure clarity in the reporting and interpretation of clinical trial results. In addition, clear guidance on how to implement the estimand framework to trials with an adaptive design is needed.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.