# Investigating estimand considerations in adaptive trials: a systematic review

## TL;DR

This paper reviews how well clinical trials using adaptive designs have adopted a new framework for defining research questions, finding that uptake remains low.

## Contribution

The study evaluates the current application of the estimand framework in adaptive trial protocols and highlights gaps in its adoption.

## Key findings

- Only 3% of eligible articles stated their primary estimand, and 2% stated all five estimand attributes.
- 64% of articles described intercurrent events, but none addressed estimand implications for interim analyses.
- The review shows limited uptake of the estimand framework in adaptive trial designs.

## Abstract

Randomised 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.

The 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.

One 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.

This 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.

The online version contains supplementary material available at 10.1186/s13063-026-09490-0.