Evaluating how clear the questions being investigated in randomised trials are: systematic review of estimands
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Objectives: To evaluate how often the precise research question being addressed about an intervention (the estimand) is stated or can be determined from reported methods, and to identify what types of questions are being investigated in phase 2-4 randomised trials. Design: Systematic review of the clarity of research questions being investigated in randomised trials in 2020 in six leading general medical journals. Data source: PubMed search in February 2021. Eligibility criteria for selecting studies: Phase 2-4 randomised trials, with no restrictions on medical conditions or interventions. Cluster randomised, crossover, non-inferiority, and equivalence trials were excluded. Main outcome measures: Number of trials that stated the precise primary question being addressed about an intervention (ie, the primary estimand), or for which the primary estimand could be determined unambiguously from the reported methods using statistical knowledge. Strategies used to handle post-randomisation events that affect the interpretation or existence of patient outcomes, such as intervention discontinuations or uses of additional drug treatments (known as intercurrent events), and the corresponding types of questions being investigated. Results: 255 eligible randomised trials were identified. No trials clearly stated all the attributes of the estimand. In 117 (46%) of 255 trials, the primary estimand could be determined from the reported methods. Intercurrent events were reported in 242 (95%) of 255 trials; but the handling of these could only be determined in 125 (49%) of 255 trials. Most trials that provided this information considered the occurrence of intercurrent events as irrelevant in the calculation of the treatment effect and assessed the effect of the intervention regardless (96/125, 77%)—that is, they used a treatment policy strategy. Four (4%) of 99 trials with treatment non-adherence owing to adverse events estimated the treatment effect in a hypothetical setting (ie, the effect as if participants continued treatment despite adverse events), and 19 (79%) of 24 trials where some patients died estimated the treatment effect in a hypothetical setting (ie, the effect as if participants did not die). Conclusions: The precise research question being investigated in most trials is unclear, mainly because of a lack of clarity on the approach to handling intercurrent events. Clear reporting of estimands is necessary in trial reports so that all stakeholders, including clinicians, patients and policy makers, can make fully informed decisions about medical interventions. Systematic review registration: PROSPERO CRD42021238053.
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Concerns have been raised that the precise research questions that randomised trials are intended to answer are often unclear.
“Concerns have been raised that the precise research questions that randomised trials are intended to answer are often unclear.168”
From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [168]
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Causal clarity in statistical software
Korf, M. N., van Geloven, N., Krijthe, J. H., & Labrecque, J. A. (2025) · International Journal of Epidemiology · doi:10.1093/ije/dyaf136
“There are many available resources to help define an estimand (e.g. [17–20]), yet, even in the reporting of randomized trials, estimands remain for the most part poorly defined [21, 22].”
Cro, S., Kahan, B. C., Patel, A., Henley, A., Joanna, C., Hellyer, P., Kumar, M., Rahman, Y., & Goulão, B. (2023) · Figshare · doi:10.6084/m9.figshare.23632533
Self-citationEMA Guidelines and Their Relationship to the Estimand Framework
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Investigating estimand considerations in adaptive trials: a systematic review
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“[7].”
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“Common examples of intercurrent events include not receiving the assigned treatment, stopping the assigned treatment early, or receiving a different treatment to the one intended [2, 5, 7].”
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- Authors
- Cro, S., Kahan, B. C., Rehal, S., Chis Ster, A., Carpenter, J. R., White, I. R., & Cornelius, V. R.
- Affiliations
- Imperial College London (GB)
- MRC Clinical Trials Unit at UCL (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- London School of Hygiene & Tropical Medicine (GB)
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 2022-08-23
- Volume
- 378
- Pages
- e070146
- ISSN
- 1756-1833 (ISSN-L)
- PMC
- PMC9396446
- OpenAlex
- W4292749537
- Cited by
- 52
- References
- 36
- Citations by year
- 2026: 6 · 2025: 23 · 2024: 8 · 2023: 12 · 2022: 3
- FWCI
- 1.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- BMJ (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- National Institute for Health Research
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Keywords
- estimands, randomised trials, intercurrent events, treatment discontinuation, treatment non-adherence, adverse events, trial reporting quality, primary outcome definition, general medical journals, treatment effect estimation
- MeSH terms
- Humans, Randomized Controlled Trials as Topic
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