{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:19:34Z","timestamp":1786119574680,"version":"build-2736575974"},"reference-count":26,"publisher":"BMJ","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004336","name":"Novartis","doi-asserted-by":"publisher","award":["Not Applicable"],"award-info":[{"award-number":["Not Applicable"]}],"id":[{"id":"10.13039\/100004336","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ EBM"],"accepted":{"date-parts":[[2026,7,19]]},"abstract":"<jats:p>Understanding the risks associated with healthcare interventions is essential for clinical decision-making and for the regulatory evaluation of new drugs. Yet, safety analyses in randomised controlled trials are often conducted without clearly specifying (a) the estimand of interest in the presence of intercurrent events (IEs) (ie, events such as treatment discontinuation or use of rescue medication that occur after randomisation and complicate outcome interpretation) or (b) the estimand implicitly targeted by the statistical estimator used in the analysis. This lack of clarity produces ambiguous results and complicates their interpretation.<\/jats:p>\n                  <jats:p>This paper provides practical guidance on applying the estimand framework from the ICH E9(R1) addendum to safety outcomes in phase III randomised trials conducted for regulatory submissions. We describe how IEs influence the interpretation of treatment effects in safety assessment and how commonly used safety estimators align with different estimands, making explicit both the clinical question and the assumptions required to estimate it.<\/jats:p>\n                  <jats:p>Although the primary emphasis is on regulatory trials, where these decisions are especially consequential, the principles outlined are equally applicable to other randomised interventions and non-interventional studies. As safety results from pivotal regulatory trials are increasingly published using estimand terminology, these concepts are essential not only for researchers such as statisticians, clinicians and regulators involved in clinical development but also for clinicians who prescribe newly approved drugs and need to interpret safety results communicated using estimand terminology to inform their clinical decision-making. This paper aims to make these concepts accessible to a broader medical audience.<\/jats:p>","DOI":"10.1136\/bmjebm-2026-114587","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T18:38:03Z","timestamp":1786041483000},"page":"bmjebm-2026-114587","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Applying the estimand framework to safety: aligning estimators with treatment effects in the presence of intercurrent events"],"prefix":"10.1136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9066-1109","authenticated-orcid":false,"given":"Pedro","family":"Lopez-Romero","sequence":"first","affiliation":[{"name":"Quantitative Safety and Epidemiology, Novartis Farmaceutica SA, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5446-8939","authenticated-orcid":false,"given":"Brenda Jean","family":"Crowe","sequence":"additional","affiliation":[{"name":"Independent Researcher (Retired, Eli Lilly and Company), Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6804-1501","authenticated-orcid":false,"given":"Philip","family":"He","sequence":"additional","affiliation":[{"name":"Biostatistics, Daiichi Sankyo Inc, Basking Ridge, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3892-5858","authenticated-orcid":false,"given":"Natalia","family":"Kan-Dobrosky","sequence":"additional","affiliation":[{"name":"Statistical Sciences, AbbVie Inc, North Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2376-8824","authenticated-orcid":false,"given":"Andreas","family":"Sashegyi","sequence":"additional","affiliation":[{"name":"Independent Researcher (Retired, Eli Lilly and Company), Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6477-4281","authenticated-orcid":false,"given":"Jonathan","family":"Siegel","sequence":"additional","affiliation":[{"name":"Bayer US, Whippany, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"2026080610201208000_bmjebm-2026-114587v1.1","doi-asserted-by":"crossref","unstructured":"Mallinckrodt C , Molenberghs G , Lipkovich I , et al . Estimators and sensitivity analysis in clinical trials. Boca Raton, FL: Chapman and Hall\/CRC, 2020.","DOI":"10.1201\/9780429488825"},{"key":"2026080610201208000_bmjebm-2026-114587v1.2","doi-asserted-by":"crossref","DOI":"10.1136\/bmj-2023-076316","article-title":"The estimands framework: a primer on the ICH E9(R1) addendum","volume":"384","author":"Kahan","year":"2024","journal-title":"BMJ"},{"key":"2026080610201208000_bmjebm-2026-114587v1.3","unstructured":"International Conference on Harmonization . ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials. Step 5. [Internet]. 2019. Available: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/ich-e9-r1-addendum-estimands-and-sensitivity-analysis-clinical-trials-guideline-statistical-principles-clinical-trials-step-5_en.pdf"},{"key":"2026080610201208000_bmjebm-2026-114587v1.4","unstructured":"U.S. Food and Drug Administration C for DE and R . E9(R1) statistical principles for clinical trials: Addendum: Estimands and sensitivity analysis in clinical trials. [Internet]. 2021. Available: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/e9r1-statistical-principles-clinical-trials-addendum-estimands-and-sensitivity-analysis-clinical"},{"key":"2026080610201208000_bmjebm-2026-114587v1.5","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1177\/17407745241230933","article-title":"A safety estimand for late phase clinical trials where the analysis period varies over the subjects","volume":"21","author":"Hedman","year":"2024","journal-title":"Clin Trials"},{"key":"2026080610201208000_bmjebm-2026-114587v1.6","doi-asserted-by":"publisher","DOI":"10.1002\/pst.1915"},{"key":"2026080610201208000_bmjebm-2026-114587v1.7","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1080\/10543406.2023.2189452","article-title":"Application of estimand framework in ICH E9 (R1) to safety evaluation","volume":"33","author":"Wang","year":"2023","journal-title":"J Biopharm Stat"},{"key":"2026080610201208000_bmjebm-2026-114587v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/pst.1739"},{"key":"2026080610201208000_bmjebm-2026-114587v1.9","doi-asserted-by":"crossref","DOI":"10.1186\/s13063-021-05354-x","article-title":"Survival analysis for adverse events with varying follow-up times (SAVVY): Estimation of adverse event risks","volume":"22","author":"Stegherr","year":"2021","journal-title":"Trials"},{"key":"2026080610201208000_bmjebm-2026-114587v1.10","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1002\/pst.2130","article-title":"Estimating and comparing adverse event probabilities in the presence of varying follow-up times and competing events","volume":"20","author":"Stegherr","year":"2021","journal-title":"Pharm Stat"},{"key":"2026080610201208000_bmjebm-2026-114587v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-023-01062-9"},{"key":"2026080610201208000_bmjebm-2026-114587v1.12","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.13103"},{"key":"2026080610201208000_bmjebm-2026-114587v1.13","first-page":"S100","article-title":"The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis","volume":"23","author":"Aletaha","year":"2005","journal-title":"Clin Exp Rheumatol"},{"key":"2026080610201208000_bmjebm-2026-114587v1.14","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.123919"},{"key":"2026080610201208000_bmjebm-2026-114587v1.15","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1080\/19466315.2024.2421753","article-title":"Chasing shadows: how implausible assumptions skew our understanding of causal estimands","volume":"17","author":"Vansteelandt","year":"2025","journal-title":"Stat Biopharm Res"},{"key":"2026080610201208000_bmjebm-2026-114587v1.16","doi-asserted-by":"crossref","unstructured":"Kalbfleisch JD , Prentice RL . 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[Internet] [Advancing Premarket Safety Analytics]. 2022. 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