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Estimands using the treatment policy strategy for addressing intercurrent events are common in Phase III clinical trials. One estimation approach for this strategy is retrieved dropout whereby observed data following an intercurrent event…

The ICH E9(R1) Addendum (International Council for Harmonization 2019) suggests treatment-policy as one of several strategies for addressing intercurrent events such as treatment withdrawal when defining an estimand. This strategy requires…

Methodology · Statistics 2023-08-28 Suzie Cro , James H Roger , James R Carpenter

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9 (R1) Addendum provides a framework for defining estimands in clinical trials. Treatment policy strategy is the mostly used…

Applications · Statistics 2024-10-10 Rong Liu , Yongming Qu

To precisely define the treatment effect of interest in a clinical trial, the ICH E9 estimand addendum describes that relevant so-called intercurrent events should be identified and strategies specified to deal with them. Handling…

Methodology · Statistics 2025-02-06 Camila Olarte Parra , Rhian M. Daniel , Jonathan W. Bartlett

The ICH E9 addendum introduces the term intercurrent event to refer to events that happen after randomisation and that can either preclude observation of the outcome of interest or affect its interpretation. It proposes five strategies for…

Methodology · Statistics 2021-07-12 Camila Olarte Parra , Rhian M. Daniel , Jonathan W. Bartlett

The estimands framework outlined in ICH E9 (R1) describes the components needed to precisely define the effects to be estimated in clinical trials, which includes how post-baseline "intercurrent" events (IEs) are to be handled. In…

Methodology · Statistics 2023-08-28 Thomas Drury , Juan J Abellan , Nicky Best , Ian R. White

The estimand framework provides guidance on handling intercurrent events, such as treatment discontinuation, in the analysis of clinical trial responses. Under ICH E9(R1), the treatment policy (TP) strategy incorporates post-discontinuation…

Methodology · Statistics 2026-04-07 Myeongjong Kang , Sangyoon Yi

When treatment policy estimands are of interest, clinical trials often attempt to collect patient data after intercurrent events (ICEs), although such data are often limited. Retrieved dropout imputation methods, which use pre-ICE and…

Methodology · Statistics 2026-03-31 Brendah Nansereko , Marcel Wolbers , James R. Carpenter , Jonathan W. Bartlett

Intercurrent (post-treatment) events occur frequently in randomized trials, and investigators often express interest in treatment effects that suitably take account of these events. A naive conditioning on intercurrent events does not have…

Methodology · Statistics 2021-11-17 Mats J. Stensrud , Oliver Dukes

Randomized controlled trials (RCT) are the gold standard for evaluation of the efficacy and safety of investigational interventions. If every patient in an RCT were to adhere to the randomized treatment, one could simply analyze the…

Applications · Statistics 2020-06-08 Yongming Qu , Linda Shurzinske , Shanthi Sethuraman

The International Council for Harmonization (ICH) E9 (R1) addendum provides the estimand framework to formulate treatment effects in a clinical trial. One of the attributes of an estimand the framework describes is intercurrent events.…

For handling intercurrent events in clinical trials, one of the strategies outlined in the ICH E9(R1) addendum targets the hypothetical scenario of non-occurrence of the intercurrent event. While this strategy is often implemented by…

Methodology · Statistics 2024-09-18 Florian Lasch , Lorenzo Guizzaro , Wen Wei Loh

Under a composite estimand strategy, the occurrence of the intercurrent event is incorporated into the endpoint definition, for instance by assigning a poor outcome value to patients who experience the event. Composite strategies are…

Methodology · Statistics 2025-07-01 Brennan C Kahan , Tra My Pham , Conor Tweed , Tim P Morris

The analysis of randomized controlled trials is often complicated by intercurrent events (IEs) -- events that occur after treatment initiation and affect either the interpretation or existence of outcome measurements. Examples include…

Methodology · Statistics 2026-04-07 Sizhu Lu , Yanyao Yi , Yongming Qu , Huayu Karen Liu , Ting Ye , Peng Ding

We provide guidance on multiple imputation of missing at random treatments in observational studies. Specifically, analysts should account for both covariates and outcomes, i.e., not just use propensity scores, when imputing the missing…

Methodology · Statistics 2025-01-23 Joseph Feldman , Jerome P. Reiter

The recently published ICH E9 addendum on estimands in clinical trials provides a framework for precisely defining the treatment effect that is to be estimated, but says little about estimation methods. Here we report analyses of a clinical…

Applications · Statistics 2023-09-25 Camila Olarte Parra , Rhian M. Daniel , David Wright , Jonathan W. Bartlett

The ICH E9(R1) addendum provides guidelines on accounting for intercurrent events in clinical trials using the estimands framework. However, there has been limited attention to the estimands framework for meta-analysis. Using treatment…

Treatment policy estimands are frequently favored by regulators, as they assess the effect of treatment assignment regardless of post-randomization events. Despite best efforts, missing data due to study discontinuation cannot be fully…

Methodology · Statistics 2026-05-13 Ajmal Oodally , Craig Wang , Zheng Li , Tim Morris , Tobias Mütze , Arunava Chakravartty

Time-to-event estimands are central to many oncology clinical trials. The estimand framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest…

Applications · Statistics 2023-07-24 Jonathan Siegel , Hans-Jochen Weber , Stefan Englert , Feng Liu

The estimand framework is increasingly established to pose research questions in confirmatory clinical trials. In evidence synthesis, the uptake of estimands has been modest, and the PICO (Population, Intervention, Comparator, Outcome)…

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