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The estimand framework proposes different strategies to address intercurrent events. The treatment policy strategy seems to be the most favoured as it is closely aligned with the pre-addendum intention-to-treat principle. All data for all…

Methodology · Statistics 2025-07-21 Sunita Rehal , Nicky Best , Sarah Watts , Thomas Drury

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

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

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

Pattern-mixture models have received increasing attention as they are commonly used to assess treatment effects in primary or sensitivity analyses for clinical trials with nonignorable missing data. Pattern-mixture models have traditionally…

Methodology · Statistics 2024-10-10 Jitong Lou , Mallikarjuna Rettiganti , Yongming Qu

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

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

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 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 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

Return-to-baseline is an important method to impute missing values or unobserved potential outcomes when certain hypothetical strategies are used to handle intercurrent events in clinical trials. Current return-to-baseline approaches seen…

Methodology · Statistics 2021-11-19 Yongming Qu , Biyue Dai

Longitudinal studies are often subject to missing data. The ICH E9(R1) addendum addresses the importance of defining a treatment effect estimand with the consideration of intercurrent events. Jump-to-reference (J2R) is one classically…

Methodology · Statistics 2023-12-06 Siyi Liu , Shu Yang , Yilong Zhang , Guanghan , Liu

Selection bias arises when the probability that an observation enters a dataset depends on variables related to the quantities of interest, leading to systematic distortions in estimation and uncertainty quantification. For example, in…

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

Estimating the causal effect of a treatment or health policy with observational data can be challenging due to an imbalance of and a lack of overlap between treated and control covariate distributions. In the presence of limited overlap,…

Methodology · Statistics 2025-03-24 Martha Barnard , Jared D. Huling , Julian Wolfson

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 statistical analysis of clinical trials is often complicated by missing data. Patients sometimes experience intercurrent events (ICEs), which usually (although not always) lead to missing subsequent outcome measurements for such…

Methodology · Statistics 2025-07-03 Brendah Nansereko , Marcel Wolbers , James Carpenter , Jonathan Bartlett

Background: Existing guidelines for handling missing data are generally not consistent with the goals of prediction modelling, where missing data can occur at any stage of the model pipeline. Multiple imputation (MI), often heralded as the…

Methodology · Statistics 2022-06-27 Rose Sisk , Matthew Sperrin , Niels Peek , Maarten van Smeden , Glen P. Martin
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