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The creation of the ICH E9 (R1) estimands framework has led to more precise specification of the treatment effects of interest in the design and statistical analysis of clinical trials. However, it is unclear how the new framework relates…

Methodology · Statistics 2024-12-20 Thomas Drury , Jonathan W. Bartlett , David Wright , Oliver N. Keene

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

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

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)…

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.…

The ICH E9(R1) guideline presents a framework of estimand for clinical trials, proposes five strategies for handling intercurrent events (ICEs), and provides a comprehensive discussion and many real-life clinical examples for quantitative…

Methodology · Statistics 2025-10-20 Yixin Fang , Man Jin

In this paper we study approaches for dealing with treatment when developing a clinical prediction model. Analogous to the estimand framework recently proposed by the European Medicines Agency for clinical trials, we propose a…

Many research questions concern treatment effects on outcomes that can recur several times in the same individual. For example, medical researchers are interested in treatment effects on hospitalizations in heart failure patients and sports…

Methodology · Statistics 2024-12-31 Matias Janvin , Jessica G. Young , Pål C. Ryalen , Mats J. Stensrud

Estimands can help to clarify the research questions being addressed in randomised trials. Because the choice of estimand can affect how relevant trial results are to patients and other stakeholders, such as clinicians or policymakers, it…

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

Causal inference is a critical research topic across many domains, such as statistics, computer science, education, public policy and economics, for decades. Nowadays, estimating causal effect from observational data has become an appealing…

Methodology · Statistics 2020-02-10 Liuyi Yao , Zhixuan Chu , Sheng Li , Yaliang Li , Jing Gao , Aidong Zhang

Intercurrent events (ICEs) and missing values are inevitable in clinical trials of any size and duration, making it difficult to assess the treatment effect for all patients in randomized clinical trials. Defining the appropriate estimand…

Applications · Statistics 2020-06-01 Yongming Qu , Junxiang Luo , Stephen J. Ruberg

While recurrent event analyses have been extensively studied, limited attention has been given to causal inference within the framework of recurrent event analysis. We develop a multiply robust estimation framework for causal inference in…

Methodology · Statistics 2025-09-30 Benjamin R. Baer , Trang Bui , Daniel Mork , Robert L. Strawderman , Ashkan Ertefaie

The current COVID-19 pandemic poses numerous challenges for ongoing clinical trials and provides a stress-testing environment for the existing principles and practice of estimands in clinical trials. The pandemic may increase the rate of…

Methodology · Statistics 2023-02-02 Yongming Qu , Ilya Lipkovich

In causal inference, the correct formulation of the scientific question of interest is a crucial step. Here we apply the estimand framework to a comparison of the outcomes of patient-level clinical trials and observational data to help…

Causal inference is a science with multi-disciplinary evolution and applications. On the one hand, it measures effects of treatments in observational data based on experimental designs and rigorous statistical inference to draw causal…

Methodology · Statistics 2022-09-05 Jingying Zeng , Run Wang

The standard approach to causal modelling especially in social and health sciences is the potential outcomes framework due to Neyman and Rubin. In this framework, observations are thought to be drawn from a distribution over variables of…

Methodology · Statistics 2025-07-18 Benedikt Höltgen , Robert C. Williamson

Causal inference has received great attention across different fields from economics, statistics, education, medicine, to machine learning. Within this area, inferring causal effects at individual level in observational studies has become…

Methodology · Statistics 2017-02-16 Thai Pham

Causal inference methods such as instrumental variables, regression discontinuity, and difference-in-differences are widely used to identify and estimate treatment effects. However, when outcomes are qualitative, their application poses…

Econometrics · Economics 2025-06-30 Riccardo Di Francesco , Giovanni Mellace
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