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. 2025 May;44(10-12):e70091.
doi: 10.1002/sim.70091.

Inference for Cumulative Incidences and Treatment Effects in Randomized Controlled Trials With Time-to-Event Outcomes Under ICH E9 (R1)

Yuhao Deng  1 , Shasha Han  2 , Xiao-Hua Zhou  3   4
Affiliations

Inference for Cumulative Incidences and Treatment Effects in Randomized Controlled Trials With Time-to-Event Outcomes Under ICH E9 (R1)

Yuhao Deng et al. Stat Med. 2025 May.

Abstract

In randomized controlled trials (RCTs) that focus on time-to-event outcomes, intercurrent events can arise in two ways: as semi-competing events, which modify the hazard of the primary outcome events, or as competing events, which make the definition of the primary outcome events unclear. Although five strategies have been proposed in the ICH E9 (R1) addendum to address intercurrent events in RCTs, these strategies are not easily applicable to time-to-event outcomes when aiming for causal interpretations. In this study, we show how to define, estimate, and make inferences concerning objectives that have causal interpretations within these contexts. Specifically, we derive the mathematical formulations of the causal estimands corresponding to the five strategies and clarify the data structure needed to identify these causal estimands. Furthermore, we introduce nonparametric methods for estimating and making inferences about these causal estimands, including the asymptotic variance of estimators and the construction of hypothesis tests. Finally, we illustrate our methods using data from the LEADER Trial, which aims to investigate the effect of liraglutide on cardiovascular outcomes.

Keywords: causal inference; estimand; intercurrent event; potential outcome; randomized controlled trial; survival analysis.

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References

    1. International Conference on Harmonization, “Addendum to Statistical Principles for Clinical Trials on Choosing Appropriate Estimands and Defining Sensitivity Analyses in Clinical Trials,” 2019. Step 4 version dated 20 November.
    1. K. Rufibach, “Treatment Effect Quantification for Time‐To‐Event Endpoints–Estimands, Analysis Strategies, and Beyond,” Pharmaceutical Statistics 18, no. 2 (2019): 145–165.
    1. B. C. Kahan, J. Hindley, M. Edwards, S. Cro, and T. P. Morris, “The Estimands Framework: A Primer on the ICH E9 (R1) Addendum,” BMJ 384 (2024): e076316.
    1. J. M. Siegel, H. J. Weber, S. Englert, F. Liu, M. Casey, and Pharmaceutical Industry Working Group on Estimands in Oncology, “Time‐To‐Event Estimands and Loss to Follow‐Up in Oncology in Light of the Estimands Guidance,” Pharmaceutical Statistics 23, no. 5 (2024): 709–727.
    1. A. Fierenz and A. Zapf, “Current Developments of the Estimand Concept,” Pharmaceutical Statistics 23 (2024): 864–869.

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