为生存数据临床试验设计了更完整的因果推断框架与事件处理方法
Estimand framework and intercurrent events handling for clinical trials with time-to-event outcomes
- 基于潜在结果定义因果估计算法，明确事件发生前的假设
- 提出六种处理截断事件的方法，包含一种新的竞争风险策略
- 支持时变协变量，适合复杂生存分析场景
ICH E9(R1) 指南为临床试验提出了估计量（estimand）框架，针对定量和分类结局提供了五种处理间发事件（ICEs）的策略，并辅以大量真实案例。然而，该指南对时间至事件（TTE）结局的讨论仍不充分。本文系统探讨了含TTE结局的临床试验中如何定义估计量及处理间发事件。具体提出了六种处理策略，包括ICH E9(R1)提出的五种以及一种新策略——竞争风险策略。本研究创新之处在于：(1) 基于潜在结果定义估计量；(2) 可直接使用时变协变量；(3) 讨论了相应的高效估计器。
原文摘要 · Abstract (English)
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 outcomes and categorical outcomes. However, in ICH E9(R1) the discussion is lacking for time-to-event (TTE) outcomes. In this paper, we discuss how to define estimands and how to handle ICEs for clinical trials with TTE outcomes. Specifically, we discuss six ICE handling strategies, including those five strategies proposed by ICH E9(R1) and a new strategy, the competing-risk strategy. Compared with ICH E9(R1), the novelty of this paper is three-fold: (1) the estimands are defined in terms of potential outcomes, (2) the methods can utilize time-dependent covariates straightforwardly, and (3) the efficient estimators are discussed accordingly.
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