Hu Haoyan, Brys Miroslaw, Ruberg Stephen J, Qu Yongming
Global Statistical Sciences, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
Eli Lilly and Company, Indianapolis, IN, USA.
Ther Innov Regul Sci. 2025 Jul 17. doi: 10.1007/s43441-025-00843-6.
The ICH E9 (R1) Addendum provides a framework to define an estimand and perform sensitivity analysis. The clinical endpoint (i.e., variable, response, outcome) is one of the important estimand attributes. In our opinion, the selection of the endpoint in Alzheimer's disease requires more exploration beyond what is used currently. The change in a cognitive and functional assessment scale from baseline to a specific time point of interest is often used as a primary or key secondary endpoint in clinical trials. However, such a change from baseline to the time point of interest may not reflect the benefit of the treatment over the course of treatment duration and may be difficult to intuitively understand by patients and clinicians. For two patients with the same change from baseline, the patient with rapid disease progression in the beginning is considered to have overall worse quality of life compared to the other patient with slow disease progression in the beginning but rapid progression toward the end. We explore time-averaged measurement (TAM) as a new endpoint and propose using the relative change to quantify the treatment difference. Estimands under the ICH E9 (R1) Addendum were considered by using various strategies in handling intercurrent events and used corresponding methods for handling missing data. We illustrate the use of TAM and compare the results with other commonly used estimand endpoints (the change from baseline, the relative disease progression model, and the slope of disease progression) for different estimands and imputation methods from retrospective analyses of a historical study.
国际人用药品注册技术协调会E9（R1）增编提供了一个定义估计量并进行敏感性分析的框架。临床终点（即变量、反应、结果）是估计量的重要属性之一。我们认为，阿尔茨海默病终点的选择需要在目前使用的基础上进行更多探索。认知和功能评估量表从基线到特定感兴趣时间点的变化通常被用作临床试验的主要或关键次要终点。然而，从基线到感兴趣时间点的这种变化可能无法反映治疗在整个治疗期间的益处，并且患者和临床医生可能难以直观理解。对于两名从基线开始变化相同的患者，与另一名开始时疾病进展缓慢但接近结束时进展迅速的患者相比，开始时疾病进展迅速的患者被认为总体生活质量更差。我们探索时间平均测量（TAM）作为一个新的终点，并建议使用相对变化来量化治疗差异。通过使用处理并发事件的各种策略来考虑国际人用药品注册技术协调会E9（R1）增编下的估计量，并使用相应的方法处理缺失数据。我们通过对一项历史研究的回顾性分析，说明了TAM的使用，并将不同估计量和插补方法的结果与其他常用的估计量终点（从基线的变化、相对疾病进展模型和疾病进展斜率）进行了比较。
