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估计框架:我们问的问题对吗?固体肿瘤背景下的案例研究。

Estimand framework: Are we asking the right questions? A case study in the solid tumor setting.

机构信息

Pfizer, Inc., Collegeville, Pennsylvania, USA.

Novartis Pharma AG, Basel, Switzerland.

出版信息

Pharm Stat. 2021 Mar;20(2):324-334. doi: 10.1002/pst.2079. Epub 2020 Nov 5.

Abstract

The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for "intercurrent" events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions ("does the drug delay recurrence if no patient had received subsequent therapy?" vs "does the drug delay recurrence with or without subsequent therapy?" vs "does the drug delay recurrence or start of subsequent therapy?"). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross-industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.

摘要

估计量框架需要对感兴趣的临床问题(估计量)进行精确定义,因为在随机分组后对“并发”事件的不同处理方式可能会导致不同的科学问题。在肿瘤学临床试验中,后续治疗的启动很常见,如果这种治疗在复发或进展事件之前开始,则被认为是并发事件。在分析中,有三种可能的方法来处理这种并发事件:在启动时进行删失,考虑在启动后续治疗之前和之后发生的复发或进展事件(包括死亡),或者将启动后续治疗本身视为一个事件。新的估计量框架澄清了这些分析解决了不同的问题(“如果没有患者接受后续治疗,药物是否会延迟复发?”与“无论是否接受后续治疗,药物是否会延迟复发?”与“药物是否会延迟复发或开始接受后续治疗?”)。该框架促进了临床试验规划和设计过程中的讨论,以确保关键问题、分析和解释之间的一致性。本文是行业间合作的结果,旨在将国际协调会议 E9 附录概念与应用联系起来。本文使用来自先前报道的肾细胞癌背景下的随机 3 期研究的数据,来考虑实体瘤研究中的常见并发事件,并举例说明不同的科学问题以及估计量选择对研究设计、数据收集、分析和解释的影响。

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