A flexible and coherent test/estimation procedure based on restricted mean survival times for censored time-to-event data in randomized clinical trials
A flexible and coherent test/estimation procedure based on restricted mean survival times for censored time-to-event data in randomized clinical trials
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DOI：
10.1002/sim.7661
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发表时间：
2018-07-10
影响因子：
2
通讯作者：
Uno, Hajime
中科院分区：
文献类型：
--
作者：
Horiguchi, Miki;Cronin, Angel M.;Uno, Hajime
在以至事件发生时间为主要结局的随机临床试验中，几乎通常将对数秩检验预先指定为主要检验，并使用风险比量化治疗效果。如果两个风险函数的比值不是常数，则对数秩检验不是最优的，风险比的解释不明显。当在设计阶段预期到这种非比例风险情况时，常规做法是预先指定加权对数秩检验的另一个成员，例如Peto-Prentice-Wilcoxon检验。可替代地，可以指定鲁棒性测试作为主要测试，其可以捕获2个事件时间分布之间的不同模式。然而，这些测试中的大多数没有伴随程序来量化治疗差异，研究人员已经退回到报告与主要测试无关的治疗效果估计。测试/估计程序中的这种不一致性可能会误导临床医生/患者，他们必须平衡治疗决策的风险-受益。为了解决这个问题，我们提出了一个灵活的和一致的测试/估计过程的基础上限制平均生存时间，截断时间是选择数据依赖。拟议的程序由预先指定的测试和相应的稳健且可解释的定量治疗效果的估计组成。基于2项随机癌症临床试验的数值研究证明了新程序的实用性;对于这些癌症临床试验中观察到的差异模式，该检验比对数秩检验、Wilcoxon检验和基于有限平均生存时间的固定检验更有效。
In randomized clinical trials where time-to-event is the primary outcome, almost routinely, the logrank test is prespecified as the primary test and the hazard ratio is used to quantify treatment effect. If the ratio of 2 hazard functions is not constant, the logrank test is not optimal and the interpretation of hazard ratio is not obvious. When such a nonproportional hazards case is expected at the design stage, the conventional practice is to prespecify another member of weighted logrank tests, eg, Peto-Prentice-Wilcoxon test. Alternatively, one may specify a robust test as the primary test, which can capture various patterns of difference between 2 event time distributions. However, most of those tests do not have companion procedures to quantify the treatment difference, and investigators have fallen back on reporting treatment effect estimates not associated with the primary test. Such incoherence in the test/estimation procedure may potentially mislead clinicians/patients who have to balance risk-benefit for treatment decision. To address this, we propose a flexible and coherent test/estimation procedure based on restricted mean survival time, where the truncation time is selected data dependently. The proposed procedure is composed of a prespecified test and an estimation of corresponding robust and interpretable quantitative treatment effect. The utility of the new procedure is demonstrated by numerical studies based on 2 randomized cancer clinical trials; the test is dramatically more powerful than the logrank, Wilcoxon tests, and the restricted mean survival time-based test with a fixed , for the patterns of difference seen in these cancer clinical trials.