论文标题

小组顺序方法用于临时监测随时间滞后结果的随机临床试验

Group sequential methods for interim monitoring of randomized clinical trials with time-lagged outcome

论文作者

Tsiatis, Anastasios A., Davidian, Marie

论文摘要

两臂临床试验中的主要分析通常涉及标量治疗效应参数的推断。例如,取决于结果,特定治疗方法,风险差异,风险比或优势比的差异。大多数临床试验都受到了早期停止的可能性的监测。由于通常只有在临时分析时,在已经入学的受试者中,只有一段时间的时间延迟才能确定任何给定受试者的结果,因此该结果仅因子集而闻名,并且对于那些没有足够长的人以供其观察到的人有效地审查。通常,临时分析仅基于已确定结果的受试者的数据。临时分析的一个目标是在证据足够强大以至于做到这一点,表明分析理想情况下应最有效地利用所有可用数据,从而包括有关审查以及其他基线和时间依赖性的协变量的信息。提出了一个通用组顺序框架,用于临床试验,并进行时间滞后。使用半参数理论得出了在临时分析中审查和合并协变量信息的治疗效应估计器,并证明比标准方法更有力地进行早期停止的证据。相关的测试统计数据显示具有独立的增量结构,因此可以使用标准软件来获得停止边界。

The primary analysis in two-arm clinical trials usually involves inference on a scalar treatment effect parameter; e.g., depending on the outcome, the difference of treatment-specific means, risk difference, risk ratio, or odds ratio. Most clinical trials are monitored for the possibility of early stopping. Because ordinarily the outcome on any given subject can be ascertained only after some time lag, at the time of an interim analysis, among the subjects already enrolled, the outcome is known for only a subset and is effectively censored for those who have not been enrolled sufficiently long for it to be observed. Typically, the interim analysis is based only on the data from subjects for whom the outcome has been ascertained. A goal of an interim analysis is to stop the trial as soon as the evidence is strong enough to do so, suggesting that the analysis ideally should make the most efficient use of all available data, thus including information on censoring as well as other baseline and time-dependent covariates in a principled way. A general group sequential framework is proposed for clinical trials with a time-lagged outcome. Treatment effect estimators that take account of censoring and incorporate covariate information at an interim analysis are derived using semiparametric theory and are demonstrated to lead to stronger evidence for early stopping than standard approaches. The associated test statistics are shown to have the independent increments structure, so that standard software can be used to obtain stopping boundaries.

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