Huque Mohammad F, Alosh Mohamed
Division of Biometrics IV, OB, OTS, CDER, Food and Drug Administration, Silver Spring, Maryland, USA.
J Biopharm Stat. 2012;22(1):160-79. doi: 10.1080/10543406.2010.513464.
A clinical trial might involve more than one clinically important endpoint, each of which can characterize the treatment effect of the experimental drug under investigation. Underlying the concept of using such endpoints interchangeably to establish an efficacy claim, or pooling different endpoints to constitute a composite endpoint, is the assumption that findings from such endpoints are consistent with each other. While such an assumption about consistency of efficacy findings appears to be intuitive, it is seldom considered in the design and analysis literature of clinical trials with multiple endpoints. Failure to account for consistency of efficacy findings of two candidate endpoints to establish efficacy, at the design stage, has led to difficulties in interpreting study findings. This article presents a flexible testing strategy for accommodating findings of an alternative to the designated primary endpoint (or a subgroup) to support an efficacy claim. The method is built on the following two premises: (i) Efficacy findings of the designated primary endpoint, although nonsignificant, need to be supportive of those of the alternative endpoint, and (ii) the significance level allocated for testing the second endpoint is determined adaptively based on the magnitude of the p-value for the designated primary endpoint. The method takes into account the hierarchical ordering of the hypotheses tested and the correlation between the test statistics for the two endpoints to increase the chance of a positive trial. We discuss control of the type I error rate for the proposed test strategy and compare its power with that of other methods. In addition, we consider its application to two clinical trials.
一项临床试验可能涉及不止一个具有临床重要意义的终点指标，每一个终点指标都可以表征正在研究的试验药物的治疗效果。将这些终点指标交替使用以确立疗效声明，或者将不同的终点指标合并以构成一个复合终点指标，其背后的假设是这些终点指标的研究结果彼此一致。虽然关于疗效结果一致性的这种假设似乎很直观，但在具有多个终点指标的临床试验的设计和分析文献中却很少被考虑。在设计阶段未能考虑两个候选终点指标的疗效结果的一致性以确立疗效，导致在解释研究结果时出现困难。本文提出了一种灵活的检验策略，以纳入指定主要终点指标（或一个亚组）的替代指标的结果来支持疗效声明。该方法基于以下两个前提：（i）指定主要终点指标的疗效结果虽然不显著，但需要支持替代终点指标的结果；（ii）为检验第二个终点指标分配的显著性水平是根据指定主要终点指标的p值大小自适应确定的。该方法考虑了所检验假设的层次顺序以及两个终点指标的检验统计量之间的相关性，以增加试验得出阳性结果的机会。我们讨论了所提出的检验策略的I型错误率控制，并将其检验效能与其他方法进行了比较。此外，我们考虑了其在两项临床试验中的应用。
