Huque Mohammad F, Alosh Mohamed, Guerra Matthew
a Adjunct Professor of Biostatistics , J. P. Hsu College of Public Health, Georgia Southern University , Statesboro , Georgia , USA.
b Division of Biometrics III , Office of Biostatistics, OTS, CDER, FDA , Silver Spring , Maryland , USA.
J Biopharm Stat. 2018;28(1):82-98. doi: 10.1080/10543406.2017.1397678. Epub 2017 Nov 16.
Composite endpoints (CEs) are commonly used in clinical trials when clinically important events are rare or when the disease is multifaceted. However, components of a CE often differ markedly in their clinical importance. The overall treatment effect on the composite can be driven by less-important, yet more frequently occurring, components, with no effects on some clinically important components. These situations create difficulties in interpreting the results of the CE. The literature has proposed several approaches for handling these conditions, for example, by setting requirements on the results of the clinically important components. However, for a rare event, it can be difficult to draw an appropriate conclusion about its contribution to the overall result of the composite. Here, we propose combining clinically important components to jointly increase their power and to require that their findings meet a prespecified level of evidence, called the consistency criterion. With the increase in power, the study can then be designed with the objectives of establishing efficacy for the composite and/or for the subset of clinically critical components. In this regard, we introduce multiple testing strategies, which account for the consistency requirement and for the correlation between these two endpoints. We illustrate the methodology using the PROactive trial.
复合终点（CEs）在临床试验中通常用于临床重要事件罕见或疾病具有多方面特征的情况。然而，复合终点的各个组成部分在临床重要性上往往存在显著差异。对复合终点的总体治疗效果可能由不太重要但更频繁发生的组成部分驱动，而对某些临床重要组成部分没有影响。这些情况给解释复合终点的结果带来了困难。文献中提出了几种处理这些情况的方法，例如，对临床重要组成部分的结果设定要求。然而，对于罕见事件，很难就其对复合终点总体结果的贡献得出恰当结论。在此，我们建议将临床重要组成部分合并起来，共同提高其检验效能，并要求它们的研究结果满足预先设定的证据水平，即一致性标准。随着检验效能的提高，研究设计可以旨在确立复合终点和/或临床关键组成部分子集的疗效。在这方面，我们引入了多重检验策略，该策略考虑了一致性要求以及这两个终点之间的相关性。我们使用PROactive试验来说明该方法。
