Importance  In a comparative clinical study with progression-free survival (PFS) or overall survival (OS) as the end point, the hazard ratio (HR) is routinely used to design the study and to estimate the treatment effect at the end of the study. The clinical interpretation of the HR may not be straightforward, especially when the underlying model assumption is not valid. A robust procedure for study design and analysis that enables clinically meaningful interpretation of trial results is warranted.

Objective  To discuss issues of conventional trial design and analysis and to present alternatives to the HR using a recent immunotherapy study as an illustrative example.

Design, Setting, and Participants  By comparing 2 groups in a survival analysis, we discuss issues of using the HR and present the restricted mean survival time (RMST) as a summary measure of patients’ survival profile over time. We show how to use the difference or ratio in RMST between 2 groups as an alternative for designing and analyzing a clinical study with an immunotherapy study as an illustrative example.

Main Outcomes and Measures  Overall survival or PFS. Group contrast measures included HR, RMST difference or ratio, and the event rate difference.

Results  For the illustrative example, the HR procedure indicates that nivolumab significantly prolonged patient OS and was numerically better than docetaxel for PFS. However, the median PFS time of docetaxel was significantly better than that of nivolumab. Therefore, it may be difficult to use median OS and/or PFS to interpret of the HR value clinically. On the other hand, using RMST difference, nivolumab was significantly better than docetaxel for both OS and PFS. We also provide details regarding design of a future study with RMST-based measures.

Conclusions and Relevance  The design and analysis of a conventional cancer clinical trial can be improved by adopting a robust statistical procedure that enables clinically meaningful interpretations of the treatment effect. The RMST-based quantitative method may be used as a primary tool for future cancer trials or to help us to better understand the clinical interpretation of the HR even when its model assumption is plausible.

重要性  在以无进展生存期（PFS）或总生存期（OS）为终点的比较临床研究中，通常使用风险比（HR）来设计研究并评估研究结束时的治疗效果。HR的临床解释可能并不直接，尤其是当基础模型假设无效时。必须进行强有力的研究设计和分析程序，以便对临床结果进行有意义的临床解释。

目的  探讨最近的免疫治疗研究作为例证，讨论常规试验设计和分析问题，并提出替代HR的方法。

设计，设置和参与者  通过在生存分析中比较两组，我们讨论了使用HR的问题，并提出了受限平均生存时间（RMST）作为患者随时间推移生存概况的汇总指标。我们展示了如何使用两组之间RMST的差异或比率作为设计和分析临床研究的替代方法，并以免疫疗法研究为例。

主要结果和指标  总体生存或PFS。小组对比测量包括HR，RMST差异或比率以及事件发生率差异。

结果  对于说明性示例，HR程序表明nivolumab显着延长了患者OS，并且在数值上优于多西紫杉醇治疗PFS。然而，多西他赛的中位PFS时间明显优于尼伏鲁单抗。因此，可能难以使用中位OS和/或PFS在临床上解释HR值。另一方面，利用RMST差异，对于OS和PFS而言，nivolumab明显优于多西他赛。我们还提供有关使用基于RMST的措施进行的未来研究设计的详细信息。

结论和相关性  可以通过采用可靠的统计程序来改善常规癌症临床试验的设计和分析，该程序能够对治疗效果进行临床上有意义的解释。基于RMST的定量方法可以用作未来癌症试验的主要工具，或帮助我们更好地理解HR的临床解释，即使其模型假设是合理的。