BACKGROUND The population-level summary measure is a key component of the estimand for clinical trials with time-to-event outcomes. This is particularly the case for non-inferiority trials, because different summary measures imply different null hypotheses. Most trials are designed using the hazard ratio as summary measure, but recent studies suggested that the difference in restricted mean survival time might be more powerful, at least in certain situations. In a recent letter, we conjectured that differences between summary measures can be explained using the concept of the non-inferiority frontier and that for a fair simulation comparison of summary measures, the same analysis methods, making the same assumptions, should be used to estimate different summary measures. The aim of this article is to make such a comparison between three commonly used summary measures: hazard ratio, difference in restricted mean survival time and difference in survival at a fixed time point. In addition, we aim to investigate the impact of using an analysis method that assumes proportional hazards on the operating characteristics of a trial designed with any of the three summary measures. METHODS We conduct a simulation study in the proportional hazards setting. We estimate difference in restricted mean survival time and difference in survival non-parametrically, without assuming proportional hazards. We also estimate all three measures parametrically, using flexible survival regression, under the proportional hazards assumption. RESULTS Comparing the hazard ratio assuming proportional hazards with the other summary measures not assuming proportional hazards, relative performance varies substantially depending on the specific scenario. Fixing the summary measure, assuming proportional hazards always leads to substantial power gains compared to using non-parametric methods. Fixing the modelling approach to flexible parametric regression assuming proportional hazards, difference in restricted mean survival time is most often the most powerful summary measure among those considered. CONCLUSION When the hazards are likely to be approximately proportional, reflecting this in the analysis can lead to large gains in power for difference in restricted mean survival time and difference in survival. The choice of summary measure for a non-inferiority trial with time-to-event outcomes should be made on clinical grounds; when any of the three summary measures discussed here is equally justifiable, difference in restricted mean survival time is most often associated with the most powerful test, on the condition that it is estimated under proportional hazards.

中文翻译：

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将随机试验的不同人群水平总结指标与事件发生时间结果进行比较，重点关注非劣效性试验。

背景人群水平汇总测量是具有事件发生时间结果的临床试验估计值的关键组成部分。对于非劣效性试验尤其如此，因为不同的总结措施意味着不同的零假设。大多数试验都是使用风险比作为总结指标来设计的，但最近的研究表明，限制平均生存时间的差异可能更强大，至少在某些情况下是这样。在最近的一封信中，我们推测概括指标之间的差异可以使用非劣效边界的概念来解释，并且为了对概括指标进行公平的模拟比较，应使用相同的分析方法，做出相同的假设来估计不同的总结措施。本文的目的是对三种常用的汇总指标进行这样的比较：风险比、限制平均生存时间差异和固定时间点生存差异。此外，我们的目的是调查使用一种分析方法的影响，该分析方法假设对使用三种汇总措施中的任何一种设计的试验的操作特征存在比例风险。方法 我们在比例风险设置中进行模拟研究。我们以非参数方式估计限制平均生存时间的差异和生存差异，而不假设比例风险。我们还在比例风险假设下使用灵活的生存回归对所有三个指标进行参数估计。结果将假设比例风险的风险比与不假设比例风险的其他汇总措施进行比较，相对性能根据具体情况而有很大差异。与使用非参数方法相比，固定汇总度量，假设比例风险总是会带来显着的功效增益。将建模方法固定为灵活的参数回归，假设比例风险，限制平均生存时间的差异通常是所考虑的最有力的总结措施。结论 当危险可能近似成比例时，在分析中反映这一点可以导致限制平均生存时间差异和生存差异的功效大幅增加。具有事件发生时间结果的非劣效性试验的总结衡量标准的选择应基于临床依据；当这里讨论的三个总结措施中的任何一个同样合理时，限制平均生存时间的差异通常与最有力的检验相关联，条件是它是在比例风险下估计的。