Snapinn Steven, Jiang Qi, Ke Chunlei
Seattle-Quilcene Biostatistics LLC, Seattle, Washington, USA.
Seagen Inc., Bothell, Washington, USA.
Pharm Stat. 2023 Jan;22(1):181-193. doi: 10.1002/pst.2267. Epub 2022 Oct 6.
In a clinical trial with a time-to-event endpoint the treatment effect can be measured in various ways. Under proportional hazards all reasonable measures (such as the hazard ratio and the difference in restricted mean survival time) are consistent in the following sense: Take any control group survival distribution such that the hazard rate remains above zero; if there is no benefit by any measure there is no benefit by all measures, and as the magnitude of treatment benefit increases by any measure it increases by all measures. Under nonproportional hazards, however, survival curves can cross, and the direction of the effect for any pair of measures can be inconsistent. In this paper we critically evaluate a variety of treatment effect measures in common use and identify flaws with them. In particular, we demonstrate that a treatment's benefit has two distinct and independent dimensions which can be measured by the difference in the survival rate at the end of follow-up and the difference in restricted mean survival time, and that commonly used measures do not adequately capture both dimensions. We demonstrate that a generalized hazard difference, which can be estimated by the difference in exposure-adjusted subject incidence rates, captures both dimensions, and that its inverse, the number of patient-years of follow-up that results in one fewer event (the NYNT), is an easily interpretable measure of the magnitude of clinical benefit.
在一项具有事件发生时间终点的临床试验中，治疗效果可以通过多种方式来衡量。在比例风险假设下，所有合理的衡量指标（如风险比和受限平均生存时间的差异）在以下意义上是一致的：取任何使风险率保持在零以上的对照组生存分布；如果通过任何指标都没有益处，那么通过所有指标也都没有益处，并且随着通过任何指标衡量的治疗益处的增加，通过所有指标衡量的治疗益处都会增加。然而，在非比例风险假设下，生存曲线可能会交叉，并且任何一对指标的效果方向可能不一致。在本文中，我们批判性地评估了各种常用的治疗效果衡量指标，并指出了它们的缺陷。特别是，我们证明了一种治疗的益处有两个不同且相互独立的维度，可以通过随访结束时的生存率差异和受限平均生存时间的差异来衡量，并且常用的衡量指标没有充分涵盖这两个维度。我们证明了一种广义风险差异，它可以通过暴露调整后的个体发病率差异来估计，涵盖了这两个维度，并且其倒数，即导致事件减少一个所需的随访患者年数（NYNT），是一种易于解释的临床益处大小的衡量指标。
