Division of Cancer Prevention, National Cancer Institute, 9609 Medical Center Dr, Room 5E606, MSC 9789, Bethesda, MD, 20892-9789, USA.
Stat Med. 2018 Feb 20;37(4):507-518. doi: 10.1002/sim.7561. Epub 2017 Nov 21.
A surrogate endpoint in a randomized clinical trial is an endpoint that occurs after randomization and before the true, clinically meaningful, endpoint that yields conclusions about the effect of treatment on true endpoint. A surrogate endpoint can accelerate the evaluation of new treatments but at the risk of misleading conclusions. Therefore, criteria are needed for deciding whether to use a surrogate endpoint in a new trial. For the meta-analytic setting of multiple previous trials, each with the same pair of surrogate and true endpoints, this article formulates 5 criteria for using a surrogate endpoint in a new trial to predict the effect of treatment on the true endpoint in the new trial. The first 2 criteria, which are easily computed from a zero-intercept linear random effects model, involve statistical considerations: an acceptable sample size multiplier and an acceptable prediction separation score. The remaining 3 criteria involve clinical and biological considerations: similarity of biological mechanisms of treatments between the new trial and previous trials, similarity of secondary treatments following the surrogate endpoint between the new trial and previous trials, and a negligible risk of harmful side effects arising after the observation of the surrogate endpoint in the new trial. These 5 criteria constitute an appropriately high bar for using a surrogate endpoint to make a definitive treatment recommendation.
在随机临床试验中，替代终点是指在随机分组后出现的、与真正的、有临床意义的终点相关的指标，该终点可以提供关于治疗对真正终点影响的结论。替代终点可以加速新治疗方法的评估，但存在误导结论的风险。因此，需要制定标准来决定是否在新试验中使用替代终点。对于多个先前试验的荟萃分析设置，每个试验都有相同的替代终点和真实终点，本文提出了在新试验中使用替代终点来预测新试验中治疗对真实终点影响的 5 项标准。前 2 项标准，根据零截距线性随机效应模型计算，涉及统计学考虑因素：可接受的样本量乘数和可接受的预测分离评分。其余 3 项标准涉及临床和生物学考虑因素：新试验与先前试验中治疗的生物学机制相似性、新试验中替代终点后二级治疗的相似性，以及新试验中观察到替代终点后出现有害副作用的风险可以忽略不计。这 5 项标准构成了使用替代终点做出明确治疗建议的适当高标准。
