Daniels M J, Hughes M D
Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
Stat Med. 1997 Sep 15;16(17):1965-82. doi: 10.1002/(sici)1097-0258(19970915)16:17<1965::aid-sim630>3.0.co;2-m.
We describe a meta-analysis approach for the evaluation of a potential surrogate marker. Surrogate markers are useful in helping to identify therapeutic mechanisms of action and disease pathogenesis, and for selecting therapies to take forward from phase II to phase III clinical trials. They have also become increasingly important for regulatory purposes by providing a basis for preliminary approval of drugs pending clinical outcome studies. Methodology for evaluating surrogate markers has focused on determining the difference in the effects of two treatments on clinical outcome in an individual clinical trial, and then estimating the proportion of this difference explained by the treatment's effects on the potential marker. Studies are, however, frequently underpowered or cease before they accumulate sufficient evidence to draw strong conclusions about the value of a potential surrogate marker using this approach, and there are also some technical difficulties with the approach. Consideration of the association between the difference in treatment effects on the clinical outcome and the difference in treatment effects on the potential marker over a range of trials provides an alternative means to evaluate a potential marker. We describe a meta-analysis approach using Bayesian methods to model this association. Importantly, this approach enables one to obtain prediction intervals for the true difference in clinical outcome for a given estimated treatment difference in the effect on the potential marker. We illustrate the methodology by applying it to results from studies of the AIDS Clinical Trials Group to assess the value of CD4 T-lymphocyte cell count as a potential surrogate marker for the treatment effects on the development of AIDS or death.
我们描述了一种用于评估潜在替代标志物的荟萃分析方法。替代标志物有助于确定治疗作用机制和疾病发病机制，以及用于选择从II期推进至III期临床试验的疗法。它们在监管方面也变得越来越重要，为在临床结果研究之前对药物进行初步批准提供了依据。评估替代标志物的方法主要集中在确定个体临床试验中两种治疗对临床结果的影响差异，然后估计该差异中由治疗对潜在标志物的影响所解释的比例。然而，研究往往缺乏足够的效力，或者在积累足够证据以使用这种方法就潜在替代标志物的价值得出有力结论之前就停止了，而且这种方法还存在一些技术难题。考虑一系列试验中治疗对临床结果的影响差异与治疗对潜在标志物的影响差异之间的关联，为评估潜在标志物提供了另一种方法。我们描述了一种使用贝叶斯方法对这种关联进行建模的荟萃分析方法。重要的是，这种方法能够针对潜在标志物效应的给定估计治疗差异，获得临床结果真实差异的预测区间。我们将该方法应用于艾滋病临床试验组的研究结果，以评估CD4 T淋巴细胞计数作为治疗对艾滋病发展或死亡影响的潜在替代标志物的价值，从而对该方法进行说明。
