Medical and Pharmaceutical Statistics Research Unit, Department of Mathematics and Statistics, Lancaster University, UK.
Stat Med. 2011 Jul 20;30(16):1952-70. doi: 10.1002/sim.4267. Epub 2011 May 18.
Many formal statistical procedures for phase I dose-finding studies have been proposed. Most concern a single novel agent available at a number of doses and administered to subjects participating in a single treatment period and returning a single binary indicator of toxicity. Such a structure is common when evaluating cytotoxic drugs for cancer. This paper concerns studies of combinations of two agents, both available at several doses. Subjects participate in one treatment period and provide two binary responses: one an indicator of benefit and the other of harm. The word 'benefit' is used loosely here: the response might be an early indicator of physiological change which, if induced in patients, is of potential therapeutic value. The context need not be oncology, but might be any study intended to meet both the phase I aim of establishing which doses are safe and the phase II goal of exploring potential therapeutic activity. A Bayesian approach is used based on an assumption of monotonicity in the relationship between the strength of the dose-combination and the distribution of the bivariate outcome. Special cases are described, and the procedure is evaluated using simulation. The parameters that define the model have immediate and simple interpretation. Graphical representations of the posterior opinions about model parameters are shown, and these can be used to inform the discussions of the trial safety committee.
许多用于 I 期剂量发现研究的正式统计程序已经被提出。大多数情况下，这些程序涉及一种新型药物，在多个剂量下进行给药，并且在单一治疗周期中，这些药物会对参与的患者产生单一的二元毒性指标。当评估用于癌症的细胞毒性药物时，这种结构是很常见的。本文研究的是两种药物的组合，这两种药物都有几种剂量。患者参与一个治疗周期，提供两个二元反应：一个是受益的指标，另一个是有害的指标。这里的“受益”一词是广义的：该反应可能是生理变化的早期指标，如果在患者中诱导，可能具有潜在的治疗价值。这种情况不一定是肿瘤学领域，而是任何旨在满足 I 期目的（确定哪些剂量是安全的）和 II 期目标（探索潜在的治疗活性）的研究。本文采用基于剂量组合强度与双变量结果分布之间的单调关系的贝叶斯方法。本文还描述了特殊情况，并使用模拟对该程序进行了评估。定义模型的参数具有直接且简单的解释。还展示了关于模型参数的后验意见的图形表示，这些表示可用于告知试验安全委员会的讨论。
