Zohar Sarah, O'Quigley John
Inserm CIC 9504, Centre d'Investigations Cliniques, Hôpital Saint-Louis, Paris, France.
Stat Med. 2006 Dec 30;25(24):4311-20. doi: 10.1002/sim.2685.
There has been much recent interest in phase I/II dose finding designs in which information on both toxicity and efficacy is used. Unlike the classic phase I dose finding design in which the aim is to identify the MTD (maximum tolerated dose corresponding to some percentile of acceptable toxicity), a phase I/II dose finding study aims to locate the most successful dose (MSD), i.e. the dose which maximizes the product of the probability of seeing no toxicity together with the probability of seeing a therapeutic response). In this work we present an abstract theoretical design for this purpose. We call this design a 'virtual' design. The virtual design, conceptually similar to that developed for phase I designs alone, is based on a bivariate response. The design has optimal properties in that the current estimates of both probability of toxicity and those for response achieve the Cramer-Rao bound for every dose level. Unhappily, the virtual design is not available for practical use but its use can be exploited in theoretical investigations in much the same way as one uses the Cramer-Rao bound for unbiased estimators, i.e. a tool which enables us to see how much room for improvement may exist for any given real design. Via examples taken from the literature on phase I/II dose finding we illustrate how this technique can provide us with further insight on the relative performance of competing designs.
最近，人们对I/II期剂量探索设计产生了浓厚兴趣，这类设计会同时利用毒性和疗效方面的信息。与经典的I期剂量探索设计不同，经典I期设计的目的是确定最大耐受剂量（对应于某个可接受毒性百分位数的最大耐受剂量），而I/II期剂量探索研究旨在找到最成功剂量（MSD），即能使无毒性概率与出现治疗反应概率的乘积最大化的剂量。在这项工作中，我们为此提出了一种抽象的理论设计。我们将这种设计称为“虚拟”设计。该虚拟设计在概念上与仅为I期设计开发的设计类似，基于双变量反应。这种设计具有最优属性，即在每个剂量水平上，毒性概率和反应概率的当前估计值都达到了克拉美 - 罗界。遗憾的是，虚拟设计无法实际应用，但它可用于理论研究，其方式与使用克拉美 - 罗界来评估无偏估计量类似，也就是说，它是一种能让我们了解任何给定实际设计还有多大改进空间的工具。通过从I/II期剂量探索文献中选取的示例，我们说明了这种技术如何能让我们对竞争设计的相对性能有更深入的了解。
