Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA.
Stat Med. 2012 Dec 30;31(30):4321-36. doi: 10.1002/sim.5559. Epub 2012 Aug 15.
Model-based dose-finding designs such as the continual reassessment method (CRM) rely on some basic working model. In the Bayesian setting, these take the form of 'guess estimates' of the probabilities of toxicity at each level. In the likelihood setting, these estimates simply take the form of a model as operational characteristics are unaffected by arbitrary positive power transformations. These initial estimates are often referred to as the model skeleton. The impact of any prior distribution on the model parameter that describes the dose-toxicity curve will itself depend on the skeleton being used. We study the interplay between prior assumptions and skeleton choice in the context of two-stage CRM designs. We consider the behavior of a two-stage design at the point of transition from a 3 + 3 design to CRM. We study how use can be made of stage 1 data to construct a more efficient skeleton in conjunction with any prior information through an example of a clinical trial. We evaluate to what extent stage 1 data might be down weighted when the maximum tolerated dose (MTD) is far from the starting level and stage 1 data is strongly informative. The results show no improvement in accuracy; thus, weighting is not necessary unless the investigators feel strongly about the location of the MTD and wish to accelerate into the vicinity of the MTD. In general, because this information is not available, we recommend that the design of two-stage trials utilize stage 1 data to establish a skeleton.
基于模型的剂量探索设计，如连续再评估方法（CRM），依赖于一些基本的工作模型。在贝叶斯设置中，这些模型以“毒性概率的猜测估计”的形式出现，这些概率估计来自于每个水平的毒性概率的猜测估计。在似然设置中，这些估计只是模型的形式，因为操作特征不受任意正幂变换的影响。这些初始估计通常被称为模型骨架。任何先验分布对描述剂量-毒性曲线的模型参数的影响都将取决于所使用的骨架。我们在两阶段 CRM 设计的背景下研究了先验假设和骨架选择之间的相互作用。我们研究了在从 3+3 设计过渡到 CRM 时，两阶段设计的行为。我们通过临床试验的例子，研究了如何利用阶段 1 数据，结合任何先验信息，构建一个更有效的骨架。我们评估了在最大耐受剂量（MTD）远离起始水平且阶段 1 数据信息量很大的情况下，阶段 1 数据可能会被多大程度地下调权重。结果表明，在准确性方面没有提高；因此，除非调查人员强烈认为 MTD 的位置并希望加速进入 MTD 附近，否则不需要进行权重调整。一般来说，由于这种信息不可用，我们建议两阶段试验的设计利用阶段 1 数据来建立骨架。
