O'Quigley J, Pepe M, Fisher L
Fred Hutchinson Cancer Research Center, Seattle, Washington.
Biometrics. 1990 Mar;46(1):33-48.
This paper looks at a new approach to the design and analysis of Phase 1 clinical trials in cancer. The basic idea and motivation behind the approach stem from an attempt to reconcile the needs of dose-finding experimentation with the ethical demands of established medical practice. It is argued that for these trials the particular shape of the dose toxicity curve is of little interest. Attention focuses rather on identifying a dose with a given targeted toxicity level and on concentrating experimentation at that which all current available evidence indicates to be the best estimate of this level. Such an approach not only makes an explicit attempt to meet ethical requirements but also enables the use of models whose only requirements are that locally (i.e., around the dose corresponding to the targeted toxicity level) they reasonably well approximate the true probability of toxic response. Although a large number of models could be contemplated, we look at a particularly simple one. Extensive simulations show the model to have real promise.
本文探讨了癌症一期临床试验设计与分析的一种新方法。该方法背后的基本思想和动机源于试图协调剂量探索实验的需求与既定医疗实践的伦理要求。有人认为，对于这些试验，剂量毒性曲线的特定形状并不重要。注意力反而集中在确定具有给定目标毒性水平的剂量，并将实验集中在当前所有现有证据表明是该水平最佳估计值的剂量上。这种方法不仅明确尝试满足伦理要求，还能够使用仅要求在局部（即对应于目标毒性水平的剂量附近）合理近似毒性反应真实概率的模型。虽然可以考虑大量模型，但我们研究了一个特别简单的模型。广泛的模拟表明该模型具有真正的前景。
