Liu Guohui, Rosenberger William F, Haines Linda M
Department of Mathematics and Statistics, University of Maryland, Baltimore, USA.
J Biopharm Stat. 2006;16(5):605-21. doi: 10.1080/10543400600860337.
Both parametric and nonparametric sequential designs and estimation methods are implemented in phase I clinical trials. In this article, we take a systematic approach, consisting of a start-up design, a follow-on design, a sequential dose-finding design, and an estimation method, to find an efficient estimate of the maximum tolerated dose under the assumption that the dose-response curve has a true underlying logistic distribution. In particular, for the problem of the nonexistence of the maximum likelihood estimates of the logistic parameters, a constraint on the probability of an undetermined maximum likelihood estimator (MLE) is incorporated into the parametric sequential designs. In addition, this approach can also be extended to incorporate ethical considerations, which prohibit an administered dose from exceeding the maximum acceptable dose. Comparison based on simulation studies between the systematic designs and nonparametric designs are described both for continuous dose spaces and discrete dose spaces, respectively.
参数化和非参数化序贯设计及估计方法都应用于I期临床试验中。在本文中，我们采用一种系统方法，该方法由一个启动设计、一个后续设计、一个序贯剂量寻找设计和一种估计方法组成，以便在剂量反应曲线具有真实潜在逻辑分布的假设下找到最大耐受剂量的有效估计值。特别地，针对逻辑参数最大似然估计不存在的问题，在参数化序贯设计中纳入了对未确定最大似然估计器（MLE）概率的约束。此外，该方法还可扩展以纳入伦理考量，即禁止给药剂量超过最大可接受剂量。分别针对连续剂量空间和离散剂量空间描述了基于模拟研究对系统设计和非参数设计的比较。
