DESIGN AND ANALYSIS OF PHASE-I CLINICAL-TRIALS
DESIGN AND ANALYSIS OF PHASE-I CLINICAL-TRIALS
复制标题
DOI：
10.2307/2531693
复制
发表时间：
1989-09-01
期刊：
影响因子：
1.9
通讯作者：
STORER, BE
中科院分区：
文献类型：
--
作者：
STORER, BE
I期临床试验是一项旨在估计新药的最大耐受剂量（MTD）的研究。虽然存在或多或少的标准类型的设计，这种试验，其发展一直在很大程度上是特设的。如通常实施的，试验设计不具有为MTD估计提供通常令人满意的基础的内在特性。在本文中，标准设计和几个简单的替代品进行了比较方面的保守性的设计，并就点和区间估计的MTD（第33百分位数）与小样本量。使用马尔可夫链表示，我们发现几种设计在以较高剂量水平入组的患者比例方面几乎与标准设计一样保守。在Monte Carlo模拟中，发现两个两阶段设计在不太理想的剂量-反应设置中提供MTD的最大似然估计的偏倚降低。在确定置信区间所考虑的三种方法中--delta方法、基于Fieller定理的方法和似然比方法--没有一种能够提供有用的窄区间和接近标称的覆盖概率。
The Phase I clinical trial is a study intended to estimate the so-called maximum tolerable dose (MTD) of a new drug. Although there exists more or less a standard type of design for such trials, its development has been largely ad hoc. As usually implemented, the trial design has no intrinsic property that provides a generally satisfactory basis for estimation of the MTD. In this paper, the standard design and several simple alternatives are compared with regard to the conservativesness of the design and with regard to point and interval estimation of an MTD (33rd percentile) with small sample sizes. Using a Markov chain representation, we found several designs to be nearly as conservative as the standard design in terms of proportion of patients entered at higher dose levels. In Monte Carlo simulations, two two-stage designs are found to provide reduced bias in maximum likelihood estimation of the MTD in less than ideal dose-response settings. Of the three methods considered for determining confidence intervals-the delta method, a method based on Fieller''s theorem, and a likelihood ratio method-none was able to provide both usefully narrow intervals and coverage probabilities close to nominal.