Storer B E
Department of Statistics, University of Wisconsin-Madison 53706.
Biometrics. 1989 Sep;45(3):925-37.
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 conservativeness 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 the 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.
I期临床试验是一项旨在估计新药所谓最大耐受剂量（MTD）的研究。尽管此类试验或多或少存在一种标准设计类型，但其发展在很大程度上是临时的。按照通常的实施方式，试验设计没有内在特性能为MTD的估计提供普遍令人满意的基础。在本文中，就设计的保守性以及小样本量下MTD（第33百分位数）的点估计和区间估计而言，对标准设计和几个简单替代方案进行了比较。使用马尔可夫链表示法，我们发现就进入更高剂量水平的患者比例而言，有几种设计与标准设计几乎一样保守。在蒙特卡罗模拟中，发现在不太理想的剂量反应情况下，两种两阶段设计在MTD的最大似然估计中能减少偏差。在考虑用于确定置信区间的三种方法——德尔塔法、基于菲勒定理的方法和似然比法——中，没有一种能够同时提供有用的窄区间和接近名义值的覆盖概率。
