A random walk rule for phase I clinical trials

被引:120
作者
Durham, SD
Flournoy, N
Rosenberger, WF
机构
[1] UNIV MARYLAND BALTIMORE CTY, DEPT MATH & STAT, BALTIMORE, MD 21250 USA
[2] AMERICAN UNIV, DEPT MATH & STAT, WASHINGTON, DC 20016 USA
[3] UNIV S CAROLINA, DEPT STAT, COLUMBIA, SC 29208 USA
[4] UNIV MARYLAND BALTIMORE CTY, SCH MED, DEPT EPIDEMIOL & PREVENT MED, BALTIMORE, MD 21228 USA
关键词
adaptive designs; experimental design; quantile estimation; sequential design; small sample distribution theory; toxicity studies; up-and-down designs;
D O I
10.2307/2533975
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
We describe a family of random walk rules for the sequential allocation of dose levels to patients in a dose-response study, or phase I clinical trial. Patients are sequentially assigned the next higher, same, or next lower dose level according to some probability distribution, which may be determined by ethical considerations as well as the patient's response. It is shown that one can choose these probabilities in order to center dose level assignments unimodally around any target quantile of interest. Estimation of the quantile is discussed; the maximum likelihood estimator and its variance are derived under a two-parameter logistic distribution, and the maximum likelihood estimator is compared with other nonparametric estimators. Random walk rules have clear advantages: they are simple to implement, and finite and asymptotic distribution theory is completely worked out. For a specific random walk rule, we compute finite and asymptotic properties and give examples of its use in planning studies. Having the finite distribution theory available and tractable obviates the need for elaborate simulation studies to analyze the properties of the design. The small sample properties of our rule, as determined by exact theory, compare favorably to those of the continual reassessment method, determined by simulation.
引用
收藏
页码:745 / 760
页数:16
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