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A method for therapeutic dose selection in a phase II clinical trial using contrast statistics
Author(s) -
Wakana Akira,
Yoshimura Isao,
Hamada Chikuma
Publication year - 2006
Publication title -
statistics in medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.996
H-Index - 183
eISSN - 1097-0258
pISSN - 0277-6715
DOI - 10.1002/sim.2552
Subject(s) - statistics , population , contrast (vision) , mathematics , clinical trial , test statistic , medicine , statistical hypothesis testing , computer science , artificial intelligence , environmental health
This paper proposes a statistical method for determining the therapeutic dose of a test drug in a confirmatory clinical trial based on a phase II clinical trial using 3 or 4 doses of the drug. This method assumes the primary variable has a normal distribution with a common variance, that a test‐drug effect is seen when the population means show a response pattern indicating a monotonic increase with dose, and that there is a prior distribution for the population means. Under the proposed method, multiple contrast statistics are determined, such as contrast statistics for linear increase and plateau, and a response pattern is selected based on the maximum contrast statistic. The posterior probability that the selected response pattern is the true one is evaluated, and if this exceeds the cut‐off value a therapeutic dose is selected based on the estimated response pattern. To select the appropriate cut‐off value, a simulation study was conducted using a loss function for which the loss due to overestimation is greater than the loss due to underestimation. It was found that, as a rule, the appropriate cut‐off value to reduce the expected loss for various response patterns is 0.75 for a 3‐group trial and 0.70 for a 4‐group trial. Using these cut‐off values, the proposed method was applied to a previous clinical trial of a leukotriene receptor antagonist in patients with bronchial asthma. The method enabled the selection of what are considered appropriate response patterns and a therapeutic dose. Thus, the proposed method appears reasonable. Copyright © 2006 John Wiley & Sons, Ltd.