title: A method for therapeutic dose selection in a phase II clinical trial using contrast statistics.
abstract: 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.
authors.affiliation: Graduate School of Engineering, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan. akirawa@mar.rikadai.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Wakana
authors.forename: Isao
authors.initials: I
authors.lastname: Yoshimura
authors.forename: Chikuma
authors.initials: C
authors.lastname: Hamada
mesh_terms: D001249:Asthma / Q000188:drug therapy; D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020024:Leukotriene Antagonists / Q000008:administration & dosage; D015233:Models, Statistical; D010366:Peak Expiratory Flow Rate / Q000187:drug effects
chemical_list: D020024:Leukotriene Antagonists