title: Bayesian adaptive patient enrollment restriction to identify a sensitive subpopulation using a continuous biomarker in a randomized phase 2 trial.
abstract: With the development of molecular targeted drugs, predictive biomarkers have played an increasingly important role in identifying patients who are likely to receive clinically meaningful benefits from experimental drugs (i.e., sensitive subpopulation) even in early clinical trials. For continuous biomarkers, such as mRNA levels, it is challenging to determine cutoff value for the sensitive subpopulation, and widely accepted study designs and statistical approaches are not currently available. In this paper, we propose the Bayesian adaptive patient enrollment restriction (BAPER) approach to identify the sensitive subpopulation while restricting enrollment of patients from the insensitive subpopulation based on the results of interim analyses, in a randomized phase 2 trial with time-to-endpoint outcome and a single biomarker. Applying a four-parameter change-point model to the relationship between the biomarker and hazard ratio, we calculate the posterior distribution of the cutoff value that exhibits the target hazard ratio and use it for the restriction of the enrollment and the identification of the sensitive subpopulation. We also consider interim monitoring rules for termination because of futility or efficacy. Extensive simulations demonstrated that our proposed approach reduced the number of enrolled patients from the insensitive subpopulation, relative to an approach with no enrollment restriction, without reducing the likelihood of a correct decision for next trial (no-go, go with entire population, or go with sensitive subpopulation) or correct identification of the sensitive subpopulation. Additionally, the four-parameter change-point model had a better performance over a wide range of simulation scenarios than a commonly used dichotomization approach. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Department of Biostatistics, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan. t126015b@yokohama-cu.ac.jp.|Biostatistics & Data Management Department, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan. t126015b@yokohama-cu.ac.jp.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ohwada
authors.affiliation: Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000627:therapeutic use; D001499:Bayes Theorem; D015415:Biomarkers / Q000378:metabolism; D000080908:Broadly Neutralizing Antibodies; D017322:Clinical Trials, Phase II as Topic / Q000379:methods / Q000706:statistics & numerical data*; D004311:Double-Blind Method; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data*; D018401:Sample Size
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D015415:Biomarkers; D000080908:Broadly Neutralizing Antibodies; D012333:RNA, Messenger; C585471:patritumab
keywords: Bayesian study design; adaptive design; continuous biomarker; enrollment restriction; sensitive subpopulation