An adaptive model switching approach for phase I dose-finding trials

Authors

  • Takashi Daimon,

    Corresponding author
    1. Medical Center for Translational Research, Osaka University Hospital, 2-15, Yamadaoka, Suita, Osaka 565-0871, Japan
    • Department of Biostatistics, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya City, Hyogo 663-8501, Japan
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  • Sarah Zohar

    1. INSERM, U872 team 22, Centre de Recherche des Cordeliers, Université Paris 5, Université Paris 6, Paris, France
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Correspondence to: Takashi Daimon, Department of Biostatistics, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya-city, Hyogo 663-8501, Japan.

E-mail: daimon@hyo-med.ac.jp

Abstract

Model-based phase I dose-finding designs rely on a single model throughout the study for estimating the maximum tolerated dose (MTD). Thus, one major concern is about the choice of the most suitable model to be used. This is important because the dose allocation process and the MTD estimation depend on whether or not the model is reliable, or whether or not it gives a better fit to toxicity data. The aim of our work was to propose a method that would remove the need for a model choice prior to the trial onset and then allow it sequentially at each patient's inclusion. In this paper, we described model checking approach based on the posterior predictive check and model comparison approach based on the deviance information criterion, in order to identify a more reliable or better model during the course of a trial and to support clinical decision making. Further, we presented two model switching designs for a phase I cancer trial that were based on the aforementioned approaches, and performed a comparison between designs with or without model switching, through a simulation study. The results showed that the proposed designs had the advantage of decreasing certain risks, such as those of poor dose allocation and failure to find the MTD, which could occur if the model is misspecified. Copyright © 2013 John Wiley & Sons, Ltd.

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