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An adaptive dose‐finding design incorporating both toxicity and efficacy
Author(s) -
Zhang Wei,
Sargent Daniel J.,
Mandrekar Sumithra
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.2325
Subject(s) - monotonic function , maximum tolerated dose , toxicity , computer science , continuation , selection (genetic algorithm) , outcome (game theory) , drug development , drug , mathematical optimization , medicine , mathematics , pharmacology , machine learning , mathematical analysis , mathematical economics , programming language
Novel therapies are challenging the standards of drug development. Agents with specific biologic targets and limited toxicity require novel designs to determine doses to be taken forward into larger studies. In this paper, we describe an approach that incorporates both toxicity and efficacy data into the estimation of the biologically optimal dose of an agent in a phase I trial. The approach is based on the flexible continuation‐ratio model, and uses straightforward optimal dose selection criteria. Dose selection is based on all patients treated up until that time point, using a continual reassessment method approach. Dose–outcome curves considered include monotonically increasing, monotonically decreasing, and unimodal curves. Our simulation studies demonstrate that the proposed design, which we call TriCRM, has favourable operating characteristics. Copyright © 2005 John Wiley & Sons, Ltd.