Abstract

Determination of appropriate dose(s) to advance into Phase III trials is one of the most challenging and important tasks during drug development. Selecting a dose too high may result in unacceptable safety problems, while a too low dose may lead to ineffective drugs. Proper estimation of dose-response profiles for relevant safety and efficacy endpoints allows the reliable evaluation of the risk-benefit profile of a drug at the end of Phase II, as well as the selection of appropriate doses to be brought into confirmatory Phase III trials. Thus how to select dose(s) in Phase II trials by combining information about the efficacy and safety in a joint model setting may play a key role in drug development programs and can serve as a gate-keeper for large confirmatory Phase III trials with greater chance of success.

Dose finding methods through joint modeling of both efficacy and safety endpoints are studied in this paper. To be more specific, we extend the popular MCP-Mod dose finding method (Bretz et al., 2005), which considered only the efficacy endpoint, to the method that incorporates both efficacy and safety endpoints through joint modeling. Method of parameter estimation for the extended models, and methods of selection of dose(s) to be brought into confirmatory Phase III trials based on Phase II study data are discussed in the paper. The performances of the proposed methods are evaluated through simulations.

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