A dose finding method in joint modeling of efficacy and safety endpoints in phase II studies - an extension of the MCP-MOD method.

摘要

Determination of appropriate dose(s) to advance into Phase III is one of the most challenging and important decisions made 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 such 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. This dissertation will address how to select dose(s) in Phase II trials by combining information about the efficacy and safety in a joint model setting. The methods we present in the dissertation may play a key role in drug development programs, and are often the gate-keeper for large confirmatory Phase III trials with greater chance of successful approval.The dose selection when both safety and efficacy are represented by continuous responses is discussed in Part I of the dissertation, while Part II addresses the methodology when the safety and efficacy are mixed type responses. Both scenarios involve joint modeling of safety and efficacy endpoints. The methodology will focus on the following: (1) Joint modeling approaches (2) Model selection (3) Identification of minimum effective dose (MED) and maximum safety dose (MSD) (4) Selection of optimal dose(s) for the Phase III program.