Design and Analysis of Dose Escalation Studies to Mitigate Dose-Limiting Adverse Effects

Abstract

This article discusses the attributes of different forced dose titration study designs to ascertain the possibility of mitigating the dose-limiting adverse effects (DLAEs) for a new drug. The early determination of whether forced dose titration can mitigate an adverse event is important in choosing the appropriate dose and method for evaluation in later stages of development. The goal is to establish definitively that a forced dose titration scheme will reduce the overall incidence of DLAEs that are identified a priori. A design methodology that takes into consideration the cumulative exposure time for both active drug and the control is recommended. The proposed design was applied to an actual clinical trial (randomized, controlled, double blind, multicenter) to demonstrate the utility of forced dose titration to reduce the potentially DLAEs of nausea and vomiting. The proposed design demonstrated that forced dose titration reduced the incidence of DLAEs.