FDA-AACR Strategies for Optimizing Dosages for Oncology Drug Products: Selecting Optimized Dosages for Registrational Trials

Abstract

The maximum tolerated dose has historically been the recommended phase two dose, and this dosage has typically been evaluated in registrational clinical trials for oncology drugs. With the emergence of targeted therapies, this approach may lead to the investigation of unnecessarily high dosages that elicit additional toxicity without added benefit. The utilization of innovative trial designs and model-informed approaches during clinical development can potentially lead to more informed dosage selection. Exposure-response analyses, clinical utility index, and other model-informed approaches have been successfully applied to understand preliminary activity and safety data for various classes of modern oncology drugs, providing insight to support the proposed dosage(s) for the registrational trial. Seamless trial designs have also played an important role in dosage selection by leveraging pre-planned flexibilities and statistical procedures to increase efficiency during the conduct of trials. Critically, both approaches can be fit for purpose, allowing for adaptation and the usage of the totality of relevant clinical and nonclinical data. Despite this, the evaluation of maximum tolerated dose remains prevalent in registrational trials. This article, the third in a series of three describing best-practice approaches to dosage optimization in oncology drug development, highlights successful applications of and relevant considerations for innovative trial designs and model-based approaches to aid the selection of better optimized dosages for evaluation in registrational clinical trials.