SC09: Statistical Considerations and Design Strategies for Dose Optimization in Simple and Complex Settings

The FDA Oncology Center of Excellence (OCE) initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. This initiative has had a profound impact on drug development, historically relying on a conventional dose-finding and selection paradigm centered on the identification of the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT). Project Optimus is motivated by the recognition that, for novel therapies, such as molecularly targeted therapies, the MTD often fails to deliver the best risk-benefit tradeoff for patients, generating more toxicity without additional efficacy. In this course, Dr. Yuan will provide an overview of the challenges of dose optimization and discuss statistical considerations and design strategies to address these challenges. The focus of the short course is on practical application. The objective is to empower participants to grasp the underlying statistical principles, furnish them with readily applicable statistical tools for addressing real-world issues, and equip them to design efficient dose optimization trials upon completing the course. We will discuss statistical considerations and design strategies to address challenges pertaining to dose optimization, including the following: • Measures of risk-benefit tradeoff • Single-agent dose optimization • Backfill and randomization for dose optimization • Dose optimization for drug combination and multiple indications • Phase 2/3 designs for dose optimization • Software and trial examples Throughout the training, participants will gain expertise in the following areas: (1) Grasping the features, challenges, and contemporary landscape of dose optimization; (2) comprehending early-phase (i.e., phase 1/2) strategies for dose optimization, as well as late-phase (i.e., phase 2/3) strategies and their respective advantages and disadvantages; (3) understanding the intricacies of efficacy-integrated dose optimization designs and two-stage dose optimization, along with their pros and cons; (4) acquiring proficiency in using software to implement innovative designs for dose optimization and applying these methods to real-world examples through hands-on training.