A Seamless Phase II/III Design with Dose Optimization for Oncology Drug Development

TL;DR

This paper introduces a novel seamless Phase II/III trial design with integrated dose optimization for oncology drugs, aligning with FDA initiatives, enhancing flexibility, reducing sample size, and maintaining statistical rigor.

Contribution

It proposes a new adaptive trial framework that combines dose optimization with seamless phase transitions, enabling efficient decision-making and sample size re-estimation.

Findings

Reliable identification of optimal dose in simulations

Reduced sample size with maintained power

Supports accelerated and regular approval pathways

Abstract

The US FDA's Project Optimus initiative that emphasizes dose optimization prior to marketing approval represents a pivotal shift in oncology drug development. It has a ripple effect for rethinking what changes may be made to conventional pivotal trial designs to incorporate a dose optimization component. Aligned with this initiative, we propose a novel Seamless Phase II/III Design with Dose Optimization (SDDO framework). The proposed design starts with dose optimization in a randomized setting, leading to an interim analysis focused on optimal dose selection, trial continuation decisions, and sample size re-estimation (SSR). Based on the decision at interim analysis, patient enrollment continues for both the selected dose arm and control arm, and the significance of treatment effects will be determined at final analysis. The SDDO framework offers increased flexibility and cost-efficiency through sample size adjustment, while stringently controlling the Type I error. This proposed design also facilitates both Accelerated Approval (AA) and regular approval in a "one-trial" approach. Extensive simulation studies confirm that our design reliably identifies the optimal dosage and makes preferable decisions with a reduced sample size while retaining statistical power.