A seamless phase II/III design with dose optimization for oncology drug development

Area of Science:

• Oncology Drug Development
• Clinical Trial Design
• Regulatory Science

Background:

• The US Food and Drug Administration's (FDA) Project Optimus initiative promotes dose optimization before marketing approval.
• Conventional pivotal trial designs require adaptation to integrate dose optimization components.
• Rethinking trial methodologies is crucial for aligning with new regulatory expectations in oncology.

Purpose of the Study:

• To propose a novel seamless phase II/III design with dose optimization (SDDO framework).
• To facilitate dose optimization within a randomized trial setting.
• To support regulatory pathways for accelerated approval (AA) and regular approval in a unified trial structure.

Main Methods:

• A seamless phase II/III design incorporating an initial dose optimization phase.
• Randomized dose optimization followed by an interim analysis for dose selection and sample size re-estimation (SSR).
• Continuation of patient enrollment based on interim analysis decisions, with final analysis determining treatment effect significance.

Main Results:

• The SDDO framework allows for flexible and cost-efficient sample size adjustments.
• The design rigorously controls Type I error while maintaining statistical power.
• Extensive simulations confirm reliable optimal dosage identification and preferable decision-making with reduced sample sizes.

Conclusions:

• The proposed SDDO framework effectively integrates dose optimization into phase II/III oncology trials.
• This innovative design enhances trial efficiency, cost-effectiveness, and regulatory flexibility.
• The SDDO framework supports a streamlined "one-trial" approach for drug approval, meeting Project Optimus goals.