Master Protocol Design With Hybrid Control for Efficient Early-Phase Trial Consolidation.

Area of Science:

• Oncology clinical trial design
• Biostatistics
• Regulatory science

Background:

• Master protocols offer efficient frameworks for evaluating multiple therapies or diseases within a single study.
• Their application in early-phase oncology is underutilized despite regulatory emphasis on randomization.
• Initiatives like FDA's Project Optimus highlight the need for robust, randomized early-phase trials.

Purpose of the Study:

• To adapt master protocol designs for early-phase oncology trials with a common backbone therapy.
• To integrate hybrid controls using existing standard-of-care data to minimize patient randomization to control arms.
• To address challenges posed by FDA initiatives, such as large sample sizes and patient reluctance to randomization.

Main Methods:

• Consolidation of early-phase trials under a shared standard-of-care control arm.
• Integration of hybrid controls derived from published standard-of-care data.
• Application of Bayesian information sharing among arms with a common background therapy.

Main Results:

• Reduction in total sample size by up to 55% compared to independent trials.
• Decrease in control arm size (2.4-2.9 times lower).
• Enhanced trial efficiency, reduced costs and duration, and improved enrollment rates.
• Increased statistical power (up to 90%) and controlled type I error rates through hybrid controls and information sharing.

Conclusions:

• Master protocols with hybrid controls and Bayesian information sharing facilitate efficient randomization in early-phase oncology trials.
• This design enhances cost-effectiveness and patient-centricity.
• The approach aligns with FDA Oncology Center of Excellence initiatives for robust clinical trial evidence.