Implementing response-adaptive randomisation in stratified rare-disease trials: Design challenges and practical...

Area of Science:

• Clinical Trials Methodology
• Biostatistics
• Rare Disease Research

Background:

• Response-adaptive randomization (RAR) is underutilized in clinical trials despite its potential.
• Practical implementation challenges, especially in small sample sizes and rare diseases, are often overlooked.
• Existing technical literature frequently neglects real-world trial complexities.

Purpose of the Study:

• To address practical challenges in implementing response-adaptive randomization (RAR) in clinical trials.
• To ensure RAR allocations are both acceptable and statistically faithful, particularly in small sample sizes.
• To determine appropriate adaptations following interim analyses when dealing with missing data.

Main Methods:

• Proposed a 'Mapping' strategy to discretize randomization probabilities into allocation ratios for improved frequentist errors.
• Analyzed the impact of missing data on operating characteristics under the Mapping strategy.
• Investigated practical considerations such as data pooling, blinding assessment, and safety reporting.

Main Results:

• The Mapping strategy enhances the desirability of RAR allocations, ensuring they are acceptable and faithful to intended probabilities, especially in small samples.
• Missing data can significantly impact operating characteristics, necessitating careful consideration during interim analyses.
• The study provides a framework for addressing practical RAR implementation issues.

Conclusions:

• The Mapping strategy offers a viable solution for improving RAR implementation in small and rare disease trials.
• Addressing missing data is crucial for successful adaptive trial designs.
• Further research and discussion on practical aspects like blinding and safety reporting are warranted for wider RAR adoption.