A burn-in(g) question: How long should an initial equal randomization stage be before Bayesian response-adaptive...

Area of Science:

• Clinical Trials Methodology
• Biostatistics
• Bayesian Statistics

Background:

• Response-adaptive randomization (RAR) enhances participant benefit in clinical trials but complicates statistical analysis.
• A non-adaptive 'burn-in' period is often used to mitigate these complexities, yet optimal duration guidance is lacking.

Purpose of the Study:

• To introduce an exact evaluation approach for assessing the impact of burn-in length on statistical operating characteristics in two-arm binary Bayesian RAR (BRAR) designs.
• To provide guidance on selecting optimal burn-in periods for BRAR trials.

Main Methods:

• Developed an exact evaluation approach to analyze statistical operating characteristics of BRAR designs with varying burn-in lengths.
• Investigated the effects of burn-in duration on type I error rates, power, and estimation bias.
• Utilized exact tests conditioning on total successes and compared them with calibration and asymptotic tests.

Main Results:

• Common calibration and asymptotic tests exhibit type I error rate inflation in BRAR designs without a burn-in period.
• Increasing burn-in length reduces but does not eliminate type I error inflation, highlighting the need for exact tests.
• Exact tests conditioning on total successes demonstrate superior average and minimum power across various burn-in lengths.
• Burn-in length significantly affects power and participant benefit, with optima often occurring at intermediate lengths.
• Test statistics influence type I error rates and power; estimation bias varies with treatment effect size and trial size.

Conclusions:

• The choice of burn-in length is critical for the statistical validity and efficiency of BRAR trials.
• Exact evaluation methods are essential for accurate assessment of BRAR designs, particularly concerning type I error rates.
• Optimal burn-in periods are not necessarily the shortest or longest, emphasizing the need for tailored design considerations.