P19 : Randomization Monitoring: Comparing Fixed Versus Complex Innovation Designs

The integrity of randomization is critical for the success of a clinical trial. Therefore, routinely performing randomization checks is important. These checks must be done by an unblinded statistical representative to ensure the appropriate blinding is preserved. For fixed randomization designs, changes in the randomization parameters are not expected (same treatments, ratio, stratification, etc.), throughout the study. Standard randomization checks consist of source randomization scheme compare, sufficient remaining records, randomizations occurring as expected, stratification (anomalies), and balance (overall and within any applicable subgroups). These checks are usually done at pre-defined timepoints or milestones (e.g., at ~10%, 50%, 75% subjects randomized).

Complex Innovative Designs such as Master Protocols, often expect randomization adaptations and changes to the randomization parameters (e.g., introducing new treatments, closing treatments, ratio allocation adjustments, introducing new subgroups) across the study. Most of the same randomization checks apply to these designs as the fixed designs, but due to their adaptive nature, there are key differences. Specifically, the reviews need to account for the different adaptions occurring, and the randomization needs to be reviewed separately for each adaptation setting period. The occurrences of these reviews are more driven by events (e.g., after introducing a new treatment, closing a treatment, ratio adjustment) versus relying solely on milestones. These reviews may also be needed to make data driven decisions for adaptations (e.g., when to adjust ratios, close treatments).

This poster intends establish the importance of randomization monitoring, outline recommended randomization review checks, and compare review approaches for fixed versus complex innovative designs.

Randomization monitoring

master protocols

complex innovative designs

treatment adaptations

adaptive designs

fixed randomization designs 

Clinical Trial Design (e.g., Innovative/Complex Design, Estimands, Master Protocol)

ASA Biopharmaceutical Section Regulatory-Industry Statistics Workshop 2023