Forced randomization: the what, why, and how

Area of Science:

• Clinical Trial Design
• Pharmaceutical Research
• Biostatistics

Background:

• Clinical sites may encounter situations where an eligible participant cannot be randomized due to unavailable treatment at the site.
• Interactive response technology (IRT) allows for 'forced randomization' (FR) to allocate participants to available treatment arms.
• Industry consensus suggests FR is acceptable in confirmatory trials if instances are limited, but statistical properties require further understanding.

Purpose of the Study:

• To explore the statistical properties and practical implications of forced randomization (FR) in randomized controlled trials (RCTs).
• To evaluate the impact of different IRT configurations and drug supply strategies on trial operations when using FR.
• To provide a framework for the development and evaluation of randomization designs incorporating FR.

Main Methods:

• Described four IRT configurations with and without FR, illustrating with an example.
• Conducted a database search (Cortellis) to determine the prevalence of FR in clinical practice.
• Developed a template for evaluating FR designs and applied it to a hypothetical multi-center RCT under various recruitment and supply scenarios, using Julia code for simulations.

Main Results:

• FR can eliminate patient refusals, improve logistics, drug management, cost-efficiency, and reduce recruitment time.
• A Cortellis search revealed limited reported use of FR, typically documented in IRT specifications.
• Simulations indicated low FR percentages in realistic settings; FR with backfilling and high re-supply minimized treatment imbalance and recruitment time, with drug overage mainly influenced by re-supply strategy.

Conclusions:

• FR, when combined with appropriate drug supply strategies, offers significant improvements in patient/site experience, trial logistics, and efficiency.
• FR effectively prevents refusals and unblinding, contributing to smoother trial conduct.
• FR is a valuable feature for multi-center RCTs when properly planned and implemented.