Large simple trials (LSTs) are defined as prospective, interventional, randomized trials that use large numbers of patients, broad inclusion criteria, multiple study sites, observational follow-up and minimal data requirements, allowing detection of small treatment effects, rare events, and improved external validity. While patient registries and other observational designs receive much attention in their ability to deliver real-world evidence for safety and effectiveness, LSTs are less common and are not typically deployed in outcomes research. However, the randomization component of LSTs and sample sizes may deliver quality data that reach beyond that of other observational designs while still being generalizable to the reference population.

This presentation highlights the applications and design elements of LSTs to answer comparative effectiveness research and safety questions. Case examples are also shared.