Learning from Case Studies: Recent Trends and Challenges in the Design of Pragmatic Clinical Trials

Pragmatic Clinical Trials (PCTs) have gained increasing attention as a means to generate evidence that informs decision-making in routine clinical practice. Unlike Explanatory Clinical Trials (ECTs), which focus on interventional efficacy under ideal conditions, PCTs evaluate the effectiveness of interventions in usual care, including diverse patient populations often excluded from conventional trials and flexible protocols. Recent advances in technology, such as electronic health records and real-world data utilization, have facilitated the implementation of PCTs, while regulatory frameworks like ICH E6(R3) Annex 2 now support more flexible and practical trial designs. This review outlines the concept and design of PCTs, highlighting key methodological considerations including the use of the estimand framework and the PRECIS-2 tool for design assessment. Case studies such as the PRIDE Study, Salford Lung Study, and RECOVERY Trial illustrate the application and impact of randomized PCTs in various therapeutic areas and situations. The review also discusses international and domestic trends, regulatory harmonization, and statistical challenges at the planning stage unique to PCTs. By bridging the gap between research and clinical practice, PCTs are expected to play a pivotal role in patient-focused drug development and evidence-based healthcare.