Bridging the Gaps in Externally Controlled Trials: A Review of Current Recommendations

Music City Center 

Externally controlled trials (ECTs) play a crucial role in evaluating the safety and effectiveness of medical products when randomized controlled trials are not feasible. Despite recent recommendations, there are still significant gaps in methodological consistency and regulatory evaluation criteria for ECTs. These inconsistencies lead to varied applications that impede decision-making, and the limited regulatory experience with ECTs may create hesitation among sponsors. This presentation reviews the existing guidance on ECTs, identifies methodological gaps, and proposes practical solutions for their design, analysis, conduct, and evaluation. We conducted a comprehensive search of electronic databases and grey literature up to 2025 to identify relevant guidance documents, white papers, and peer-reviewed articles. Each document was analyzed for its scope, key recommendations, and methodological considerations. Our findings emphasize best practices, identify inconsistencies, and suggest standardized evaluation criteria to ensure uniformity and reliability in assessing ECTs. These criteria will help sponsors navigate the complexities of regulatory submissions and generate evidence to inform treatment guidelines.

external controls

clinical trial design

real-world data

target trial emulation

bias reduction

causal inference 

Biopharmaceutical Section