Purpose
External control arms (ECAs) are sometimes considered as an alternative to phase III trials, enabling comparisons without head-to-head trials. Deploying ECAs is complex, partially due to varying regulatory guidelines. We aimed to assess their acceptance in oncology by Health Technology Assessment (HTA) bodies across France, England, Germany, and Norway from 2021 to 2023.
Methods
We conducted a review of HTA evaluation reports for oncology treatments using ECAs. Reports were extracted from national HTA body websites and systematically reviewed. Data extraction included drug characteristics, ECA methodology, acceptance status, and reported issues. ECAs were categorized by type of data: Individual Patient Data (IPD), Aggregated Data (AgD), or naive comparisons.
Results
We analysed 175 ECAs from 123 reviews, none were accepted without restrictions, and only 17% were not rejected. Acceptance rates varied significantly between countries, with England showing the highest non-rejection rate (accepted with restrictions) (41%), followed by France (14%) while Germany and Norway rejected all ECAs. The main methodological issues identified were lack of/unclear data (54%), heterogeneity between studies or risk of bias (51%), study design concerns (29%), and statistical methodology limitations (26%). These challenges were consistent across different types of ECAs, though their relative importance varied by country.
Conclusions
Despite the increasing use of ECAs in oncology trials, their acceptance by HTA bodies remains limited. Our findings highlight significant disparities in assessment approaches between countries and persistent challenges in data quality and methodological consistency. Future efforts should focus on improving transparency, robustness, and residual bias assessment of ECA methodologies.