Discrepancies in regulations in post-marketing safety surveillance of drug-device combination products in the EU and US: a review

This article captures the differences in regulations in post-marketing safety surveillance in drug device combinations in the US and the EU. Drug-device combinations have improved the landscape of health care through both drug effectiveness and personalized medicine. Regulatory frameworks in the U.S. and E.U. ensure these products are safe and effective. In the E.U., combination products are officially regulated according to their primary mode of action (PMOA) as per EU MDR 2017/745 and MPD 2001/83/E.C., executed by the European Medicines Agency (EMA) and National Competent Authorities (NCAs). Products are classified as integral, co-packaged, or cross-labeled, with extensive pre-marketing assessment and post-marketing surveillance. In the United States, the combination products are regulated per 21 CFR 3.2(e) by the Office of Combination Products (OCP) and lead centers (CDER, CDRH, CBER), which ensure adequate compliance. Post-marketing surveillance, risk management, and safety signal identification, are key features of the FDA’s Adverse Event Reporting System (FAERS) and Risk Evaluation and Mitigation Strategies (REMS). While the E.U. and U.S. have robust regulatory frameworks for drug-device combination products, they differ in their approaches, leading to challenges in global harmonization. In the EU, no single regulatory authority oversees the entire lifecycle of combination products. The MDR focuses on device performance and risk management while the EMA focuses on medicinal product efficacy and safety. The drug safety reporting system EudraVigilance focuses on the medicinal component, with EUDRAMED. In the U.S., the FDA oversees these products, with the Center for Drug Evaluation and Research (CDER) or the Center for Devices and Radiological Health (CDRH) determining the regulatory path whether the product acts primarily as a drug or a device. Misalignment between the EU and US frameworks creates issues for global harmonization, affecting access, manufacturing, and patient safety. International cooperation and the implementation of standardized guidelines are crucial for advancing global healthcare and ensuring the efficacy and safety of drug-device combination products. This article aims to discuss discrepancies in regulation between the US and EU and discuss the feasibility of the current problems.