Global Trends in Fixed-Dose Combination Drug Development: Regulatory Alignment and Structural Insights From FDA, EMA,...

This study analyzes all fixed-dose combination (FDC) products approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), and Ministry of Food and Drug Safety (MFDS) from 2016 to 2024 to evaluate (1) distribution across therapeutic areas, (2) levels of innovation (Types 1-4), (3) global regulatory harmonization, and (4) characteristics and strategic positioning of FDC development by the different regions.

Approval data were collected from FDA Drugs@FDA, EMA European Public Assessment Reports, and MFDS records. FDCs were classified into four types: Type 1 (simple combination of existing drugs), Type 2 (new combination of existing drugs), Type 3 (new drug + existing drug), and Type 4 (all components are new substances). Comparisons were made across therapeutic areas and innovation types. Additional analyses included temporal trends, composition complexity, regional overlap, and therapeutic focus of MFDS-only FDCs.

Over this 9-year period, a total of 57 FDC products were approved by the FDA, 35 by the EMA, and 104 by the MFDS. FDA and EMA approvals of FDC products were mostly two-drug combinations targeting respiratory diseases, HIV, oncology, and infectious diseases, with Types 2 and 3 being predominant. MFDS approvals, in contrast, were focused mainly on metabolic and cardiovascular indications, particularly diabetes and dyslipidemia, and were predominantly Type 1. However, MFDS also prioritized the authorization of Type 3 FDCs that incorporate domestically developed novel agents, reflecting a focus on local pharmaceutical innovation. MFDS exercised distinctive regulatory authority by approving numerous three- and four-drug combinations, including cardiovascular polypills and multi-mechanism antidiabetic regimens, which are absent from FDA and EMA datasets. Taken together, the three regulatory systems share a common conceptual foundation: FDCs containing novel active substances undergo full new-drug review, whereas combinations of known drugs may rely on prior evidence supplemented by combination-specific data. Differences among the FDA, EMA, and MFDS lie primarily in their legal frameworks and administrative organizations, rather than in their fundamental regulatory principles.

This comparative analysis suggests that while the FDA, EMA, and MFDS share common scientific principles in evaluating FDCs, observed differences in approval patterns are associated with variations in regulatory architecture and national innovation contexts, highlighting the importance of system-level considerations in global assessments of combination-drug development.