Navigating the Regulatory Landscape for Combination Products: An Expanded Review of Regulatory Data, Global Perspectives, and Emerging Challenges

Abstract

Combination products therapeutic and diagnostic systems that bring together drugs, biologics, and medical devices form one of the fastest-growing segments in modern healthcare. By combining mechanisms of action, these integrated systems can improve clinical outcomes, yet their hybrid nature also creates considerable regulatory complexity. This review offers a structured, critical look at how the U.S. Food and Drug Administration (FDA) regulates combination products, covering statutory definitions, classification systems, primary mode of action (PMOA) determinations, center assignment, designation procedures, and premarket approval routes such as 510(k), PMA, NDA, ANDA, and BLA. It also examines emerging difficulties, including the limits of PMOAbased classification, gaps in post-market surveillance, and the uncertainty surrounding newer technologies such as nanomedicine and AI-enabled devices. A comparison with international systems, the European Commission’s framework and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) is included as well. Taken together, the analysis points to a need for more adaptive regulation, closer coordination between agency centres, and greater global harmonization so that both innovation and patient safety can be served.