Regulatory Challenges and Opportunities for Cell-Derived Extracellular Vesicles in Pharmaceutical Development: A European and Global Perspective.

Cell-derived extracellular vesicles (EVs) attract growing interest as biologically active, acellular platforms for therapeutic and diagnostic use in regenerative medicine, immunomodulation, and drug delivery. While EV-based products advance into clinical development worldwide, their acellular nature maps non-uniformly onto pre-existing categories. In the European Union, the 2025 European Medicines Agency/Committee for Advanced Therapies (EMA/CAT) guideline clarifies that "not substantially modified extracellular vesicles" fall outside the current advanced therapy medicinal products (ATMPs) definition, requiring case-by-case development within other medicinal-product frameworks. Conversely, the United States Food and Drug Administration (FDA) regulates exosome/EV products for disease treatment as drugs and biological products subject to premarket requirements, while other regions apply existing drug and regenerative-medicine-related instruments using jurisdiction-specific classification criteria. This heterogeneity creates challenges for regulatory positioning, quality assessment, comparability, and cross-regional clinical development. We critically examine the evolving landscape of EV-based therapeutics, focusing on regulatory, technical, safety, and ethical considerations from a global perspective. We argue EV-based products should be developed within existing medicinal product frameworks (e.g., biologics, ATMP-related instruments), provided regulatory tools are applied consistently, and operational grey zones (e.g., classification criteria, critical quality attributes (CQAs), potency strategies, and comparability) are identified for clarification. Without proposing normative frameworks, this work provides a state-of-the-art synthesis intended to support ongoing regulatory dialogue across regions. The discussion is relevant for international agencies such as the EMA, FDA, the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, the World Health Organization (WHO), and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), as well as for scientific societies such as the International Society for Extracellular Vesicles (ISEV) promoting methodological convergence. By aligning scientific insight with regulatory awareness, this review supports advancing EV-based therapies toward safe, reproducible, and internationally credible clinical use.