Comparative overview of biosimilar regulatory frameworks and international harmonization trends

Biosimilar development is undergoing regulatory change, with growing emphasis on analytical comparability and targeted clinical pharmacology rather than routine comparative efficacy studies. A focused review is therefore needed to understand how global regulatory expectations are evolving, where they are converging, and what this means for future development.

This review examines biosimilar regulatory frameworks across agencies, including the FDA, EMA, PMDA, WHO, Health Canada, and ANVISA. It outlines the shift toward a stepwise, totality-of-evidence approach in which analytical similarity, functional characterization, pharmacokinetic/pharmacodynamic comparability, and immunogenicity assessment provide the basis for establishing biosimilarity. It also considers recent regulatory changes supporting a reduced role for comparative efficacy studies, broader use of foreign comparators and reliance pathways, and the emerging application of artificial intelligence in comparability assessment and model-informed development. Relevant regulatory documents and peer-reviewed literature were reviewed to summarize current trends, differences, and likely future directions.

For many well-characterized biosimilars, particularly monoclonal antibodies, robust analytical and clinical pharmacology data can address most uncertainty, making routine comparative efficacy studies less necessary in many cases. Greater alignment in comparator policies, study expectations, and responsible use of artificial intelligence could help streamline development, reduce duplication, and improve patient access.