From analytical similarity to clinical confidence: how regulatory evolution ensures comparable immunogenicity in...

Biosimilars are biological medicines developed once exclusivity for the reference product has lapsed and are regulated through a stringent approval pathway, demonstrating the same efficacy, similar safety, and immunogenicity as their reference products. After two decades of clinical experience and scientific progress, regulatory agencies worldwide are transitioning toward a streamlined (also named tailored) biosimilar development that primarily relies on analytical and pharmacokinetic (PK) similarity, without routinely requiring comparative efficacy studies (CES). This narrative review discusses how comparable immunogenicity is demonstrated within streamlined development. Comparable analytical data provide the pivotal evidence for concluding comparable immunogenicity of a biosimilar candidate. Scientific evidence shows that PK similarity studies provide immunogenicity outcomes highly concordant with those observed in CES. Well-designed PK studies, particularly in healthy volunteers, provide sensitive and clinically informative immunogenicity assessments while minimizing confounding factors associated with disease and concomitant treatments. These studies can adequately characterize the onset, magnitude, and evolution of humoral immune responses without underestimating comparative immunogenicity. In the future, in silico and in vitro tools may enable additional risk-based assessment of immunogenicity differences between biosimilar and reference product. In conclusion, extensive scientific and regulatory evidence supports that streamlined biosimilar development provides a scientifically rigorous framework for demonstrating comparable immunogenicity.