Multidisciplinary approach to evaluating immunogenicity of biosimilars: lessons learnt and open questions based on 10 years' experience of the European Union regulatory pathway

Abstract

Abstract: Clinical evaluation of comparative immunogenicity represents an important component of the European Union regulatory review process for candidate biosimilar products. The clinical evaluation is part of a multidisciplinary review that cross-refers to product quality attributes as well as preclinical and ongoing risk management considerations. Results from the monitoring of anti-drug antibody formation in relevant populations treated for an adequate period of time are interpreted in relation to clinically relevant endpoints, including pharmacokinetics, pharmacodynamics, efficacy, and safety parameters. The European Union regulatory standard for designation of biosimilarity requires a suitable weight of evidence, determined on a product-specific basis, to demonstrate that the immunogenicity associated with the biosimilar product does not lead to a higher negative impact on clinically relevant outcomes compared with the reference product. The experience gained during the 10-year period following the implementation of the European Union biosimilars pathway indicates that a suitably cautious approach was applied, insofar as no immunogenicity-related issues have emerged for the approved applications of the different biosimilar products. In some cases, product quality-related issues were identified in the preauthorization setting as being potentially relevant for heightened risk of immunogenicity and were duly taken into account for the biosimilarity decision. Some unresolved issues remain, most notably concerning the limitation of noninterventional post-marketing surveillance measures to monitor the potential for changes in immunogenicity over the longer term, eg, following introduction of changes in manufacture, formulation, or primary product container. Lack of standardization of bioanalytical methods precludes comparison of anti-drug antibody formation for different products that are evaluated in noncomparative clinical studies, and correlation with relevant clinical parameters is also lacking.