Immunogenicity Assessment of Biosimilars: A Multidisciplinary Perspective

Abstract

Evaluation of the relative immunogenicity of a biosimilar candidate in direct comparison to the reference product is a general regulatory requirement, with the main weight of evidence deriving from head-to-head clinical studies in populations that are adequately sensitive to reveal clinically meaningful differences across the proposed conditions of use.

This chapter provides case examples to illustrate the multi-disciplinary nature of the exercise, which involves interpretation of bioanalytical measures of the immune response in relation to differences detected in the product quality profile, as well as potential biases in bioanalytical methodology and confounding patient-related factors. Most importantly, the design of the clinical immunogenicity evaluation needs to reflect the risk profile established for the reference product, allied to uncertainty about possible impact of minor heterogeneity in product-related variants and process-derived impurities, and limitations of the methodology for detection of clinically meaningful consequences. Thus, a difference in the measured anti-drug antibody incidence may not necessarily preclude a conclusion of biosimilarity if this does not translate into a negative impact on efficacy or safety: examples of authorized biosimilar products are discussed to show how regulators have applied a “totality of evidence” approach to deal with apparent numerical differences in immune response parameters.

Validity of extrapolating conclusions about relative immunogenicity in one therapeutic setting to other indications is reviewed based on actual clinical results obtained for products associated with clinically impactful immunogenicity. Then, experience gained from transitioning between product versions is discussed in the context of interchangeability considerations. Finally, reflection is given to longer-term management of potential immunogenicity-related risks associated with manufacturing changes during the independent post-authorization life-cycles of different product versions.