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

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 productspecific 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.

Recommendations for the Development and Validation of Neutralizing Antibody Assays in Support of Biosimilar Assessment

“…With regard to using a one-assay approach (usually using biosimilar reagents) or a two-assay approach (i.e., each assay optimized for the respective drug) for immunogenicity assays (2,4,25,26), the industry trend is now leaning towards the oneassay approach for immunogenicity assays (communications among multiple AAPS biosimilar subcommittees and regulatory agencies). The AAPS Biosimilar committee recommends using one assay for Biosimilar NAb evaluation (Table I).…”

Demonstrating Biosimilar and Originator Antidrug Antibody Binding Comparability in Antidrug Antibody Assays: A Practical Approach

“…The resulting inhibition curves should be overlapping [17,18]. A similar experiment is described in the tenth WRIB report in 2016 [21].…”

“…But when it comes to the practical conduct of immunogenicity studies in the bioanalytical biosimilar context, the literature is sparse (Table 1) [14][15][16][17][18][19][20].…”

“…This could be considered as an acceptable risk when using the biosimilar as a capture agent only the immunogenicity of the originator might be affected by false-negative results and hence underestimated [18]. Chamberlain suggest a middle ground where the oneassay approach is applied, but study samples are then inhibited with both biosimilar and originator [17]. The variability of a two-assay setup is circumvented, and biosimilar potential novel epitopes can, in principle, be detected, but challenges remain on cut-point applications and interpretation of data.…”

“…Another described approach is to evaluate antibiosimilar and antioriginator PCs during development and, if comparable, to include only antibiosimilar PC during validation and analysis [20]. Finally, one author considers that the inclusion or evaluation of antibiosimilar and antioriginator PCs is not necessary and does not provide any added value due to the surrogate nature of polyclonal antibodies [17,18]. It is noteworthy that the usage of commercially available antibodies is mentioned and might constitute a viable option as system sustainability control during sample analysis [17].…”