Developing the Totality of Evidence for Biosimilars: Regulatory Considerations and Building Confidence for the Healthcare Community

Abstract

Biosimilars are highly similar versions of approved branded biologics. Unlike generics, they are not exact replicas of reference products. Minor differences between biosimilars and reference products in some aspects are expected; likewise, biosimilar products will differ from each other. The objective of this review is to discuss the challenges associated with the development and approval of biosimilar products that are unique because of their complex structure and specialized manufacturing processes, which can impact not only efficacy but also immunogenicity and safety. Regulatory guidelines recommend a totality-of-evidence approach focused on stepwise development that involves demonstration of structural similarity and functional equivalence. Structural and functional characteristics of the proposed biosimilar are compared with the reference product; similarity of these functions forms the foundation of the biosimilar development program, including potential animal studies, a human pharmacokinetics/pharmacodynamics equivalence study, and a clinical study to confirm similar efficacy, safety, and immunogenicity. The clinical study should be performed in a sensitive population using appropriate endpoints to allow detection of any clinically meaningful differences between the biosimilar and the reference product if such differences exist. In conclusion, development of biosimilars is focused on the minimization of potential differences between the proposed biosimilar and reference product and the establishment of a robust manufacturing process to consistently produce a high-quality biosimilar product.

Fig. 1

Stepwise process for biosimilarity demonstration. PD pharmacodynamics, PK pharmacokinetics

Fig. 2

a ADCC activity differs for mAb1 despite being produced in the same cell type. Three different batches of proposed biosimilar mAb1 were produced by process 1 (red and green) or process 2 (orange) and tested for ADCC activity. Neither process condition was able to produce an antibody with ADCC activity similar to that of the originator mAb1 (blue). In contrast, b demonstrates similar ADCC activity for mAb2 despite being expressed in differing cell systems. The graph compares US-sourced (black) reference product and EU-sourced (blue) reference product produced in murine cells, compared with the mAb2 proposed biosimilar (red) produced in CHO cells. Ab antibody, ADCC antibody-dependent cellular toxicity, CHO Chinese hamster ovary, mAb monoclonal antibody

Fig. 3

Characterization of product-related substances and impurities using stability-indicating assay. SE-HPLC size exclusion high performance liquid chromatography

Fig. 4

Schematic representation of exemplary quality attributes of a biosimilar monoclonal antibody. C-Term Lysine C-terminal lysine, Fab fragment antigen-binding, Fc fragment crystallizable, FcRn neonatal Fc receptor, FcγR Fc-gamma receptor, N-Term Lysine N-terminal lysine, N-Term Pyro Glu N-terminal pyroglutamate

Fig. 5

Iterative steps in the process development and analytical similarity assessment for a proposed biosimilar product. DP drug product, DS drug substance