Demonstration of Biosimilarity, Extrapolation of Indications and Other Challenges Related to Biosimilars in Europe

Abstract

The regulatory framework for biosimilars was established across Europe in 2005 based on the concept of biosimilarity. This legislation secures the manufacturing, evaluation, and market authorization (MA) of high-quality safe and efficacious biopharmaceuticals that are highly similar to their reference medicinal product (biosimilars). Demonstration of biosimilarity is documented by full-scale comparability exercises between the biosimilar and the reference product at quality, preclinical, and clinical level. However, the complexity, diversity, and heterogeneity of biosimilars, both in structure and manufacturing, combined with the scientific knowledge accumulated in biotechnological analysis of recombinant therapeutic proteins requires continuous improvement of the regulatory framework based on the evolution and experience gained in this field. This current opinion article presents the concept of biosimilarity, discusses the extrapolation of indications that is acceptable based on a case-by-case basis by CHMP/EMA and uncovers other challenges lying ahead in the development of biosimilars. Biosimilars are still quite 'young' products that require worldwide attention.

Anti-TNFs: Originators and Biosimilars

“…Interchangeability includes the choice of a drug between 2 or more drugs targeted for the same therapeutic or prophylactic purposes [4]. It may be considered for 2 or more ORGs (e.g.…”

“…Having no access to ORG proprietary data, a BS developer must set up his own production line from ground zero [2,4,16] . Pre-requisites are the in-depth knowledge of the manufacturing process and its QAs, adherence to MAA guidelines of the regulatory agency and a full 'quality-in design' system to ensure the synthesis of an appropriately folded molecule and control many post-translational molecular modifications, such as glycosylation, acetylation, phosphorylation, etc.…”

“…Similarity must be documented via a stepwise comparability exercise program using BS samples from several batches intended for commercialization and commercially available ORG batches [7,11,14] . Comparability in pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, safety and efficacy must be demonstrated at quality, non-clinical and clinical levels [2,4,6,14] using the most sensitive analytical tests, animal models and condition where the treatment effect is maximized focusing on the most relevant and sensitive end points [6,7] or 'in which to detect clinically meaningful differences in safety and effectiveness' (FDA) [11] . Trials should confirm clinical equivalence of the BS to its ORG within a strictly pre-defined equivalence interval rather than non-inferiority [4,26,27] .…”

“…Comparability in pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, safety and efficacy must be demonstrated at quality, non-clinical and clinical levels [2,4,6,14] using the most sensitive analytical tests, animal models and condition where the treatment effect is maximized focusing on the most relevant and sensitive end points [6,7] or 'in which to detect clinically meaningful differences in safety and effectiveness' (FDA) [11] . Trials should confirm clinical equivalence of the BS to its ORG within a strictly pre-defined equivalence interval rather than non-inferiority [4,26,27] . After approval, the sponsor must provide a risk management plan and a robust pharmacovigilance program for ongoing surveillance of deviations in purity, safety and efficacy of the BS [6,14,27] .…”

“…Patent expiration of biologics has sparked the interest of industry to produce copy versions ('biosimilars' [BSs]) of IFX and ADL ( table 1 ). The European Medicines Agency (EMA) was the first regulatory authority to establish and regularly update a full framework for marketing authorization application (MAA) of biologics, including mAbs [4][5][6][7][8][9] . Health Canada, USA-Food and Drug Administration (FDA) and World Health Organization (WHO) have also issued guidance for BS of mAbs [10][11][12] .…”