The Diversity of Biosimilar Design and Development: Implications for Policies and Stakeholders

Abstract

Biosimilars are required to be similar or highly similar in structure to their biologic reference product but are neither expected nor required to contain identical active substances. For example, glycosylated biosimilars approved to date demonstrate quantitative and qualitative structural differences from their reference product and exemplify the latitude of variations permitted for biosimilars. Although differences between a candidate biosimilar and its reference product will be evaluated for differential clinical effects during biosimilarity assessment, it is unlikely that potential differences between any two indirectly related biosimilars will be formally evaluated. Furthermore, biosimilar pathways permit variations in pharmaceutical attributes, clinical development approaches, and regulatory outcomes, resulting in further diversity of attributes among approved biosimilars. Because biosimilars may vary across the ranges of structural and functional acceptance criteria, they should not be treated like multisource, generic drugs.

Biosimilars: ensuring safety in the search for savings

“…In contrast, rather than being interchangeable, prescribers should consider biosimilars 'individual therapeutic alternatives'. 6 Indeed, the Medicines and Healthcare products Regulatory Agency (MHRA) recommends prescribing all biopharmaceuticals, including biosimilars, by brand. So, unlike generics, a pharmacist cannot substitute an alternative.…”

“…For example, changes in glycosylation (specifically increased N-glycan branching and sialylation) seem to increase the potency of epoetin, primarily by altering half-life. 6 In another example, a biosimilar manufacturer used a genetically engineered yeast to produce growth hormone. The original product was derived from genetically engineered Escherichia coli.…”

“…Living cells often produce a cocktail of variants (isoforms) rather than a single product, which includes differences in glycosylation (glycoforms). 6 Indeed, several factors contribute to variability between batches of a biopharmaceutical including their complexity and size. 9 The typical biopharmaceutical is between 100 and 1000 times larger than that of a chemically synthesised drug.…”

“…12 Formulations, containers and other elements of the packaging may differ, which potentially leads to differences in structure and stability between brands. 6 Furthermore, patients trust their device and biopharmaceutical to control their serious, chronic disease. So, they might find the change disconcerting.…”

Glycosylation of biosimilars: Recent advances in analytical characterization and clinical implications

“…This was clearly demonstrated by a recent evaluation of glycosylated biosimilars approved in the EU and Japan. It was shown that differences in N-glycosylation not only exist between a biosimilar and a single originator product, but also exists among the different biosimilar products [41].…”