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

BioDrugs (2015) 29:365–372 DOI 10.1007/s40259-015-0147-0 CURRENT OPINION The Diversity of Biosimilar Design and Development: Implications for Policies and Stakeholders Gustavo Grampp1 • Sundar Ramanan2 Published online: 18 November 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com 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. Key Points Although biosimilars are highly similar to their reference products, they are not identical to them. Regulatory pathways permit slight differences in structural and other product quality attributes of biosimilars; such difference are unlikely to be formally evaluated among indirectly related biosimilars, resulting in a potential for a broader range of potential differences in quality attributes among approved biosimilars. Policies and practices related to the identification and use of biosimilars should take into account potential molecular differences among multiple biosimilars of the same reference product and should not treat them like generics. Specific recommendations to distinguish biologics from generic drugs in practice include ensuring that all biologics have distinguishable names and are prescribed by a distinguishable name, that a clinician is involved in decisions to switch among noninterchangeable biologics, and that patient medical records track biologics by their distinguishable names. 1 Introduction & Sundar Ramanan 1 Amgen Inc., Longmont, CO, USA 2 Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA Biologic medicines consist of mixtures of structural isoforms (e.g., glycoforms), whereas the active ingredient of a chemically synthesized drug is typically a single entity with a defined structure [1]. Unlike generic products for chemically synthesized drugs, which contain the same active ingredient 366 as their reference product, biosimilar products do not contain active drug substances identical to their reference product [2–4]. Minor structural differences between biosimilars and their reference product are expected and allowed because of their inherent molecular complexity and differences in manufacturing processes among biologics manufacturers [4]. However, such minor structural differences are expected not to result in functional or clinically meaningful differences in terms of quality, safety, or efficacy [3]. Beyond the implications for potential differences in drug substances, biosimilar development pathways also include opportunities and incentives for diversity in drug product and clinical attributes, including formulations, presentations, devices, indications, and routes of administration [5]. Although these features also apply to chemically synthesized drugs, the nature of the biosimilars pathway may tend to promote more diversity in these aspects to compensate for the intrinsic molecular heterogeneity and intellectual property. Because biosimilars differ from chemically synthesized drugs in many critical aspects, policies and practices applicable to generic drugs from multiple manufacturers generally are not directly transferable to biosimilars [4, 6, 7]. This brief report highlights examples of structural variances (i.e., at the level of the drug substance) of biosimilars approved in the European Union (EU) and Japan to illustrate that biosimilarity is not transitive. We also provide an example of how interactions between structural attributes could be relevant to the design of a biosimilar. The biosimilar approval process relies on a comparison of one biosimilar candidate with one reference product, whereas multiple biosimilars of a given reference product can be expected in the marketplace. Therefore, we suggest that policies and practices related to the identification and use of biosimilars take into account the potential molecular differences between biosimilars and their reference products and the lack of transitivity among multiple biosimilars of the same reference product. Specific recommendations to distinguish biologics from generic drugs in practice include ensuring that each biologic has a unique name and that it is prescribed by that unique name, that a clinician is involved in decisions to switch among non-interchangeable biologics, that patient medical records track biologics by their unique names, and that reimbursement claims systems use a unique code for each individual biosimilar. 2 Differences Between Biosimilars and Reference Products Necessitate Product-Specific Identification A review of glycosylated biosimilars approved in the EU and in Japan demonstrates that structural variances exist between biosimilars and their reference products (Table 1). G. Grampp, S. Ramanan For example, with RetacritÒ (epoetin zeta; SB309), an EUapproved biosimilar of EprexÒ/ErypoÒ (epoetin alfa), the extent of glycoforms without an O-linked glycan chain was found to be higher in the biosimilar than in the epoetin alfa reference product [8]. Conversely, levels of variants of sialic acid (N-glycolylneuraminic acid and O-acetyl neuraminic acid) were higher in the reference product [8]. Independent studies, as well as our internal analysis (Table 2) performed after RetacritÒ (epoetin zeta) was approved in the EU, have revealed additional structural differences, including higher levels of lactosamine repeats and lower levels of sialylation relative to EprexÒ (epoetin alfa) [9]. As an example of diversity in drug product formulation or presentation, differences in potency between these products have also been reported, with the biosimilar product demonstrating 8 % lower bioactivity relative to the reference product, likely due to a difference in protein concentration [8]. Another EU-approved biosimilar of EprexÒ/ErypoÒ (epoetin alfa), BinocritÒ (epoetin alfa; HX-575), contains higher levels of phosphorylated high mannose glycans (mannose-6-phosphate glycans) at one glycosylation site, Asn-24, and lower levels of sialic acid (N-glycolylneuraminic acid a (...truncated)