The Path Towards a Tailored Clinical Biosimilar Development

Abstract

Since the first approval of a biosimilar medicinal product in 2006, scientific understanding of the features and development of biosimilar medicines has accumulated. This review scrutinizes public information on development programs and the contribution of the clinical studies for biosimilar approval in the European Union (EU) and/or the United States (US) until November 2019. The retrospective evaluation of the programs that eventually obtained marketing authorization and/or licensure revealed that in 95% (36 out of 38) of all programs, the comparative clinical efficacy studies confirmed similarity. In the remaining 5% (2 out of 38), despite meeting efficacy outcomes, the biosimilar candidates exhibited clinical differences in immunogenicity that required changes to the manufacturing process and additional clinical studies to enable biosimilar approval. Both instances of clinical differences in immunogenicity occurred prior to 2010, and the recurrence of these cases is unlikely today due to state-of-the-art assays and improved control of process-related impurities. Biosimilar candidates that were neither approved in the EU nor in the US were not approved due to reasons other than clinical confirmation of efficacy. This review of the development history of biosimilars allows the proposal of a more efficient and expedited biosimilar development without the routine need for comparative clinical efficacy and/or pharmacodynamic studies and without any compromise in quality, safety, or efficacy. This proposal is scientifically valid, consistent with regulation of all biologics, and maintains robust regulatory standards in the assessment of biosimilar candidates. Note: The findings and conclusion of this paper are limited to biosimilar products developed against the regulatory standards in the EU and the US.

Type and Extent of Information on (Potentially Critical) Quality Attributes Described in European Public Assessment Reports for Adalimumab Biosimilars

“…Glycosylation is a PTM that occurs through an enzymatic process at specific sites in a protein drug and can influence the biological activity (potency and efficacy), serum half-life clearance (pharmacokinetics), and immunogenicity (safety). Minor differences in glycosylation were observed in adalimumab biosimilars, which are the most frequent notable differences in biosimilars and reference biologicals in general [9][10][11][12].…”

“…However, the developer company of GP2017 reported functional and pharmacological characterizations demonstrating indistinguishable binding profiles and subsequent induction of reverse signaling to support the rationale for extrapolation across indications [28]. Therefore, functional pCQAs provide the final insight into the (dis)similarity at the quality level and useful information in predicting the outcomes of clinical studies [9][10][11], forming the basis for supporting the extrapolation of biosimilars across all indications authorized for the reference biological [59][60][61][62].…”

“…Standardized reporting of pCQAs in EPARs would benefit regulatory learning by allowing future researches to track pCQAs over time. Learning of pCQAs over time might result in reducing the need for comparative clinical trials and streamlining biosimilar approvals [9][10][11][12].…”

“…Biosimilar development and regulatory approval predominantly rely on demonstrating the biosimilarity to the reference biological, which involves a stepwise comparability assessment. The comparability assessment of quality attributes (QAs) is a fundamental step, and it forms the basis for establishing biosimilarity and determining the scope and range of the in-vitro and clinical studies needed for biosimilar approval [9][10][11][12]. Minor differences in QAs between the biosimilar and reference biological may exist but should not be clinically relevant to obtaining regulatory approval.…”

The Biosimilar Landscape: An Overview of Regulatory Approvals by the EMA and FDA

“…Excellent and detailed overviews of the process and clinical trials have been recently published [ 12 , 13 ]. Recently, the relative value of the comparative pharmacokinetic and efficacy trials in the assessment process has been debated, with an emerging view that demonstrating comparable pharmacokinetics has been, so far, the critical element in successful development and approval of most biosimilars [ 14 , 15 ].…”