Safety, Immunogenicity and Interchangeability of Biosimilar Monoclonal Antibodies and Fusion Proteins: A Regulatory Perspective

Abstract

Background Biosimilars have been used for 15 years in the European Union (EU), and have been shown to reduce costs and increase access to important biological medicines. In spite of their considerable exposure and excellent safety record, many prescribers still have doubts on the safety and interchangeability of biosimilars, especially monoclonal antibodies (mAbs) and fusion proteins. Objectives The aim of this study was to analyse the short-and long-term safety and interchangeability data of biosimilar mAbs and fusion proteins to provide unbiased information to prescribers and policy makers. Methods Data on the safety, immunogenicity and interchangeability of EU-licensed mAbs and fusion proteins were examined using European Public Assessment Reports (EPARs) and postmarketing safety surveillance reports from the European Medicines Agency (EMA). As recent biosimilar approvals allow self-administration by patients by the subcutaneous route, the administration devices were also analyzed. Results Prelicensing data of EPARs (six different biosimilar adalimumabs, three infliximabs, three etanercepts, three rituximabs, two bevacizumabs, and six trastuzumabs) revealed that the frequency of fatal treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation of treatment, serious adverse events (SAEs), and main immune-mediated adverse events (AEs) were comparable between the biosimilars and their reference products. The availability of new biosimilar presentations and administration devices may add to patient choice and be an emerging factor in the decision to switch patients. Analysis of postmarketing surveillance data covering up to 7 years of follow-up did not reveal any biosimilar-specific adverse effects. No product was withdrawn for safety reasons. This is in spite of considerable exposure to biosimilars in treatmentnaïve patients and in patients switched from the reference medicinal product to the biosimilar. Analysis of data from switching studies provided in regulatory submissions showed that single or multiple switches between the originator and its biosimilar versions had no negative impact on efficacy, safety or immunogenicity. Conclusions In line with previous reports of prelicensing studies of biosimilar mAbs and etanercepts, this study demonstrated comparable efficacy, safety, and immunogenicity compared with the reference products. This is the first study to comprehensively analyze postmarketing surveillance data of the biosimilar mAbs and etanercept. An analysis of more than 1 million patient-treatment years of safety data raised no safety concerns. Based on these data, we argue that biosimilars approved in the EU are highly similar to and interchangeable with their reference products. Thus, additional systematic switch studies are not required to support the switching of patients.

Interchangeability of Biosimilars: Overcoming the Final Hurdles

“…Furthermore, these studies may be considered ethically questionable since they draw from limited clinical resources. The findings presented by Kurki et al [10] further strengthen the rationale put forward in an earlier Kurki-authored paper in 2017 [14] on biosimilar switching and interchangeability, where they argued that biosimilars licensed in the EU could be considered interchangeable.…”

“…In 2019, Ebbers and Schellekens [9] argued that sufficient experience and data have been gathered regarding biosimilar evaluation and their use in clinical practice and called upon stakeholders to close the discussion on their interchangeability. In this issue of Drugs, Kurki et al [10] and Mysler et al [11] present two unique papers that address the topic of biosimilar interchangeability and provide important findings to inform and drive the debate to a conclusion. While both papers investigate the topic of interchangeable biosimilar use from different perspectives-regulatory and clinical-and do so through different approaches, they arrive at similar conclusions.…”

“…While the analysis by Kurki et al [10] and their conclusions are reassuring and an important message for stakeholders about biosimilar use in practice, this message needs to effectively reach the medical and policy-making community. The authors also acknowledge this: "Learned societies, regulators, and policymakers should act swiftly to create a common European position on interchangeability to promote rational use of biologicals."…”

“…In this issue of Drugs , Kurki et al [ 10 ] and Mysler et al [ 11 ] present two unique papers that address the topic of biosimilar interchangeability and provide important findings to inform and drive the debate to a conclusion. While both papers investigate the topic of interchangeable biosimilar use from different perspectives—regulatory and clinical—and do so through different approaches, they arrive at similar conclusions.…”

“…While both papers investigate the topic of interchangeable biosimilar use from different perspectives—regulatory and clinical—and do so through different approaches, they arrive at similar conclusions. Kurki et al [ 10 ] provide insights from the EU regulatory perspective on interchangeability, and Mysler et al [ 11 ] focus on biosimilar-to-biosimilar switching from the clinical perspective. In this commentary, we discuss both papers, mainly from a European perspective.…”