Analysis of regulation of biosimilars in the EU concludes that regulation is progressing as more knowledge is gained, which is reflected in the changing nature of regulatory guidelines. The authors conclude that the EU framework generates safe and effective biosimilars .
The EU first set up a regulatory framework for biosimilars in 2005 and defines a biosimilar as a ‘biological medicinal product which is similar, but not identical, to a reference biological medicinal product’.
Since 2005, there has been a steady increase in the number of biosimilars approved in the EU. In order to assess trends in biosimilars regulation over this time, a recently published study  analysed marketing authorisation applications (MAAs), approved biosimilars, clinical development programmes for biosimilars, and adverse event reports related to biosimilars in the EU.
They found that, since 2005, 12 guidelines have been issued, nine of which were updated in line with new knowledge. Guidelines on the development of biosimilars in the EU have been described as ‘living documents’, as they are continuously revised and updated as necessary.
Up to December 2019, 90 MAAs were submitted to the European Medicines Agency (EMA) and 53 biosimilars were approved (for 14 different classes of biologicals), demonstrating the EU’s increasing experience in regulating biosimilars.
The researchers’ review of European public assessment reports (EPARs) found that product-specific guidelines were generally followed by applicants. In cases where deviations from the guidelines occurred, approval was still granted if the overall application demonstrated biosimilarity.
A review of clinical development programmes found that the average number of phase I clinical trials was generally higher than phase III trials, excluding for biosimilars approved in 2016 (in which the number of phase I and III trials were the same).
Phase I trials mainly involved healthy volunteers. However, exceptions to this trend were observed in the clinical development of biosimilars of rituximab, insulin glargine and infliximab.
In some cases, e.g. clinical development programmes of bevacizumab, etanercept and trastuzumab, the researchers observed that only healthy male volunteers were enrolled. Under-representation of women in clinical trials is a well-known issue, they say, related to the fact that women have childbearing potential and drugs may have unknown side effects on the fetus.
In some cases, clinical development programmes consisted of only phase I clinical trials, without phase III studies, such as for certain pegfilgrastim biosimilars. However, approval in such cases was dependent on adequate scientific justification of the absence of phase III studies, as well as scientific advice being sought during development.
In terms of safety, analysis of disproportionate adverse event reports identified no new safety concerns, indicating that biosimilars are well tolerated. Results from the analysis of Medical Dictionary for Regulatory Activities (MedDRA) also suggested a high degree of similarity in the safety profile of originators and their biosimilars.
The authors summarize that the EU defines therapeutic equivalence through pharmacokinetic/pharmacodynamic (PK/PD) endpoints, extrapolation, PD markers and PK reliance. They say this integrated way of demonstrating biosimilarity reduces the number of clinical trials needed and may shorten clinical development timelines, accelerating access to medicinal products for patients.
They also commend the process of offering scientific advice, which they say is a useful tool that allows applicants to discuss their development strategies with the regulator.
The authors conclude that clinical development programmes of biosimilars and approval requirements for biosimilars are changing over time in the EU, as guidelines are constantly being updated to reflect new knowledge. Ultimately, their analysis indicates that the EU framework results in quality, safe and efficacious biosimilars.
Conflict of interest
The authors of the paper  declare no conflict of interest.
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1. Zuccarelli M, Micallef B, Cilia M, et al. The EU regulatory network and emerging trends – a review of quality, safety and clinical development programmes. Generics and Biosimilars Initiative Journal (GaBI Journal). 2021;10(2):83-99. doi:10.5639/gabij.2021.1002.009
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