Emerging trends in biosimilar development as seen through the EU regulatory network may improve patient access
An evaluation of the regulatory experience for biosimilars in the EU since 2005 provides interesting insights into the changing landscape for these biotechnological medicinal products.
The EU’s regulatory framework for biosimilar marketing authorisation applications (MAAs) is built on guidelines, largely issued by the EMA, which complement legal directives from the European Commission. Over 20 years, this regulatory framework has stimulated a steady increase in the number of biosimilar MAAs in the field of chronic, debilitating, and life-threatening conditions.
EMA guidelines are ‘living documents’ and are successively revised and reissued over time. A trend has emerged for less emphasis on confirmatory clinical efficacy trials and more acceptance of evidence from physicochemical assays of similarity, suggesting that accumulated knowledge and experience with biosimilars has gradually lessened stringency to gather data deemed unnecessarily repetitive. There has been a shift toward reliance on evidence from non-clinical in vivo data and use of pharmacodynamic markers as surrogate clinical efficacy endpoints. For highly characterised products such as pegfilgrastim biosimilars granted marketing authorisation after 2018, no phase III clinical trials were required – for these products, biosimilarity was determined in healthy volunteers based on absolute neutrophil count values.
Extrapolation of indications may be granted with justification if the biosimilar demonstrates comparable PK/PD similarity, immunogenicity, and safety data. Some biosimilars have restricted extrapolation of indications, for example if there are uncertainties about beneficial effects. These biosimilars may be granted approval subject to additional monitoring in the risk management plan over the products’ lifecycle.
EudraVigilance reports adverse events associated with a biosimilar during post-marketing phase and compares it with those observed for its originator biologic prior to biosimilar launch. Of 144 disproportionally reported events, 18 were only present pre-approval, 84 were present pre- and post-approval, and 42 were only present in post-approval phase – of which 9 were unexpected reports. Causality analysis of ‘signals’ considered serious enough to warrant further exploration did not lead to any new safety concerns related to biosimilars.
Following regulatory experience of approving biosimilars, guidelines are being updated. Streamlining development programmes has had no noticeable effect on the robust quality, safety, and efficacy of new approved biosimilars. Shorter approval pathways within the EU framework imply faster access to medicinal products for patients.
EMA regulatory framework documents continuously evolve over time, providing the most up-to-date process for biosimilar approval. Over time, the approval pathways have become streamlined, thus implying faster patient access to biosimilar products.