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.

Key takeaway

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.

Biosimilars are set to become integral to cancer therapy

A prospective review of the future of oncology and haematology therapeutics concludes emphatically that biosimilars have arrived in this space. The impact of these agents on cancer care will be great – as long as challenges to their uptake can be overcome.

Biological drugs (biologics) are a cornerstone of treatment for advanced solid tumours and haematological malignancies. However, they are structurally complex and expensive to develop and manufacture, and biologic treatment costs remain high. Patent expiration for various anti-cancer biologics has enabled the development of biosimilars – highly similar biologic products that have gained regulatory approval. Biosimilars are subject to abbreviated approval pathways and their lower development cost usually translates to discounted prices once marketed.

The EMA and FDA’s stepwise approach to establish comparability between a candidate biosimilar and its reference product involves a range of analytical, pre-clinical, and clinical studies. These trials determine that the biosimilar pharmacokinetics and efficacy are statistically equivalent (or non-inferior) to the reference product and that there are no differences in safety, pharmacodynamics, and immunogenicity. Regulatory approval of a biosimilar may be granted if the totality of evidence from all these investigations shows no clinically meaningful difference between the biosimilar and the originator. Extrapolation, licensing permission for the additional indications held by the originator biologic, may be considered by regulatory authorities if evidence shows it is scientifically justified. As an example, the anti-CD20 antibody rituximab’s mechanism of action is lysis of B cells expressing this surface protein, therefore the rituximab biosimilar CT-P10 was considered by EMA likely to exert therapeutic effects against other CD20+ cancers and extrapolated approval for these indications accordingly.

To date, biosimilars approved for cancer treatment are generally licensed for all indications held by their originator product. Parallel considerations have also led to broader acceptance that chronic patients may be switched from biologics to biosimilars without affecting treatment outcomes – subject to national and regional regulations on interchangeability. Nonetheless, decisions regarding switching should be led by treating physicians. Further data collection in this area is strongly encouraged.

The availability of new biosimilars offers the potential for direct cost savings as well as stimulating competition among alternative biologic/biosimilar options, pushing down prices and enabling better patient access to these vital treatments. Barriers to the marketing and uptake of biosimilars must be addressed to attain the full benefits of these drugs.

Key takeaway

Biosimilars have abbreviated approval pathways leading to lower market costs. Biosimilars approved for cancer treatment are generally licensed for all indications held by their originator product offering the potential for direct cost savings as well as stimulating competition among alternative biologic/biosimilar options. Current barriers to uptake need to be addressed to increase biosimilar market share.

Pegfilgrastim biosimilar MYL-1401H exerts equivalent efficacy to reference product in preventing chemotherapy-induced neutropenia in patients with breast cancer

Biologics have great therapeutic potential but are associated with a high cost, which consequently affects their availability – the two principal limitations that biosimilars are designed to address. Among the first biosimilars to receive EMA/FDA approval was filgrastim, indicated for the prophylaxis of chemotherapy-induced neutropenia (CIN), infections, and dose reductions in cancer patients. Whereas filgrastim is administered daily, its long-acting form, pegfilgrastim, can be given once per chemotherapy cycle. MYL-1401H is a pegfilgrastim biosimilar with preclinical and pharmacokinetic/pharmacodynamic data that supports equivalence to the originator drug. This phase III safety and efficacy trial was designed to confirm equivalence between MYL-1401H and pegfilgrastim for CIN prophylaxis.

The study included patients with breast cancer eligible to receive adjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide (TAC) chemotherapy every 3 weeks for six cycles. CIN prophylaxis was administered 24 hours after day 1 of each chemotherapy cycle.


Mean duration of severe neutropenia in both the MYL-1401H and pegfilgrastim groups was 1.2 days, demonstrating equivalent efficacy between the two groups. Secondary endpoints including absolute neutrophil count (ANC) nadir and time to ANC nadir were also similar. Across all cycles, febrile neutropenia (FN) occurred in 6% patients receiving MYL-1401H and 2% pegfilgrastim, suggesting noninferiority of this parameter. All cases of FN were of short duration and no infections required treatment. Similar rates of treatment-emergent adverse events (TEAEs) were observed between groups. One patient in the pegfilgrastim group and no patients in MYL-1401H group had treatment-induced antidrug antibodies.

In this study MYL-1401H demonstrated equivalent efficacy to pegfilgrastim for prophylaxis of CIN in patients with breast cancer undergoing TAC chemotherapy. Both products were generally well tolerated, with no clinically meaningful differences of TEAEs.

Key takeaway

Long-acting pegfilgrastim is indicated for the prophylaxis of CIN, infections, and dose reductions in cancer patients. This phase III trial demonstrated equivalent efficacy of the biosimilar MYL-1401H to the originator product.

MYL-0140 is bioequivalent to both EU-trastuzumab and US-trastuzumab in healthy subjects

Trastuzumab is a humanised monoclonal antibody that binds to HER2 and effectively fights breast cancer cells overexpressing this oncoprotein. This study looked at the pharmacokinetics of a novel biosimilar version of trastuzumab and aimed to confirm its bioequivalence with both EU- and US-sourced originator biologics.

Monoclonal antibody (mAb) biologics that target the host immune response or modify specific intracellular pathways have been successfully established for the treatment or palliation of many different cancers. Trastuzumab is a mAb directed against HER2, an oncoprotein overexpressed in some patients with breast and gastric cancers. MYL-0140 is the first FDA-approved trastuzumab biosimilar. In this phase I bioequivalence study, its pharmacokinetics profile was compared with those of both EU- and US-sourced trastuzumab (i.e., EU-trastuzumab and US-trastuzumab).

Healthy male subjects were randomized to take a single infusion of MYL-0140, EU-trastuzumab, or US-trastuzumab. Blood samples were collected regularly over the first 48 hours post-infusion and at approximately 1–2-week intervals thereafter for up to 10 weeks. Treatment-emergent adverse events (TEAEs) were monitored throughout the study.


Serum trastuzumab concentration–time curve was similar across all three treatment groups. All pharmacokinetic parameters (peak serum concentrations and the area under the curve values) across the groups were within the pre-defined bioequivalence interval. All TEAEs were mild or moderate in severity, and the number of subjects with antidrug antibodies (ADAs) was comparable among the groups.

This study demonstrates bioequivalence between single-dose MYL-0140, EU-trastuzumab, and US-trastuzumab administered to healthy subjects. All three drugs had similar safety profiles and there was no evidence of immunogenicity.

Key takeaway

Trastuzumab is a monoclonal antibody directed against HER2-overexpressing cancers. This phase I bioequivalence study demonstrated bioequivalence between single-dose MYL-0140, EU-trastuzumab, and US-trastuzumab administered to healthy subjects.