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.
Since the launch of the first biosimilar (Omnitrope®; somatropin) in 2006, 58 biosimilars have been approved in the EU and 26 in the USA. Licensing of biosimilars has several advantages for healthcare systems: increases medication choice, lowers costs, frees up budgets to provide more treatments, supports competition and sustainability in the pharmaceutical industry, and fosters innovation.
There are, however, several potential barriers to broad uptake of biosimilars in clinical practice. Some physicians may lack knowledge of these drugs or confidence in their use and may also have restrictions in choosing or switching between them. In many cases, pharmacopeia stocking of specific biologic agents are decided by administrative bodies and hospital pharmacists without consulting prescribers – often on grounds of cost considerations alone.
Bevacizumab is the first therapeutic agent for which biosimilars are available in mCRC. Like all biosimilars, these were EMA- and FDA-approved based on submitted data confirming structural similarity and functional equivalence as well as confirmatory clinical efficacy and safety studies versus the reference product. The goal of the latter exercise is not to re-establish clinical parameters by unnecessarily repeating the entire clinical development program for the reference product, but to confirm similar benefits in the most sensitive patient population. For bevacizumab biosimilars, sponsors and regulatory bodies agreed overall response rate in patients with NSCLC was a scientifically justified endpoint to confirm similarity. Since bevacizumab exerts its mode of action – the inhibition of tumour angiogenesis – regardless of the type of cancer, based on totality of evidence the licensed indications for bevacizumab biosimilars could be extrapolated to the treatment of mCRC.
Licensing of biosimilars has a several potential advantages for healthcare systems, although there are several possible barriers to uptake. Bevacizumab biosimilars could serve as an example of extrapolation based on the totality of evidence.
Haematopoietic cell transplantation (HCT) is an expensive modality and developing a transplant program is especially challenging in developing countries.
For oncology and haematology patients, including those requiring haematopoietic cell transplant (HCT), high medication-related expenses (related largely to antibiotics and growth factor-type biologics), are known to hinder access to healthcare worldwide. Patent expiration for biologics may result in biosimilars entering drugs markets and thereby helping to reduce the high costs associated with these therapies.
Biosimilars are chemically similar versions of reference biologic products with no clinically significant differences. Their regulatory approval is granted based on analytical validation studies and preclinical and clinical trials, usually involving a phase III randomised comparator study versus the originator biologic.
The Worldwide Network for Blood and Marrow Transplantation (WBMT) has reported that, despite having among the highest recent increases in HCT activity, only 2% of transplant teams operate in lower-income countries such as in the Eastern Mediterranean and African regions. Latin America has a 20–40-fold lower frequency of HCT compared with Europe and North America, and this limitation is probably due to limited funding. These findings underline an urgent need to implement effective strategies to cut costs for HCT in countries with restricted resources.
Biosimilars used in the field of HCT include granulocyte colony-stimulating factors (G-CSF) for stem cell mobilization, rituximab for graft-versus-host disease (GVHD), and, possibly, infliximab and etanercept in paediatric GVHD. In a meta-analysis of reported studies, most showed no significant difference in efficacy between biosimilar and originator biologic, and where cost analysis was included, reductions were noted for biosimilars.
Biosimilars have been shown to substantially reduce costs in developing countries. By 2024, the use of biosimilar G-CSFs and anti-neoplastics is predicted to result in a 10% cost reduction. The bulk of responsibility for raising awareness of biosimilars lies with governments, regulatory bodies, and local societies. Focusing on the benefits of biosimilars is an important aim for professional organisations specializing in HCT, especially for the education of practitioners in low-income countries.
Although licensed biosimilars are subject to rigorous regulation frameworks and close post-marketing surveillance, they are still underused in the real-world setting.
Biologics account for half the pharmacological market in oncology; however, their main drawback is their high cost. Biosimilars were developed as cheaper alternatives with the dual aims of facilitating access to novel treatments and reducing healthcare expenditures.
Biosimilars are defined by the US FDA and European Medicines Agency as highly similar biological products with no clinically meaningful differences to an existing approved reference product in terms of safety, purity, and potency. Because biosimilars are not identical to their reference biologic, biosimilarity must be demonstrated by evidence from pharmacokinetic and pharmacodynamic studies. Despite the stringent requirements for reliable scientific data and successful clinical trials for all approved biosimilars, knowledge concerning these drugs is lacking – with one quarter of oncologists reportedly able to describe a biosimilar, and one fifth of prescribers familiar with the concept.
As patents for biologics expire, more biosimilars are set to enter the oncology drugs market. The main concern of cancer clinicians over the use of biosimilars is risk of immunogenicity, as even minor differences in molecular structure, impurities, route of administration, and storage conditions between these drugs and reference products could potentially incur adverse effects. Ongoing pharmacovigilance and post-marketing safety monitoring activities – which are mandatory for all approved biologics and biosimilars – should help to dispel these worries over the long term.
Biosimilars represent significant cost savings to healthcare systems. It has been calculated that a 20% reduction in the price of six off-patent biologics would create savings of billions of euros, which when spread out would enable patients access to more treatments. However, these price forecasts also depend on the cost of reference biologics and the competition market.
For patients with cancer, biosimilars are more affordable drugs with a similar safety and toxicity profile and no clinically meaningful difference compared with their reference biologics. Current underuse of biosimilars may be attributed to lack of awareness among patients and clinicians of the benefits and challenges of these important medications. Healthcare professionals, and the public alike, should be properly educated on multiple aspects of biosimilars to ensure their successful incorporation in routine oncology care.
Healthcare practitioner knowledge concerning biosimilars is lacking. There needs to be greater educational opportunities covering all aspects of biosimilar safety and efficacy to ensure successful incorporation of biosimilars in routine oncology care.