How Europe can harness the full potential of biosimilars
The message underpinning the WHO’s latest European Health Report could not have been clearer: Europe must confront its soaring chronic disease rates. With one quarter of the European working population currently suffering from a chronic disease and an ever-ageing population set to further compound the issue, healthcare systems face a growing financial burden and increasing challenges in delivering optimal patient care.
The statistics are particularly alarming for certain therapeutic areas. For instance, the number of adults diagnosed with diabetes in Europe has almost doubled over the last two decades, new cancer cases reached 2.74 million in 2022, and the prevalence rate of auto-immune diseases continues to grow, with two million people currently affected by rheumatoid arthritis.
Estimated to have saved European healthcare systems €56 billion and provided 5.8 million patient treatment days to date, biosimilars - clinically equivalent alternatives to original biologic drugs - play a vital role in addressing the unmet health needs of European citizens and reducing the financial strain on healthcare services.
Their potential impact is yet to be fully realised, however, largely due to the protracted and complex clinical development process that biosimilars must undergo. Streamlining this process could greatly enhance patient access to these life-enhancing medicines and maximise the potential of biosimilars in supporting more financially sustainable and equitable healthcare systems.
Understanding the biosimilar development pathway
The development of biosimilars follows a multi-stage process, with regulatory bodies such as the MHRA, EMA, and FDA advocating a stepwise and totality-of-evidence approach. It begins with a detailed molecular analysis of the reference biologic to more clearly understand its structure, function, and variability – known as analytical characterisation. Next, a Comparative Analytical Analysis (CAA) compares the biosimilar candidate to the reference product with the aim of optimising the manufacturing process and ensuring that an ideal biosimilar may be developed. Following this, preclinical studies involve extensive biologic and functional testing to compare the biosimilar with the reference biologic and assure that the biologic function is the same.
Comparative clinical trials then commence, always comparing the biosimilar candidate to the reference product and starting with phase one trials that evaluate pharmacokinetics (how the drug is absorbed, distributed, metabolised, and eliminated), together with safety and immunogenicity; usually in healthy volunteers, unless toxicity concerns require patient testing. Phase two trials are unnecessary, since the effective dose is already established by the reference biologic. However, all more complex biosimilars that have been approved up to now have involved a lengthy phase three or clinical efficacy study (CES) trial, a conservative measure to confirm the biosimilar's equivalent clinical behaviour in one therapeutic indication. As with any drug that is approved by a regulatory body, ongoing monitoring of the biosimilar’s performance is further conducted in the real world, known as pharmacovigilance, which includes reporting and analysing any adverse events to ensure long term safety and efficacy.
The burden of phase three trials and the case for change
Phase three trials are notably time-consuming and costly, often involving 300-600 patients, spanning two to four years, and costing between £20 million and £150 million. The expense is largely due to the significant number of patients enrolled, which is necessitated by the predefined narrow equivalence margin – the range in which the biosimilar’s efficacy may vary from the reference product. Biosimilars can be neither inferior nor superior to their reference biologics and the predefined equivalence margin is necessary to statistically demonstrate equivalence with confidence. The anticipated rise of next generation biosimilars that can be used in combination with other treatments is set to further compound this issue, as therapeutic margins are often even slimmer for these combination treatments, meaning many more patients – and therefore greater financial resources – will be required.
The experience and evidence obtained after more than 100 approved biosimilars in the EU presents a strong argument that the decision whether a drug may be approved as a biosimilar may be taken without conducting phase three trials by default. Current regulatory thinking is shifting to the view that regulatory bodies could grant marketing authorisation based on a robust Comparative Analytical Analysis (CAA) plus a successful pharmacokinetic study that includes safety and immunogenicity data alone. Phase three trials may only be warranted where uncertainty remains regarding clinical performance that cannot be resolved through other comparability data.
The FDA reported that in the 80 biosimilar applications it received up to October 2024, no new issues were identified in phase three trials that had not already been detected by the CAA. This underscores the sensitivity and reliability of the CAA in detecting meaningful differences between biosimilars and their reference products, making routine phase three trials redundant in many cases. Exceptions might include situations lacking sensitive analytical methods or where the mechanism of action of a medicinal product is not understood.
Unlocking innovation, time, and resources
The opportunity cost of unnecessary phase three trials is enormous. Time and resources devoted to these studies could be redirected towards developing novel therapies and advancing innovation in the biopharmaceutical industry. Reducing unnecessary trials minimises patient burden and allows resources to be focused where they are most needed. Less reliance on phase three trials would also remove a significant barrier to entry, opening up the market to underserved products and areas and increased competition, which would drive down prices even further and thus increase patient access to essential medicines.
In a recent reflection paper, the EMA signalled a willingness to waive phase three trials if similar clinical efficacy and safety pharmacology can be inferred from a sufficiently stringent evaluation of analytical comparability, in vitro pharmacology, and a comparative clinical PK trial. Furthermore, Health Canada just published a revised Draft guidance stating that, in most cases, a comparative efficacy and safety trial is not required.
This aligns with more recentinternational publications, including those authored by the FDA. However, without finalising updated guidance and a first, precedent-setting decision to approve a complex biosimilar application without a phase three trial, biosimilar manufacturers will remain locked in a state of caution, and inefficiencies will persist.
Educating stakeholders and embracing a new paradigm
Over the last two decades, we have accumulated a significant amount of knowledge and experience when it comes to bringing biosimilars to market. Now the challenge is to ensure all stakeholders – whether health authorities, clinicians, or patients – have access to this knowledge and are educated on the rigorous evaluation and regulatory oversight process that biosimilars must undergo to ensure they are as safe and effective as their reference biologics.
Streamlining biosimilars’ development by forgoing unnecessary phase three trials will enhance patient access to essential medicines, optimise resource allocation, and free up space for innovation. As healthcare systems grapple with financial and operational pressures, making the clinical development process more efficient is vital to unlocking the full potential of biosimilars and promoting financially sustainable healthcare for all.
About the author
Dr Elena Wolff-Holz is VP, global head clinical development at Biocon Biologics and has led the clinical development and global submission of three recently approved Biocon Biologics products since she joined the company in 2023. Prior to that, she was a senior regulator at Germany's National Competent Authority Paul-Ehrlich-Institute for 14 years and has extensive knowledge in the development of biologic therapeutics, with a focus on cancer and immunology. Dr Wolff-Holz was the head of the Biosimilar Medicinal Products Working Party (BMWP) within the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) from 2016 until 2023 and also served as member of the Scientific Advice Working Party (SAWP) of the CHMP during that time. With over 30 years of experience, she has held several leadership positions in clinical development and medical marketing functions at major biotech companies in both US and Germany. As a result of her work, Dr Wolff-Holz has earned multiple authorships and co-authorships in esteemed scientific journals and moderated or presented at national and international conferences. She obtained her MD/PhD degree from Heidelberg University and completed a postdoctoral fellowship at Harvard Medical School.
