Contributed Commentary by Anna Guildford, PhD and Edyta Dzialo, PhD, KCR Consulting 

November 22, 2024 | The global biosimilars market is experiencing substantial growth, valued at $29.45 billion in 2023, it is projected to reach $150.3 billion by 2033 (CAGR of 17.7%). This upward trajectory is primarily driven by the ability of biosimilars to offer safe, clinically effective, and cost-effective alternatives to reference biologics, expanding patient access to treatments for the ever-rising number of chronic and severe illnesses.  

The Food and Drug Administration (FDA) agency has already approved 60 biosimilar products (by end of September 2024), underscoring their significant potential not only to save the healthcare system billions of dollars but also to expand treatment options considerably. Concurrent with this growth, the regulatory landscape for biosimilars is undergoing dynamic evolution, particularly highlighted by recent modifications to the requirements for interchangeable biosimilars. These regulatory shifts, combined with market trends and technological advancements, set the stage for a comprehensive exploration of the current state and future trajectory of the biosimilar sector.   

Regulatory Landscape, Biosimilars and Interchangeable Biosimilars. 

In recent years, the FDA has continuously updated its guidelines to align with scientific and technological advances crucial for biosimilar development. The 2019 Guidance for Industry discussed two terms—biosimilars and interchangeable biosimilars. While both should be considered equally safe and effective, interchangeable biosimilars can be directly substituted without prescriber approval due to additional requirements of conducting a switching study. 

The FDA has since released seven more guidance documents to elucidate the regulatory pathway for biosimilars and interchangeable biosimilars. However, recent publications indicate a progressive easing of interchangeability requirements. Starting in 2023, the FDA revised labeling guidance and Q&A to recommend an identical "biosimilarity statement" for both interchangeable and non-interchangeable biosimilars—eliminating the previous "interchangeability statement" that purportedly gave a misrepresented sense of a separate safety and efficacy standard for interchangeable biosimilars.  

Furthermore, in May 2024, a podcast by the FDA suggested considering all biosimilars as interchangeable. This was followed by a new draft guidance published in June 2024 allowing companies to demonstrate interchangeability through either switching study data or a statement that their existing dataset already demonstrates the safe practice of switching. These recommendations, when finalized, will provide easier requirements for biosimilar interchangeability status, ready to allow more competition within the biosimilar market.   

Notably, the FDA's long-term strategic plan under the Biosimilar User Fee Amendments (BsUFA) framework prioritizes increased reliance on analytical data and exploration of alternatives to human studies, including leveraging AI and machine learning. These regulatory shifts and technological advancements are poised to impact biosimilars significantly.  

Unlike the evolving interchangeability discussions surrounding the FDA, the European Medicines Agency (EMA) promotes a unified stance on biosimilars. The EMA bases biosimilar approval on comparability studies evaluating factors like protein structure, efficacy, safety, and immunogenicity. Importantly, the EU allows interchangeability of all EU-approved biosimilars, a position reinforced by EMA and Heads of Medicines Agencies’ (HMA) statement in 2022.  

The EMA is also exploring a novel approach to biosimilar approval. In a concept paper, the agency proposes the waiving of extensive efficacy trials if a biosimilar demonstrates a high degree of comparability to the reference product at analytical and functional levels. This shift is based on scientific evidence, questioning the sensitivity of large clinical trials in detecting differences between biosimilars and their references. The biotechnology industry has long advocated for minimizing efficacy study requirements for new biosimilars and thus welcomes this innovative regulatory proposal (Pharmaceutics, DOI: 10.3390/pharmaceutics16030321). 

Strategic Adaptations in the Expanding Biosimilar Market  

The shift in the regulatory landscape combined with patent expirations suggest an imminent influx of biosimilars to the market. Over 19 top-selling biologics are set to face biosimilar rivals by 2028, putting $180 billion in sales at risk for the top 20 biopharma companies.  In response, biopharmaceutical companies employ strategic moves to protect their revenue streams. One tactic is the transformation of drug administration to extend exclusivity. For example, Merck is developing a subcutaneous version of its cancer drug Keytruda, which could secure an additional patent extending Keytruda’s market exclusivity by several years.  

Alongside product innovations, there is a more strategic drive toward aggressive internal development. As patents expire, companies scout for more potential acquisitions, especially those in late-stage development and close to market entry. This strategic activity of companies facing patent expiry demonstrates an adaptive approach to market challenges, aimed at securing continued revenue despite the impending entrance of biosimilars.   

On the other hand, challenges faced by biosimilar companies have led some major players to adopt a more cautious approach. Boehringer Ingelheim has exited European markets to focus solely on the U.S. Pfizer has pulled back on biosimilar development by dropping five preclinical projects in favor of later-stage programs. This risk-averse behavior reflects the intense competition and potentially low returns. A key factor is the high cost of biosimilar development.  

Biosimilars are typically 15-35% less expensive than the reference product but more expensive than generics (Jama Health Forum, DOI: 0.1001/jamahealthforum.2022.3180).  This is due to their origins; generics are made from simple chemicals and biosimilars from complex living sources. The simplicity of the generic allows them to skip stages of the approval process benefiting from the FDA Abbreviated New Drug Application (ANDA). In contrast, the complexity and inconsistency of biosimilars involve significantly higher research and development costs, with  McKinsey estimating the cost of a typical biosimilar to range from $100 million to $300 million and take 6-9 years from analytical characterization to approval. 

Nonetheless, technological advances could pave the way to streamline these processes and unlock the true growth potential of biosimilars. Biosimilar companies already exploit automation and robotic technologies with significant developments in AI and machine learning also accelerating drug discovery timelines. Algorithms can predict interactions between biological compounds and human targets much faster than traditional research methods, as exemplified by IBM's Watson analyzing scientific literature to identify new drug candidates. These digital breakthroughs could solve the high costs and long development times that have historically plagued the biosimilar market.  

Impact of Biosimilars on Healthcare Systems and Patient Access  

Biosimilars have significantly impacted healthcare systems and patient drug access. According to U.S. Generic & Biosimilar Medicines Savings report, since the approval of the first biosimilar in 2015, biosimilars have generated savings of $23.6 billion for the healthcare system. During this period, patients have utilized biosimilars for nearly 700 million days of therapy, with 344 million days representing care that might not have been otherwise accessible. European data shows that since 2006, 86 biosimilars have been approved for use in critical domains like cancer, diabetes, and rheumatoid arthritis. Evidence indicates minimal clinical differences in efficacy and safety when transitioning from reference biologics to their biosimilar counterparts, with data from over 1 million patient-treatment years supporting the interchangeability and reliability of biosimilars. These findings have paved the way for integrated healthcare systems to incorporate biosimilars into clinical practice.  

Despite these achievements, hurdles to biosimilar adoption related to policy differences, pricing, and reimbursement still exist. Fostering trust among patients and physicians regarding the safety, efficacy, and interchangeability of biosimilars remains crucial. Education plays a vital role in addressing these concerns and promoting informed decision-making in healthcare.  

The growing number of biosimilars in different therapeutic areas and healthcare settings demonstrates their role in expanding affordable and effective patient treatment options. The number of products with exclusivity loss and the evolving regulatory pathways will encourage forward-thinking companies to mobilize their commercial models and accelerate their R&D further driving the projected growth and changes in the biosimilars landscape. Importantly, the expansion of biosimilars is proving crucial in controlling healthcare costs and increasing patient access to necessary therapies, contributing significantly to global health equity. 

Anna Guildford is a Senior Consultant with KCR Consulting. With more than 22 years of industry experience, she is an expert in medical writing, scientific research, clinical study documentation, and an author for many academic and industry publications. She obtained a PhD in biomaterials and is passionate about using science to promote healthy aging and combat disease. She can be reached at anna.guildford@kcrcro.com 

Edyta Działo is an Associate Consultant at KCR, Edyta Dzialo has years of experience covering various aspects of clinical trials and five years of pre-clinical work in the doctoral study settings of medical biology.