Biosimilars are large, complex molecules with high similarity to an existing and licensed biotherapeutic product, developed for use when the current patent comes to an end. In recent years, biosimilars have led to more accessible treatment for a large variety of diseases due to more competitive pricing and greater accessibility for a large variety of diseases.
As more biotherapeutic products lose patent exclusivity, the global market for biosimilars is set to increase. However, to reach the market, biosimilars must follow a strict regulatory pathway and meet stringent requirements set by different regulatory agencies across the globe, which gives rise to a unique set of challenges. The need for standardization when assessing biosimilarity is paramount to shorten the pathway for approval, lower the cost, and expand treatment options for patients. Scientists at biotherapeutic companies can choose to address these challenges through in-house efforts, or partner with other organizations offering specialized services and products in this area, such as Labcorp and Svar Life Science.
As an assay provider offering both bioanalytical services and functional, mechanism of action (MoA)-reflective products, Svar Life Science has extensive experience in requests dealing with analytics in biosimilar development. “As more and more biologics are going off-patent, we are definitely seeing an increase in requests within this area. Customers come to us because they need biologically relevant assays that are MoA reflective but are robust enough to meet the strict requirements set by authorities”, says Therese Segerstein, Portfolio Director at Svar.
As a leading service provider within these areas, Labcorp also supports drug development with services throughout the entire value chain, and these types of assays. In this exclusive interview, we speak with Heather Watson, Senior Manager in the Immunochemistry Department at Labcorp, to find out more about their expert view of opportunities and challenges in biosimilar development.
HW: The company’s mission is to improve health and improve lives by delivering world-class diagnostic solutions, bringing innovative medicines to patients faster, and using technology to improve the delivery of care. I’m part of Labcorp Drug Development, which supports the full breadth of drug development needs including nonclinical safety assessment, clinical trial testing, and clinical trial management services. Labcorp Drug Development, which I’ve been a part of for the past 14 years, has had the opportunity to support more than 100 unique biosimilars of 23 innovator products.
HW: Where approval for an innovator is driven by the clinical data and clinical pharmacology to support safety and efficacy, the requirement for biosimilars is proof of similarity to the originator. This encompasses physicochemical characteristics, biological activity, PKs, efficacy, and safety. This puts the burden squarely on the analytical strategy to appropriately demonstrate the biosimilar may be administered in place of an FDA-licensed biologic.
While the Affordable Care Act provided an abbreviated licensure pathway for biosimilars, and revised guidance was released in 2019 for demonstrating biosimilarity, there is still a need for clear guidance that takes molecule type and even drug development stage into consideration. The strategy for how to demonstrate biosimilarity must evolve in parallel from early manufacturing and scale-up, through to clinical trials. This can be further complicated as you are initially comparing an early-phase product in the process of scaling up to a marketed product. This puts a burden on the analytical methods used. Selection of the right methods utilizing the appropriate reagents or cell lines, with specificity to both the innovator and biosimilar product, is paramount. To add to this, you may also have the added challenge of a US and EU version of the innovator.
Unfortunately, published analytical approaches or data available for the innovator may be of less use. These were often established under a different regulatory landscape and analytical procedures have evolved and improved significantly in some instances.
HW: There are two parts. The first is product release testing and characterization (protein structure, identity, post-translational modifications, biological functionality/activity), and the second is the preclinical and clinical study-related analytical methods, which are used to support biosimilarity when it comes to efficacy and safety (including immunogenicity). A common mistake is to not think enough in advance about your analytical strategy, particularly for the reagents used in those methods. Improper reagents could set you back months or even a year if you need to generate monoclonal antibodies, polyclonal antibodies, or a cell line that demonstrates equivalent specificity to both the innovator and biosimilar. This may need to encompass considerations for molecules where lot-to-lot variation in potency is to be expected, even within the same manufacturing process. This is not limited to only biosimilars – it’s relevant for all biological drugs.
HW: Characterization of the biosimilar very early on is key. As the processes drive the biologic, careful analysis not only of the protein structure, identity, and post-translational modifications, but of the biological functionality/activity is important. It is also important to test against the innovator product with methods that are specific and sufficiently sensitive. Cell-based methods used in potency testing for product release must demonstrate comparable specificity/sensitivity to both the innovator (EU/US versions) and biosimilar. Conversely, these same methods for potency are often adapted to support immunogenicity testing.
HW: Cell-based potency assays are often adapted into neutralizing antibody methods to support characterization of the immune response to both the innovator and biosimilar. Demonstrating that there is no difference in immunogenicity between the innovator and biosimilar is key to establishing biosimilarity. The question is often: Does one establish a single assay format or separate assays?
The Biosimilars Action Program Committee (APC) was established under the American Association of Pharmaceutical Scientists (AAPS) as a working group to discuss this topic and a single assay format was recommended. There are multiple benefits, but antigenic equivalence must be proven which puts the burden on the selection of the correct cell line to truly demonstrate the mechanism of action, as well as the associated surrogate positive controls.
HW: It really comes down to specificity and full characterization of the analytical method, and the associated reagents used. In the end, your data supporting biosimilarity is only as good as the analytical method used.
HW: While regulatory authorities led by the European Medicines Agency (EMA) have issued guidance for the development of biosimilars, and the WHO/FDA have established guidelines for approval, there is still a lack of finalized regulatory guidance around the requirements for biological testing of biosimilars, and even less for the analytical procedures supporting PK and immunogenicity assessment. How do we demonstrate biosimilarity between the innovator and biosimilar product? In the future, we can expect more focus and stringency on the reagents used to support these analytical methods, cell characterization for potency assays/NAb, and specificity of critical reagents to both molecules, as well as more rigorous statistical analysis.
HW: Labcorp has seen multiple companies go after the same innovator products, there is a wealth of opportunity for off-the-shelf reagents or assays that may expedite the process and shorten approval timelines.
Labcorp is uniquely positioned to support sponsor’s biosimilar analytical needs, present and future. With our Biosimilar CMC Analytical Master Files that can serve as the foundation for risk-mitigated biosimilarity assessment, client data evaluation and consultation to support your biosimilar program throughout its lifecycle. Additionally, Labcorp is the only CRO that can provide an integrated biosimilar development strategy including nonclinical needs with in-vivo studies (efficacy/pharmacology, pharmacokinetic (PK) and toxicity), bioanalytical method validation and sample analysis, and immunochemistry including anti-drug antibody (ADA) and neutralizing antibody (NAb) assessment in animal and human matrices.
Additionally, while we are currently focused on the first few waves of biologics that are going off-patent, these were simpler molecules, proteins, or antibody therapies. Over the years, we’ve seen a continued increase in the complexity of molecules, from antibody-drug conjugates (ADCs), to bi-specific antibodies, peptides, and gene therapies. The need for harmonization in how to best assess biosimilarity with increasingly complex molecules will be paramount to the goal of shortening the pathway for approval and ultimately getting these cost-effective drugs in the hands of those that need them.
The process of developing biosimilars is complex and variable, and robust characterization tools are needed.
In order to lead the market and continue successfully pioneering new biosimilar solutions, it’s sometimes necessary to team up and establish strong partnerships with collaborators, big and small.
Svar Life Science is such a biosimilar development partner with a long track record in assisting in the various phases of drug development, and offering a range of analytical tools that enable drug developers to bring biosimilar products to market.
The iLite® cell-based reporter-gene assays are MOA-reflective and biologically relevant assays that offer a fast and convenient way to accurately measure and quantify drug activity and immunogenicity. As an added benefit, the cells are provided assay-ready for a quicker workflow and contain a second normalization reporter-gene for added convenience.
By also offering bioanalytical services for biosimilar development, Svar Life Science can help overcome several of the common challenges, such as bioanalytical program design, analyzing the clinical significance of identified differences and obtaining critical reagents. In addition, Svar can help put processes in place for PK and immunogenicity biosimilar assay design, validation aspects, along with biosimilar bioanalytical development and sample analysis.
So regardless of your needs, Svar Life Science can help you navigate the analytical challenges of biosimilar drug development.