Developing a robust and reliable strategy for analytical studies of a biosimilar in development is crucial for a successful regulatory pathway. The importance of biosimilar products is tied to the push for more affordable, accessible biological treatments. However, bringing a biosimilar to market has strict challenges because the biosimilar developer must have a large set of analytical similarity data compared to the innovator biologic. In addition, the biosimilar developer must also contend with demonstrating interchangeability (1).
Establishing biosimilar analytical studies
There are several key criteria to consider when establishing analytical studies for a biosimilar drug candidate to ensure its safety, efficacy, and similarity compared to the reference product, says Olaf Stamm, PhD, technical business development director, Biopharmaceutical Testing Solutions, Charles River Laboratories.
Among these criteria are comparability, biological activity, impurity assessment, and stability studies, Stamm notes. He explains that, for comparability, the biosimilar needs to demonstrate similarity to the reference product in terms of structure, function, purity, and potency. Analytical methods should thus be chosen or developed to compare critical quality attributes (CQAs) between the biosimilar and the reference product. “This involves assessing the physicochemical properties of the biosimilar, such as molecular weight, size, charge, and higher-order structure. Techniques [such as] mass spectrometry, chromatography, spectroscopy, and electrophoresis are commonly used for this purpose,” Stamm says.
The biological activity of the biosimilar should also be evaluated in analytical studies to ensure it matches the biological activity of the reference product. Analytical studies for determining biological activity may involve in-vitro assays, cell-based assays, or other relevant biological assays depending on the mechanism of action of the drug, Stamm remarks.
Identifying and quantifying impurities should include process-related impurities, degradation products, and contaminants. This is a crucial aspect of biosimilar development, Stamm notes. “Analytical methods should be sensitive enough to detect impurities at levels that are relevant to safety and efficacy,” he states. Stamm also points out that analytical methods should be established to identify and quantify residual host cell proteins to ensure they are within acceptable limits because their presence could impact safety and efficacy as well. “The evaluation of process-related impurities, such as residual solvents, reagents, and by-products, should be performed using appropriate analytical techniques,” he adds.
Meanwhile, stability studies are essential for assessing the biosimilar product’s shelf-life under various storage conditions. Analytical methods used for stability studies should monitor degradation pathways and stability-indicating parameters over time.
Biosimilarity versus interchangeability
In biosimilars development, it is not enough to establish analytical evidence of the product’s biosimilarity to the reference product, but also its interchangeability. Luckily, establishing analytical studies for testing biosimilarity and interchangeability involves similar principles, Stamm explains. However, there are some key differences in the objectives and scope of these studies.
Stamm points out that the primary objective of analytical studies for demonstrating biosimilarity is to demonstrate that the proposed biosimilar is highly similar to the reference product in terms of quality, safety, and efficacy. “The goal is to show that any differences between the biosimilar and the reference product are not clinically meaningful,” he says.
In comparison, the objective of studies for interchangeability goes beyond demonstrating similarity. “[Interchangeability studies] aim to provide evidence that the biosimilar can be substituted for the reference product without any additional risk in terms of safety or diminished efficacy compared to using the reference product alone,” Stamm states.
Stamm further explains that interchangeability studies may involve additional clinical work. “Clinical studies for interchangeability are specifically designed to assess the impact of switching between the biosimilar and the reference product on safety and efficacy outcomes. These studies may include switching studies, pharmacokinetic (PK) and pharmacodynamic (PD) assessments, and immunogenicity evaluations in both naive and switch populations,” he says.
Data required for regulatory evaluation
Both biosimilarity studies and interchangeability studies provide information that is crucial for regulatory authority evaluation. Stamm emphasizes that each type of study yields required data as explained in the following sections.
Biosimilarity studies
Comparative analytical data. According to Stamm, biosimilarity studies generate extensive analytical data comparing the biosimilar product’s CQAs with the CQAs of the reference biologic, including physicochemical characterization, biological activity assays, impurity profiling, and stability data.
Clinical data. Meanwhile, clinical studies provide evidence of equivalent efficacy, safety, and immunogenicity between the biosimilar and the reference product in sensitive patient populations. These studies typically include PK/PD assessments as well as comparative clinical trials in relevant patient populations.
Immunogenicity data. Immunogenicity data—including an assessment of the development of anti-drug antibodies—is also a critical component of biosimilarity studies because these data help evaluate the potential risk of immunogenic reactions to the biosimilar.
Interchangeability studies
Clinical switching data. Interchangeability studies yield data on the safety and efficacy of switching between the biosimilar and the reference product, notes Stamm, who explains that these studies also include assessments of PK/PD, immunogenicity, and clinical outcomes following multiple switches between the two products.
Switching impact. Data from interchangeability studies also provide insights into patient outcomes from the impact of switching medications, including any potential risks associated with switching between the biosimilar and the reference product.
Immunogenicity with switching. Immunogenicity of the biosimilar product is also assessed in patients who undergo repeated switching between the biosimilar and the reference product.
Clinical relevance of switching. Regulatory authorities require evidence demonstrating that switching between a biosimilar and its reference product neither compromises clinical outcomes nor poses additional risks to patient safety or efficacy compared to using the reference product alone.
“Overall, both biosimilarity and interchangeability studies generate comprehensive data sets that regulatory authorities evaluate to assess the similarity, safety, efficacy, and interchangeability of biosimilar products compared to their reference products. These studies are essential for the regulatory approval of biosimilars and for ensuring their safe and effective use in clinical practice,” Stamm concludes.
Reference
1. Mirasol, F. Moving Biosimilars Forward in a Hesitant Market. BioPharm Int. 2024, 37 (3), 8–9,29.