Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

1. ?The "Scientific Considerations in Demonstrating Biosimilarity to a Reference Product" document offers industry guidance on proving the similarity of a proposed therapeutic protein product to a reference product, as mandated for marketing application submission under section 351(k) of the Public Health Service Act.
2. This guidance is designed to help sponsors grasp key scientific aspects when demonstrating biosimilarity and to guarantee that the submitted evidence meets FDA review standards. It underscores the significance of a gradual approach, incorporating structural assessments, functional tests, animal data, and clinical trials, to substantiate the biosimilarity demonstration.
3. Bio-similars are intricate and require thorough analytical and other assessments to establish structural similarities. Factors such as protein modifications and higher order structure can be influenced by various elements like formulation, environmental conditions (such as light, temperature, moisture), packaging materials, container closure systems, and materials used in delivery devices. Furthermore, both process-related and product-related impurities can impact the likelihood and severity of an immune response to a protein product, while certain excipients may pose challenges in characterizing the protein product.
4. Demonstrating biosimilarity between a proposed product and a reference product is typically more complex than evaluating comparability in a product before and after manufacturing changes by the same manufacturer.
5. Generally, sponsors must provide comprehensive data to demonstrate biosimilarity through direct comparison of the proposed product with the reference product. Analytical studies, at least one clinical pharmacokinetic (PK) study, and if applicable, at least one pharmacodynamic (PD) study, are essential to support a demonstration of biosimilarity under section 351(k) of the Public Health Service (PHS) Act, unless scientifically justified otherwise.
6. The FDA recommends a stepwise approach for developing the necessary data and information to demonstrate biosimilarity.
7. The FDA will assess the totality of the evidence, including structural and functional characterization, nonclinical evaluations, human PK and PD data, clinical immunogenicity data, and comparative clinical study data, submitted in the application.
8. Moreover, the document stresses the necessity of human pharmacology data, such as comparative human pharmacokinetic (PK) and pharmacodynamic (PD) studies, alongside clinical immunogenicity assessments, to validate biosimilarity. It offers in-depth considerations for animal toxicity studies, animal PK and PD metrics, and the interpretation of animal immunogenicity findings.
9. The guidance also highlights the significance of comparative clinical trials, including the careful selection of relevant endpoints and study populations, to evaluate clinically significant distinctions between the proposed and reference products. It underscores the importance of employing endpoints capable of assessing clinically meaningful differences and choosing an appropriate study population consistent with the population studied during the licensure of the reference product.In summary, the document furnishes extensive guidance to industry sponsors regarding the scientific considerations, methodologies, and evidence necessary for demonstrating biosimilarity to a reference product when pursuing FDA approval for a proposed therapeutic protein product. It emphasizes the need for a thorough and systematic approach, as well as the requirement for comprehensive data to substantiate the demonstration of biosimilarity.

References:

https://www.fda.gov/media/82647/download