The US Food and Drug Administration (FDA) has issued three final guidances on biosimilars. The final guidances are: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product, and Scientific Considerations in Demonstrating Biosimilarity to a Reference Product.
The guidance, Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009,provides answers to common questions from sponsors interested in developing proposed biosimilar products, biologics license application (BLA) holders, and other interested parties regarding FDA’s interpretation of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). The questions and answers (Q&As) are grouped below in the following categories: biosimilarity or interchangeability; provisions related to requirement to submit a BLA for a biological product; and exclusivity.
The BPCI Act amends the Public Health Service Act (PHS Act) and other statutes to create an abbreviated licensure pathway in section 351(k) of the PHS Act for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product (see sections 7001 through 7003 of the Patient Protection and Affordable Care Act (Pub. L. 111–148) (Affordable Care Act)). On November 2 and 3, 2010, FDA held a public hearing and established a public docket to obtain input on specific issues and challenges associated with the implementation of the BPCI Act (see Docket No. FDA-2010-N-0477). This guidance describes FDA’s current interpretation of certain statutory requirements added by the BPCI Act and reflects consideration of the comments concerning those requirements that were submitted to the public docket.
The guidance, Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product, describes the FDA's current thinking on factors to consider when demonstrating that a proposed therapeutic protein product is highly similar to a reference product licensed under section 351(a) of the PHS Act for the purpose of submitting a marketing application under section 351(k) of the PHS Act. Specifically, this guidance is intended to provide recommendations to sponsors on the scientific and technical information for the chemistry, manufacturing, and controls (CMC) section of a marketing application for a proposed product submitted under section 351(k) of the PHS Act.
Since 1996, the FDA has approved many manufacturing process changes for licensed biological products based on a demonstration of product comparability before and after the process change, as supported by quality criteria and analytical testing and without the need for additional nonclinical data and clinical safety and/or efficacy studies. In some cases, uncertainty about the effect of the change and/or the results of the biochemical/functional comparability studies has necessitated assessment of additional data, including nonclinical and/or clinical testing, to demonstrate product comparability. These concepts were further developed in the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use and resulted in the ICH guidance for industry Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process.
"Although the scope of ICH Q5E is limited to an assessment of the comparability of a biological product before and after a manufacturing process change made by the same manufacturer, certain general scientific principles described in ICH Q5E are applicable to an assessment of biosimilarity between a proposed product and its reference product," said the FDA in the guidance. "However, demonstrating that a proposed product is biosimilar to an FDA-licensed reference product manufactured by a different manufacturer typically will be more complex and will likely require more extensive and comprehensive data than assessing the comparability of a product before and after a manufacturing process change made by the product’s sponsor. A manufacturer that modifies its own manufacturing process has extensive knowledge and information about the product and the existing process, including established controls and acceptance parameters. By contrast, the manufacturer of a proposed product will likely have a different manufacturing process (e.g., different cell line, raw materials, equipment, processes, process controls, acceptance criteria) from that of the reference product and no direct knowledge of the manufacturing process for the reference product," said the FDA in its guidance.
The new guidance describes the analytical studies that are relevant to assessing whether the proposed product and a reference product are highly similar to support a demonstration of biosimilarity. The document is not intended to provide an overview of FDA’s approach to determining interchangeability, which will be addressed in a separate guidance document. Although this guidance applies specifically to therapeutic protein products, the general scientific principles may be informative for the development of other protein products, such as in vivo protein diagnostic products. The guidance describes considerations for additional CMC information that are relevant to assessing whether the proposed product and the reference product are highly similar. All product applications should contain a complete and thorough CMC section that provides the necessary and appropriate information (e.g., characterization, adventitious agent safety, process controls, and specifications) for the product to be adequately reviewed. This guidance should be used as a companion to other guidances available from FDA that describe the CMC information appropriate for evaluation of protein products.
In addition to comparative analytical studies, an assessment of whether a proposed product is biosimilar to a reference product generally will include animal studies (including the assessment of toxicity) and a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics and/or pharmacodynamics). When assessing whether products are highly similar, the guidance specifies that manufacturers should consider a number of factors, including the following: expression systems, manufacturing processes, assessment of physicochemical properties, functional activities/assays, receptor binding and immunochemical properties, impurities (including a risk-based assessment on any differences in process-related impurities identified between the proposed product and the reference product), reference product and reference standards, finished drug product, and stability.
The final guidance, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, is intended to assist sponsors in demonstrating that a proposed therapeutic protein product is biosimilar to a reference product for purposes of the submission of a marketing application under section 351(k) of the PHS Act.The BPCI Act amends the PHS Act and other statutes to create an abbreviated licensure pathway in section 351(k) of the PHS Act for biological products shown to be biosimilar to or interchangeable with an FDA-licensed biological reference product (see sections 7001 through 7003 of the Patient Protection and Affordable Care Act (Affordable Care Act) (Public Law 111-148). Although the 351(k) pathway applies generally to biological products, this guidance focuses on therapeutic protein products and gives an overview of important scientific considerations for demonstrating biosimilarity. The scientific principles described in this guidance may also apply to other types of proposed biosimilar biological products.
The guidance provides a stepwise approach to demonstrating biosimilarity, which can include a comparison of the proposed product and the reference product with respect to structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), clinical immunogenicity, and clinical safety and effectiveness. It also provides what the FDA has termed a "totality-of-the-evidence" approach that FDA will use to review applications for biosimilar products, consistent with a longstanding agency approach to evaluation of scientific evidence. The guidance also provides general scientific principles in conducting comparative structural analyses, functional assays, animal testing, human PK and PD studies, clinical immunogenicity assessments, and comparative clinical studies (including clinical study design issues).
Additional topics addressed in the guidance include: considerations of the complexities of therapeutic protein products when designing a biosimilar development program, including manufacturing process considerations; use of data derived from studies comparing a proposed product with a non-US-licensed comparator product; and postmarketing safety monitoring considerations.