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U.S. Department of Health and Human Services


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Fact Sheet: Issuance of Draft Guidances on Biosimilar Product Development

FDA issued three draft guidance documents on biosimilar product development. These documents provide FDA’s current thinking on approaches to demonstrate that a proposed biological product is biosimilar to an FDA-approved biological product (the “reference product”) using the abbreviated pathway under section 351(k) of the Public Health Service Act (PHS Act). The abbreviated pathway was established by the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), enacted on March 23, 2010, as part of the Patient Protection and Affordable Care Act. FDA is accepting public comment on these draft guidance documents. Instructions on how to submit comments will be announced in an upcoming Federal Register notice.

Guidance: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

This draft guidance is intended to assist sponsors in demonstrating that a proposed therapeutic protein product is biosimilar to a reference product for the purpose of submitting an application under 351(k) of the PHS Act (a 351(k) application) to the FDA. 

  • Focuses on therapeutic protein products. FDA will consider multiple factors as part of the biosimilarity assessment, including, but not limited to, the product’s complexity, formulation, and stability; as well as usefulness of biochemical and functional characterizations.
    • The incorporation of these factors is risk-based and is affected by knowledge regarding various product characteristics including, for example, the mechanism of action, the product structure-function relationships, the clinical experience with the reference product, and the manufacturing process.
  • Describes the totality-of-the-evidence approach that FDA intends to use for review of biosimilar applications.
    • FDA intends to use a risk-based totality-of-the-evidence approach to evaluate all available data and information submitted in support of the biosimilarity of the proposed product.  The type and amount of analyses and testing that will be sufficient to demonstrate biosimilarity will be determined on a product-specific basis.
    • FDA recommends sponsors use a stepwise approach in developing evidence to support a demonstration of biosimilarity, ensuring that development at each step evaluate the extent to which there is residual uncertainty regarding a demonstration of biosimilarity between the proposed and reference product, and identify next steps to address that uncertainty. 
    • FDA will be able to provide meaningful advice on the scope and extent of necessary animal and human testing after a thorough review of data from structural and functional analyses.  Additional animal and clinical studies should be tailored to address residual uncertainty regarding the biosimilarity between the two products to ensure such testing is appropriately targeted.
  • Recommends early consultation with the FDA. FDA anticipates that early discussions with FDA about product development plans will facilitate biosimilar development.

Guidance: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product

This draft guidance provides an overview of analytical factors that may be relevant to assessing whether a proposed therapeutic protein product and a reference product are highly similar, as required for a determination of biosimilarity under the BPCI Act.

    • Discusses general scientific principles, including the importance of extensive analytical, physicochemical and biological characterization. Recommends that the type, nature, and extent of any differences between the proposed biosimilar product and the reference product, and the potential effect of any differences on the safety, purity, and potency of the proposed product should be clearly described and discussed by the sponsor in the 351(k) application. 
    • Recognizes that advances in analytical sciences and manufacturing technology, including integration of Quality by Design approaches, may facilitate a “fingerprint”-like analysis of therapeutic protein products, and thus may provide appropriate bases for a more selective and targeted approach to subsequent animal and/or clinical studies to support a demonstration of biosimilarity.

Guidance: Biosimilars:  Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

This draft guidance 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 BPCI Act. The question and answer format is intended to promote transparency and facilitate development programs for proposed biosimilar products by addressing questions that may arise in the early stages of development. The draft guidance will be posted on FDA’s Web site and will be updated to include additional Q&As as appropriate.