Alerts and Updates

FDA Issues Draft Guidance Documents to Implement the Biologics Price Competition and Innovation Act of 2009

February 13, 2012

FDA provided guidance on acceptable differences between a proposed biosimilar product and a reference product, and reliance on comparative data with a non-U.S. licensed product to support a demonstration of biosimilarity.

On February 9, 2012, the U.S. Food and Drug Administration (FDA) issued eagerly anticipated draft guidance documents on biosimilar product development in three installments, collectively the "Biosimilar Draft Guidances":

While the FDA Biosimilar Draft Guidances provide some answers regarding the requirements for demonstrating biosimilarity, FDA leaves other guidance for interchangeability and exclusivity minimally addressed.

In the Biosimilar Q-&-A, FDA answered questions from sponsors interested in developing biosimilar products, biologics license application (BLA) holders and other interested parties, taking into account the public's comments concerning the statutory requirements added by the BPCI Act. The questions and answers were grouped into three categories: (1) biosimilarity or interchangeability, (2) provisions on determining whether a "biological product" is subject to a BLA or a New Drug Application (NDA) and (3) exclusivity.

In the first category of questions and answers on biosimilarity and interchangeability, FDA provided guidance on acceptable differences between a proposed biosimilar product and a reference product, and reliance on comparative data with a non-U.S. licensed product to support a demonstration of biosimilarity. However, FDA also left guidance on determining interchangeability for another day, as it continues to consider the type of information sufficient to make that determination.

More specifically, FDA confirmed that a proposed biosimilar product and a reference product may differ with respect to the formulation and the delivery device or container closure system. Further, an applicant for a proposed biosimilar product may obtain a license for: (1) fewer than all routes of administration for which an injectable reference product is licensed; (2) fewer than all presentations (e.g., strengths or delivery device or closure systems) for which a reference product is licensed; and (3) fewer than all conditions of use for which the reference product is licensed. However, as FDA must further consider the type of information sufficient to determine biosimilarity or interchangeability, additional guidance on this point was left for another day.

FDA also confirmed that a sponsor can rely on comparative animal or clinical data with a non-U.S.-licensed product to support demonstration of biosimilarity, but cautioned that the sponsor should provide adequate data or information not only to justify the relevance of the comparative data to an assessment of biosimilarity, but also to establish an acceptable bridge to the U.S.-licensed reference product.

In the second category, FDA provided guidance on determining whether a biological product is subject to a BLA or an NDA. The Agency proposed defining a "protein" subject to a BLA submission as "any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size." Because FDA carefully excluded "peptides" and "chemically synthesized polypeptides" from the definition of protein, those compositions would be subject to NDA submission, unless they otherwise met the statutory definition of a biological product (e.g., a peptide vaccine).

In the third category, FDA proposed that an applicant can include in its § 351(a) BLA application a request for reference product exclusivity, but otherwise largely left its interpretation of the statutory exclusivity provisions for the future. However, FDA recommends an applicant specifically describe how the proposed product meets the statutory requirements for exclusivity, including adequate data and information to support the request. Such information will likely help the FDA develop its framework for exclusivity determinations under the statutory provisions.

The Scientific and Quality Considerations draft guidance details (1) the FDA’s proposal to use a risk-based, totality-of-the-evidence approach to evaluate all of the data and information provided by a sponsor in reviewing applications for biosimilar products; (2) the FDA's recommendation that sponsors use a stepwise approach to demonstrating biosimilarity; and (3) general scientific principles in conducting comparative analyses. Additional scientific considerations addressed by FDA include consideration of the complexities of therapeutic protein products when designing a biosimilar development program, use of data derived from studies comparing a proposed product with a non-U.S.-licensed product, and postmarketing safety monitoring considerations. The Quality Considerations draft guidance provides recommendations to applicants on the scientific and technical information of the chemistry, manufacturing and controls section of a marketing application for a proposed biosimilar product.

FDA observed that the totality of the evidence submitted to FDA in a stepwise approach may include structural and functional characterization; nonclinical data such as toxicity; pharmacokinetic (PK), pharmacodynamic (PD) and immunogenicity data in animals; human PK and PD data; clinical immunogenicity data; and clinical safety and effectiveness data. FDA also recommended that at each stage of the stepwise approach to developing the data and information in the application, sponsors should evaluate the extent to which there is residual uncertainty about the biosimilarity of the proposed product, and identify and design studies to address that uncertainty. FDA also confirmed that a sponsor may be able to demonstrate biosimilarity even though formulation or minor structural differences exist, as long as the sponsor provides sufficient evidence demonstrating that the differences are not clinically meaningful and the proposed product otherwise meets the statutory criteria for biosimilarity.

Comments on the Biosimilar Draft Guidances can be submitted within 60 days of the FDA notices.

For Further Information

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