Six years after legislation was adopted creating a new pathway for the approval of biological products that are biosimilar to existing FDA-approved biologics, the Food and Drug Administration (FDA) continues to issue guidance to clarify its interpretation of the law.

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) created an abbreviated licensure pathway within the Public Health Service Act (PHS Act) for biological products that are biosimilar to or interchangeable with an FDA-licensed biological product. The BPCI Act essentially created a pathway similar to an Abbreviated New Drug Application, which is used to approve generic drugs, that applies to biologics.

In a series of three final guidance documents issued in late April 2015, the FDA seeks to explain its interpretation of assorted issues concerning the BPCI Act. Those issues include scientific considerations of establishing biosimilarity, quality considerations demonstrating biosimilarity of a therapeutic protein product, and other issues concerning biosimilarity, and requirements for submitting a biologic license application (BLA). Draft versions of these guidance documents were issued in February 2012. The FDA has been seeking input on the BPCI Act since shortly after its enactment; in November 2010, the FDA held a public hearing and established a public docket to solicit input on issues related to implementing the BPCI Act.

Interested persons may submit comments regarding these guidance documents either athttp://www.regulations.gov or to the Division of Dockets Management.

Scientific Considerations

The guidance document titled Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, Guidance for Industry intends to assist sponsors in demonstrating biosimilarity between a therapeutic protein product (i.e., the proposed product) and a reference product through the abbreviated licensure pathway created under Section 351(k) of the PHS Act. As an initial matter, the guidance points out that sponsors should be aware of the complexities of protein products and take this into consideration when designing a development program to demonstrate biosimilarity. The guidance then addresses an approach to demonstrating biosimilarity and how the FDA will evaluate that demonstration.

The FDA recommends a stepwise approach to obtain the data and information necessary to support the demonstration of biosimilarity. Using the stepwise approach will allow a sponsor to evaluate uncertainties about the biosimilarity of the proposed product and identify additional steps necessary to address that uncertainty. The FDA lays out a model of the stepwise approach starting with extensive structural and functional characterization which should serve as the foundation for the development program. The guidance also recommends that sponsors consider animal studies, their role in assessing toxicity, and in some cases bolstering support for the biosimilarity demonstration. The guidance also provides information on generic scientific principles for demonstrating biosimilarity, including structural analysis, functional assays, animal data, and clinical studies.

The guidance indicates that when the FDA evaluates the sponsor’s demonstration, it will use the totality-of-the-evidence approach when considering the information submitted in the biosimilar application. The FDA will consider the proposed product’s characterization, nonclinical evaluation, immunogenicity data, comparative clinical study data, etc. The FDA plans to use a risk-based approach in its evaluation, which will allow for minor structural or formula differences in the proposed product and the reference but still lead to a finding of biosimilarity.

Finally, the guidance addresses post-marketing safety considerations. The guidance indicates that post-marketing safety monitoring should focus on any particular safety or effectiveness issues associated with the reference product or the proposed product. Monitoring should also be designed to differentiate between adverse events associated with the reference product and the proposed product. The FDA may require post-marketing safety studies to evaluate certain safety risks. Because of the complexity and uniqueness of these products, the guidance encourages consultation with the FDA throughout the development process.

Quality Considerations

The guidance document titled Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product deals with the technical aspects of “chemistry, manufacturing, and controls” (CMC) information for a proposed biosimilar application. This guidance intends to provide sponsors with an overview of analytical factors that are relevant to determining whether a proposed product and the reference product are highly similar for the purpose of submitting a marketing application through the abbreviated licensure pathway under section 351(k) of the PHS Act. While the 351(k) pathway applies generally to biological products, this guidance focuses specifically on therapeutic protein products.

This guidance finalizes the draft guidance issued by the FDA in February 2012. In response to comments made on the draft guidance, the final guidance provides further clarification on general principles on topics including the use of comparative analytical data to provide the foundation for a biosimilar development program, the timing of submission of analytical similarity data, the appropriate number of lots needed, and the type of bridging data needed when sponsors use a non-U.S.-licensed comparator product in certain studies.

Additionally, this guidance describes key factors for consideration when assessing whether a proposed product and the reference product are highly similar, including (1) Expression System; (2) Manufacturing Process; (3) Assessment of Physiochemical Properties; (4) Functional Activities; (5) Receptor Binding and Immunochemical Properties; (6) Impurities; (7) Reference Product and Reference Standards; (8) Finished Drug Product; and (9) Stability.

Q&A

The guidance document titled Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, Guidance for Industry answers questions posed to the FDA about the FDA’s interpretation of certain statutory requirements added by the BPCI Act. The questions reflect comments submitted to the public docket, and the FDA used the question and answer format in an effort to promote transparency. The FDA plans to update the guidance document to include additional questions and answers in the future.

The questions and answers cover three broad categories: (1) biosimilarity and interchangeability; (2) provisions related to the requirement to submit a BLA for a biological product; and (3) exclusivity.

The bulk of the guidance addresses issues concerning biosimilarity and interchangeability. It clarifies that a biosimilar’s application need not exactly mirror all aspects of the reference product. For example, a biosimilar product can have a formulation and a delivery device or container closure system different from the reference product. The application must demonstrate the product is highly similar to the reference product, and that the differing delivery device or container closure system is compatible for use with the final formulation. The FDA also states that a biosimilar product can obtain a license for fewer than all presentations (e.g., strengths or delivery devices or container closure systems) for which the reference product is licensed. An applicant also need not seek a license for all the conditions of use for which the reference product is licensed.

On the issue of demonstrating that a proposed injectable biosimilar product has the same “strength” as the reference product, the FDA explains that the biosimilar product generally must have the same total content and concentration of drug substance as the reference product. However, “for certain complex biological products, a modified approach may be needed.”

The BPCI Act amends the definition of “biological product” to include a “protein (except any chemically synthesized polypeptide),” and the guidance document answers the question of how the FDA interprets this definition. The FDA provides a definition for both “protein” – any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size – and “chemically synthesized polypeptide” – any alpha amino acid polymer that is made entirely by chemical synthesis and is less than 100 amino acids in size.

Finally, the guidance addresses issues of exclusivity. The BPCI Act provides various exclusivity periods, including for reference products and for the first product determined to be interchangeable with a reference product. The FDA answered the question of how a prospective biosimilar applicant can determine if there is unexpired orphan exclusivity for an indication for which the reference product is licensed. The guidance points to the FDA’s website, which contains a searchable database for orphan designated and/or approved products and indications. The FDA clarifies that it will not approve a subsequent application for the “same drug” for the indication during the seven-year period of orphan exclusivity, except as otherwise provided in the Federal Food, Drug, and Cosmetic Act, and 21 C.F.R. part 316.