In early February, the U.S. Food and Drug Administration (“FDA” or “the Agency”) issued the following three draft guidance documents to assist industry in developing biosimilar products:

• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
• Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product
• Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

The draft guidances represent FDA’s current thinking on the abbreviated licensure pathway for biological products that are demonstrated to be biosimilar to, or interchangeable with, an FDA-licensed biological product.

Background
Two years ago, an abbreviated pathway for licensure of biosimilar products was established by the Biologics Price Competition and Innovation Act of 2009 (“BPCI Act”), as part of the Patient Protection and Affordable Care Act. The BPCI Act amended Section 351 of the Public Health Service Act (“PHS Act”) to create an abbreviated approval pathway for biological products that are biosimilar to, or interchangeable with, a licensed biological product (known as the “reference product”). The purpose of the BPCI Act is similar to that of the Drug Price Competition and Patent Term Restoration Act of 1984 (commonly known as the “Hatch-Waxman Act”), which established abbreviated approval pathways for drug products under the Federal Food, Drug, and Cosmetic Act (“FD&C Act”).

Under Section 351 of the PHS Act, a “biosimilar” is a biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the proposed and reference products in terms of the safety, purity, and potency. An application for a biosimilar product must include, among other things, information that it is “biosimilar” to a reference product, and that both it and the reference product utilize the same mechanism of action, condition of use, route of administration, dosage form, and strength. An application may also include information demonstrating “interchangeability” between the biosimilar and reference products.

Interchangeability is demonstrated by showing that the proposed product is “biosimilar” to the reference product, can be expected to produce the same clinical result as the reference product in any given patient, and, for a biological product that is administered more than once to a patient, can be switched interchangeably with the reference product without decreasing safety or efficacy compared to using the reference product alone.

FDA’s recent draft guidances for biosimilar product development are informed by a November 2010 public hearing and comments on specific issues and challenges associated with the implementation of the BPCI Act. Although the biosimilar pathway applies generally to biological products, the guidance documents focus primarily on therapeutic protein products and are limited to discussions of biosimilarity without fully addressing the higher standard of “interchangeability.” The following summarizes key aspects of these documents.

Scientific Considerations in Demonstrating Biosimilarity
The Scientific Considerations Guidance sets forth FDA’s method of determining biosimilarity, consistent with the Agency’s longstanding approach for evaluating scientific evidence. In light of complexities associated with protein products, including both scientific and manufacturing process considerations, the draft guidance identifies the following two approaches as central to FDA’s current thinking on demonstrating biosimilarity:

1. A stepwise approach, including “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”; and
2. A risk-based, totality-of-the-evidence approach that FDA intends to use to evaluate all available data and information submitted to support biosimilarity of the proposed product to the reference product.

The draft guidance provides a detailed discussion of general scientific principles applicable to conducting comparative structural and functional analyses, functional assays, animal studies, and clinical studies, including human PK and PD studies, immunogenicity assessments, and safety and effectiveness studies needed to demonstrate biosimilarity. FDA also addresses a number of other topics in the draft guidance, including:

• Considerations relating to 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-U.S.-licensed reference product; and
• Postmarketing safety monitoring.

Depending on the biological product, it may not be possible to identify in advance all necessary components of a development program at each step. The evaluation at one step may influence the type and amount of data required in the next step. Accordingly, sponsors are strongly encouraged to consult extensively with FDA early in the process and throughout development, as needed. FDA’s evaluation of biosimilarity will be based on the totality of the data and information submitted in an application under Section 351(k).

Quality Considerations in Demonstrating Biosimilarity
Biosimilarity must be demonstrated on the basis of, among other things, “analytical studies that demonstrate that the biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components.” The Quality Considerations Guidance provides FDA’s current thinking on analytical studies that may be relevant to assessing whether a proposed biological product is “highly similar.” The draft guidance focuses on factors to determine which studies should be conducted, and on scientific and technical information that should be included in the chemistry, manufacturing, and controls (“CMC”) section of an application for licensure of a biosimilar product. It builds on FDA’s existing guidances related to approvals of manufacturing process changes for licensed biological products; however, the draft guidance provides only general principles and relies heavily on International Conference on Harmonisation (“ICH”) guidelines to supply details.

Despite unique characteristics of protein products, FDA believes that analytical science has advanced to the point where some protein products may now be extensively characterized in terms of their physicochemical and biological properties, and that parallel advances in manufacturing science and production methods may now allow new protein products to be manufactured that may be highly similar to a reference product.

The draft guidance stresses the importance of fully characterizing the proposed and reference products and thoroughly assessing any differences between the products in terms of their potential impact on safety or biological functionality. It then lists factors to consider when assessing whether products are highly similar.

Like the Scientific Considerations Guidance, the Quality Considerations Guidance stresses that comprehensive characterization of the proposed and reference products is necessary early in the development process, as the nature of the requirements for subsequent nonclinical or clinical studies could be impacted by the ability to discern differences between the proposed and reference products, as well as any effect on product safety, purity, and potency.

Q&A Regarding Implementation of the BPCI Act of 2009
The Biosimilars Q&A Guidance is intended to promote transparency and facilitate biosimilar product development programs by addressing comments related to the approval pathway for biosimilar products. FDA plans to update the guidance to include additional questions and answers, as appropriate.

The draft guidance contains information in Q&A format organized into three sections: (1) Biosimilarity or Inter-changeability, (2) Provisions Related to Requirement to Submit a BLA for a “Biological Product,” and (3) Exclusivity. The first section answers several questions related to the biosimilar product development process and substantive requirements for establishing biosimilarity to or interchangeability with a reference biological product. For example, a proposed biosimilar product may obtain licensure even if its formulation, conditions of use, design of the delivery device, or route of administration differs from the reference product; however, additional considerations will apply for a proposed interchangeable product. In addition, although it is possible for FDA to make a determination of interchangeability in an original 351(k) application, the draft guidance confirms that it is far more likely that this determination will be made in a supplement to a 351(k) application.

In the second section, FDA clarifies the amended definition of “biological product” in Section 351(i)(1) of the PHS Act, and explains how “product class” is defined for purposes of determining whether an application for a biological product may be submitted under Section 505 of the FD&C Act.

Finally, the third section of the Biosimilars Q&A Guidance explains when it is appropriate to request reference product exclusivity, and how a proposed biosimilar product applicant can determine whether a reference product has unexpired orphan exclusivity.

Opportunity To Comment and Public Hearing
FDA is seeking public comments on the draft guidance documents and encourages submission by April 16, 2012, to ensure that comments are considered in the development of the final guidances. In addition, the Agency is holding a one-day public hearing on May 11, 2012, to obtain comments on issues related to biosimilar product development. Specifically, FDA is interested in feedback on the draft guidances, as well as comments on the Agency’s priorities for the development of future policies for biosimilar products, including whether such priorities align with stakeholder needs. Topics currently under FDA consideration for future guidances related to biosimilar products include determinations of interchangeability, reference product exclusivity, product naming, and clinical pharmacology evaluation.

---

Heather D. Bañuelos is counsel in the Washington, D.C. office of Hunton & Williams LLP (www.hunton.com) in the firm’s Food and Drug Practice. She can be reached by email at hbanuelos@hunton.com. Allison Reschovsky is an associate in the Firm’s Food and Drug Practice. She can be reached at areschovsky@hunton.com.