On February 9, 2012, the U.S. Food and Drug Administration (FDA) released a set of three draft guidance documents as one of the first major steps in the Agency's implementation of the abbreviated approval pathway for "biosimilar" biological products created by the Biologics Price Competition Act of 2009 (the "BPCA"). The BPCA was enacted as part of Section 351 of the Patient Protection and Affordable Care Act of 2010. FDA is accepting comments on these draft guidance documents, each of which is discussed in detail below, until April 16, 2012. FDA is also holding a public hearing on May 11, 2012 to receive feedback from interested parties on the draft guidances.

Biological products are therapies used to treat diseases and health conditions, but, unlike small-molecule drugs, are created by biologic processes and living organisms rather than from chemical synthesis. Examples of biological products used as therapeutics to treat disease include vaccines, blood or blood components, allergenics, gene therapies, and therapeutic proteins. A biosimilar is a biological product that is "highly similar" to a biological product that has already been approved by FDA (e.g., an FDA-licensed reference biological product), notwithstanding minor differences in clinically inactive components, and provided there are no clinically meaningful differences between the products in terms of safety, purity and potency.

Through the new abbreviated pathway, biosimilar biological products can be approved by demonstrating that they are biosimilar to, or interchangeable with, an approved biological reference product. Key features of FDA's new guidance documents are discussed below.

I. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

FDA's draft guidance document "Scientific Considerations in Demonstrating Biosimilarity to a Reference Product," describes FDA's risk-based "totality of evidence" approach to evaluate all available information and data submitted in support of the biosimilarity of a proposed product. The guidance describes the "stepwise approach" sponsors should implement when developing data to support biosimilarity. Recommended steps include developing:

• Structural characterization of both the proposed and referenced product using state-of-the-art-technology (e.g., amino acid sequence for protein products);
• Functional evaluation comparing proposed product to reference product (e.g., bioassays, biological assays, binding assays, and enzyme kinetics);
• Clinical immunogenicity assessment (comparison of proposed product and reference product with respect to incidence and severity of human immune responses);
• Data derived from animal studies, if necessary (e.g., comparative bridging toxicology studies, animal pharmacokinetic (PK) and pharmacodynamic (PD) measures, immunogenicity studies);
• Comparative human PK and PD studies in appropriate populations, if necessary (such clinical studies will only be necessary if there remains uncertainty about the biosimilarity of the two products after conducting structural/functional characterization and possible animal studies); and
• Comparative clinical safety and effectiveness data, if necessary (such clinical studies will only be necessary if there remains uncertainty about the biosimilarity of the two products based on structural/functional characterization, animal testing, human PK and PD data and clinical immunogenicity).

Furthermore, with sufficient scientific justification, a sponsor may be permitted to extrapolate clinical data intended to support biosimilarity for one indication of a reference product, to one or more additional indications for which the reference product is licensed. Such scientific justification should address the mechanisms of action (MOAs) for each indication, the biodistribution and PK of products in different patient populations, and differences in expected toxicities for each indication. Postmarket safety monitoring considerations are also discussed in the draft guidance.

The type and amount of data necessary to support a biosimilar application will be determined on a product-specific basis. Accordingly, because the evaluation at one step may influence the type and amount of data required in the following step, before finalizing a clinical program, biosimilar sponsors are encouraged to consult extensively and meet with FDA initially and during the development process.

II. Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product

FDA's draft guidance document "Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product," provides information on analytical studies that may be relevant to determining whether a potential biosimilar protein¹; product is "highly similar" to a reference product. The guidance focuses on factors to determine which studies should be conducted, as well as on scientific and technical information that should be included in the chemistry, manufacturing and controls ("CMC") section of a biosimilar application.

According to the draft guidance, protein products may now be extensively characterized in terms of their physicochemical and biological properties. Advances in manufacturing science and production methods now allow new protein products to be manufactured that may be "highly similar" to a reference biologic product. When assessing whether products are highly similar, sponsors must fully characterize both the proposed and reference products, comparing and thoroughly assessing any differences between the products in terms of their potential impact on safety or biological functionality. In this regard, sponsors should compare, among other things, the (1) expression system, (2) manufacturing process, (3) physicochemical properties, (4) functional activities, (5) receptor binding and immunochemical properties, (6) impurities, (7) reference product and reference standards, (8) properties of the finished drug product, and (9) stability.

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¹FDA defines "protein" to mean "any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size."

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

FDA's draft guidance document "Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009" provides answers to questions commonly posed by sponsors interested in developing biosimilar products. The questions and answers (Q&A) are grouped into three categories: (1) Biosimilarity and Interchangeability, (2) Provisions Related to Requirements to Submit a biologics license application (BLA) for a "Biological Product", and (3) Exclusivity. The Q&A format is intended to promote transparency and facilitate development programs for proposed biosimilar products.

(1) Biosimilarity and Interchangeability

Fifteen Q&As related to the biosimilar product development process as well as to the substantive requirements for establishing biosimilarity to, or interchangeability with, a reference product are included in the guidance.

As explained in the Q&As, differences may exist between the formulation of a proposed product and the reference product, unless those differences are determined to be "clinically meaningful." Similarly, certain design differences in the "delivery device or container closure system" used with the proposed biosimilar may be permitted, so long as appropriate studies demonstrate the presentation to be compatible for use with the final formulation of the biological product.

The Q&As further clarify that a sponsor may obtain licensure of a proposed biosimilar product for fewer than (1) all conditions of use or (2) all routes of administration, for which a reference product is licensed. Also addressed, among other things, are issues related to the use of animal or clinical data from a non-U.S.-licensed product, extrapolation of clinical data in one condition to support use in another condition, and how the "strength" of a proposed biologic may be shown to be the same as the reference product.

The Q&As also make clear that sponsors should request an initial meeting with FDA at such time as the sponsor can provide a proposed plan for its biosimilar development program, manufacturing process information, and preliminary comparative analytical data with the reference biologic.

(2) Provisions Related to Requirement to Submit a BLA for a "Biological Product"

These Q&As clarify the amended definition of "biological product" in the BPCA (which now includes "protein (except any chemically synthesized polypeptide)"), and explain how "product class" is defined for purposes of determining whether an application for a biological product may be submitted.

(3) Exclusivity

These Q&As explain when it is appropriate to request reference product exclusivity, and how a sponsor of a proposed biosimilar can determine whether a reference product has unexpired orphan exclusivity.

For Further Information
The draft guidances represent an important first step in FDA's implementation of an abbreviated approval process for biosimilars. If you have questions concerning FDA's guidance documents or would like more information about this subject, please contact Frederick A. Stearns (stearns@khlaw.com or 202-434-4288) or Azim Chowdhury (chowdhury@khlaw.com or 202-434-4230)