“Soon” Has Finally Come; FDA Issues Three Highly Anticipated Biosimilars Draft Guidances

By Kurt R. Karst –      

Within moments of FDA’s (Dr. Janet Woodcock) announcement during the February 9th House Energy and Commerce hearing on generic drug and biosimilar user fees that the Agency would issue draft guidance on biosimilar product development later in the day, Twitter was, well . . . . all atwitter with the news.  Release of the draft guidances, which perhaps have been overpromised as “coming soon” since last summer, was officially announced by FDA just a couple of hours later. 

FDA issued three draft guidances, which provide the Agency’s current thinking on key scientific and regulatory factors involved in submitting applications for biosimilar products to FDA pursuant to the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  The BPCIA amended the Public Health Service Act (“PHS Act”) to, among other things, create an approval pathway for biosimilar and interchangeable versions of reference products (so-called § 351(k) applications) and establish a 12-year exclusivity period for reference products licensed under PHS Act § 351(a).  FDA’s three draft guidances are pretty dense and take into consideration comments the Agency received in response to a November 2010 public hearing on BPCIA implementation, as well as FDA’s experience thus far in meeting with sponsors of biosimilar products.  (It was recently reported that FDA has held 21 Pre-IND sponsor meetings, has received 35 Pre-IND meeting requests for proposed biosimilars to 11 reference products, and has received 9 INDs.)

Draft Guidance No. 1 – Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009:  This draft guidance document is intended to provide answers to common questions from sponsors interested in developing proposed biosimilar products.  The Q&As are grouped into three categories: (1) Biosimilarity or Interchangeability; (2) Provisions Related to Requirement to Submit a BLA for a “Biological Product;” and (3) Exclusivity (presumably carefully worded to avoid another tussle over “market” versus “data” exclusivity – see our previous post here). 

Many of the questions are drafted to elicit an initial proposed answer of “yes” or “no,” which is then futher explained and modified.  For example, FDA answers "yes" to each of the following burning questions:

• Can a proposed biosimilar product have a delivery device or container closure system that is different from its reference product?
• Can an applicant obtain licensure of a proposed biosimilar product for fewer than all routes of administration for which an injectable reference product is licensed?
• Can an applicant obtain licensure of a proposed biosimilar product for fewer than all presentations (e.g., strengths or delivery device or container closure systems) for which a reference product is licensed?
• Can an applicant obtain licensure of a proposed biosimilar product for fewer than all conditions of use for which the reference product is licensed?
• Can a sponsor use comparative animal or clinical data with a non-U.S.-licensed product to support a demonstration that the proposed product is biosimilar to the reference product?
• Can an applicant extrapolate clinical data intended to support a demonstration of biosimilarity in one condition of use to support licensure of the proposed biosimilar product in one or more additional conditions of use for which the reference product is licensed?

Among other things, the draft guidance provides FDA’s interpretation of the category of “protein (except any chemically synthesized polypeptide)” in the amended definition of “biological product” in PHS Act § 351(i)(1).  FDA defines the term “protein” to mean “any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size,” and the term “chemically synthesized polypeptide” to mean “any alpha amino acid polymer that (1) is made entirely by chemical synthesis; and (2) is less than 100 amino acids in size.”  FDA goes on to note that the Agency considers “any polymer composed of 40 or fewer amino acids to be a peptide and not a protein.”  Therefore, says FDA, “unless a peptide otherwise meets the statutory definition of a 'biological product'“, it will be regulated as a “drug” under the FDC Act.

Draft Guidance No. 2 – Scientific Considerations in Demonstrating Biosimilarity to a Reference Product:  This draft guidance – the longest of the three draft guidances – is where FDA lays out the Agency’s approach to determining biosimilarity.  “FDA intends to consider the totality of the evidence provided by a sponsor to support a demonstration of biosimilarity, and recommends that sponsors use a stepwise approach in their development of biosimilar products” (italics in original) says FDA.  Under the risk-based, “totality of the evidence” approach, FDA will consider “the totality of the data and information submitted in the application, including structural and functional characterization, nonclinical evaluation, human PK and PD data, clinical immunogenicity data, and clinical safety and effectiveness data.”  Under the stepwise approach, biosimilar sponsors should evaluate at each step “the extent to which there is residual uncertainty about the biosimilarity of the proposed product and identify next steps to try to address that uncertainty,” and should start with an “extensive structural and functional characterization of both the proposed product and the reference product.” 

Draft Guidance No. 3 – Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product:  The final draft guidance is intended to provide recommendations to biosimilar applicants on the scientific and technical information of the CMC section of a 351(k) application, and includes an overview of analytical factors to consider when assessing biosimilarity between a proposed therapeutic protein product and a reference product.  FDA notes in the draft guidance that although it applies specifically to therapeutic protein products, “the general scientific principles may be informative for the development of other proteins, such as in vivo protein diagnostic products.” 

Under the PHS Act, as amended by the BPCIA, the terms “biosimilar” or “biosimilarity” mean that “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components,” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product” (emphasis added).  FDA’s draft guidance provides a list and discussion of various factors to consider when assessing whether products are, in fact, highly similar.

We’re likely to see quite a bit of commentary submitted to FDA on the draft guidances in the coming weeks and months.  We’ve also heard that FDA might be scheduling a public hearing to elicit further comments on and discussion of the draft documents and the Agency’s approach to biosimilarity laid out therein.