On May 13, the FDA released a draft question-and-answer guidance document, titled “Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009.”  The new draft document follows a previous draft Q&A document from February 2012 and a final document released in April 2015.  Last month’s Q&A document finalized the 2012 draft, but notably omitted a number of questions and noted that a new draft document including those same or revised questions and proposed answers would be forthcoming.  This week’s document resurrects those questions and answers in draft form.  As a result, a number of the questions originally posed in 2012 will undergo an additional period of public comment.

The guidance document released in April finalized many of the Q&As that were made available for comment in February 2012, but reserved a number of others so they could be presented in a revised guidance document, the one from last week, and benefit from further comment from stakeholders.  Noteworthy omissions from the finalized guidance included draft Q&As regarding whether an innovator company could request determination of marketing exclusivity for its biologic product in its biologics license application (BLA), also known as a 351(a) application, and whether a biosimilar applicant could obtain a determination of interchangeability with a reference biologic product as part of its abbreviated regulatory application, also referred to as a 351(k) application, signaling that the FDA had yet to crystallize its thinking on these important issues. A number of Q&As relating to the pre-clinical and clinical data needed to demonstrate biosimilarity and extrapolation were revised to reflect some of the thinking that FDA shared when approving Sandoz’s Zarxio as a biosimilar to Amgen’s Neupogen and its process for extrapolating the clinical data that Sandoz provided for one of indication to all of the licensed indications for Neupogen.

An interesting addition to the final Q&A guidance was FDA’s elaboration on its interpretation of “biological product” which includes a “protein (except any chemically synthesized polypeptide).”   In the 2012 draft document, “protein” was defined as “any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size.”  A “chemically synthesized polypeptide” – which is not a biological product – is “any alpha amino acid polymer that is (a) made entirely by chemical synthesis, and (b) is less than 100 amino acids in size.” As a result, whether a protein product that is between 41-99 amino acids in length is regulated as a biological product depends entirely on how it is synthesized.  If it is chemically synthesized, it is not a biological product.  The April 2015 document maintains these definitions of “protein” and “chemically synthesized polypeptide,”  but adds to both definitions the sentence “For purposes of this definition, the size of the molecule is based on the total number of amino acids and is not limited to the number of amino acids in a contiguous sequence.”  In other words, a protein is a biological product if it is a collection of more than forty amino acids whether those amino acids are contiguous or not as long as it is not entirely chemically synthesized when it has less than a total of 100 amino acids.

The May 2015 guidance document includes a number of draft Q&As that were omitted from the April document and incorporates new Q&As for comment.  For example, the document includes the previously-omitted question about determining interchangeability as part of an original 351 (k) application.  The proposed answer is still yes but the FDA states in May 2015, as it did in February 2012, that “[a]t this time, it would be difficult as a scientific matter for a prospective biosimilar applicant to establish interchangeability in an original 351(k) application given the statutory standard for interchangeability and the sequential nature of that assessment.”  FDA has given no indication when the answer to this question will be finalized or when it will provide guidance on interchangeability. As in 2012, FDA notes that it “is continuing to consider the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product.”

Another previously-omitted Q&A has to do with the ability of reference product sponsor to request a determination of marketing exclusivity for its proposed biologic product in its regulatory application.  The proposed answer is still yes without any revision from the original Q&A.

FDA also revised a few of the 2012 Q&As to provide additional guidance and released new Q&As that address a variety of topics.  The topics include pediatric assessments, the “dosage form” of injected biosimilars, and marketing applications for proposed antibody-drug conjugates. The comment period on the draft May 2015 guidance document runs 60 days, until July 13, 2015.