On August 5, 2014, FDA announced the availability of its most recent biosimilars guidance entitled, “Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act” (“FDA Draft Guidance”). The Draft Guidance puts some sponsors of BLAs past, present, and future, on notice that FDA wants them to submit certain information for their biologics to be considered for “reference product exclusivity.”  But that’s a burden that sponsors will likely gladly bear, because FDA’s proposed broad interpretation of structural modification, a key term in determining whether a related product differs enough from a sponsor’s structurally related product to merit its own exclusivity, makes more products eligible for exclusivity than is required under the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).

The Draft Guidance begins by restating some of what we already know.  The BPCIA establishes a 12-year exclusivity period for reference products from the date of first licensure of the reference product, during which approval of a biosimilar application cannot be made effective.  The BPCIA includes certain limits on 12-year exclusivity.  Specifically, the 12-year exclusivity period does not apply if the licensure is for:

  1.  a supplement for the biological product that is the reference product; or
  2.  a subsequent application filed by the same sponsor or manufacturer of the biological product that    is the reference product (or a licensor, predecessor in interest, or other related entity) for –
    1. a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or
    2. a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.

In most cases, the date of first licensure will be the initial date the product was licensed in the U.S.  For products that may or may not be entitled to reference product exclusivity, however, the Agency suggests a four-step process for sponsors to provide relevant information.  FDA encourages sponsors to provide this information at the time of application, but they may do so as an amendment to the application.

 Step 1: Sponsors should compile a list of all the licensed biological products that are structurally related to the biological product that is the subject of the BLA being considered.  This includes products that share the same molecular target or have some of the same principal molecular features.  Where molecular targets have not been defined, this includes products that share the narrowest target that can be characterized.  If a sponsor determines there are no licensed products that fall into these categories, it must provide an “adequate justification” to support this assertion.

 Step 2: Of the licensed products from Step 1, sponsors should enumerate products for which they or one of their affiliates, including any licensors, predecessors in interest, or related entities, are the current or previous license holder.  The agency casts a broad net in defining “licensor, predecessor in interest, or other related entity,” including, and thereby denying new exclusivity to sponsors who take over, merge with, purchase or grant exclusive rights to biologics from previous BLA holders.

 Step 3: Sponsors should describe the structural similarities and differences between the proposed product and any products identified in Step 2.  For protein products, sponsors are asked to discuss “differences in amino acid sequence, glycosylation patterns, tertiary structures, post-translational events (including any chemical modifications of the molecular structure such as pegylation) and infidelity of translation or transcription.”  FDA goes on to say that in making its determination of whether the product represents a modification to the structure of a previously licensed product, it will consider the “principal structural molecular features of both products and whether the modified product affects the same molecular target as the previously licensed product.”  This appears to be a rather broad definition of structural modification, and is likely to attract a significant number of comments.

 Step 4: If a sponsor believes that it has shown a structural modification, it must next provide evidence of the change in safety, purity, and/or potency.  FDA will make decisions in this area on a case-by-case basis and will look for “measurable effects,” typically demonstrated by data from clinical or preclinical studies and bioassays, and possibly including evidence that there is a “meaningful benefit to public health, such as a therapeutic advantage.”  If the proposed product demonstrates that it affects a different molecular target than the original product, FDA will generally presume that a modification has resulted in a change to the proposed product’s safety, purity, or potency.   

While FDA is requiring sponsors to provide copious amounts of scientifically and technically complex information in order to win exclusivity, it appears that this draft guidance provides reference product sponsors with ample opportunity to make their case that their related products are eligible for reference product exclusivity.

Comments on the FDA Draft Guidance can be submitted to FDA until October 6, 2014 (here).  If you are interested in other issues surrounding biosimilars, see our previous coverage of other related FDA draft guidance documents (here) and (here).

James E. Valentine