You Had Us At “Biosimilars,” FDA; Agency Ties Up Yet Another Biosimilars Loose End With Petition Response Concerning Certain “Biological Drugs”

By Kurt R. Karst –      

FDA’s issuance of three long-awaited and highly anticipated draft biosimilar guidances earlier this year (see our previous post here) seems to have hardly whet industry’s appetite for information on the Agency’s interpretation of Section 351(k) of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  (A follow-up presentation from FDA on the draft guidances is available here and here.  Another draft guidace on “Submission of Clinical Pharmacology Data as Evidence of Biosimilarity for Biologics and Protein Products” is on FDA’s guidance agenda for later this year.)  Like Renée Zellweger’s character in the movie “Jerry Maguire,” who at a key scene in the film utters the line “You had me at hello” after listening to a long speech from the sports agent character played by Tom Cruise beginning with the word “hello,” industry’s attention seems to be immediately captured by FDA’s mere mention of the word “biosimilars.”  (Indeed, it seems to create a feeding frenzy of sorts.)   So we thought we would throw out another “hello” from FDA.

As we previously reported, shortly after FDA released the three draft biosimilars guidances, the Agency denied outstanding requests in two citizen petitions submitted to the Agency in April 2003 (Docket No. FDA-2003-P-0003) and April 2004 (Docket No. FDA-2004-P-0214) by the Biotechnology Industry Organization and Genentech, Inc. concerning the submission and approval of 505(b)(2) applications under the FDC Act for “biotechnology-derived products” or “follow-on therapeutic proteins.”  Apparently there was a third pre-BPCIA citizen petition submitted to FDA in January 2009 (Docket No. FDA-2009-P-0004).  The two-page citizen petition submitted by Therapeutic Proteins, Inc. simply requests that FDA “allow acceptance of applications for marketing authorization of equivalent forms of biological drugs” (i.e., certain protein and peptide products); or, as FDA’s rephrases the “ask”:  “that FDA accept an ANDA submitted under section 505(j) of the FD&C Act for a protein or peptide product intended to be the ‘same’ as a product that previously was approved under either the FD&C Act or the PHS Act.”  FDA’s six-page response granting in part and denying in part the petition appears to provide further insight into FDA’s thinking on biosimilars approval. 

As FDA notes in the Agency’s petition response, “the availability of an abbreviated approval pathway for a protein or peptide product that seeks to rely, to some extent, upon a previously approved product is governed by the statutory authority under which the previous product was approved or licensed as well as by scientific considerations.”  The ANDA pathway, says FDA, may be used to approve protein and peptide products only where the Reference Listed Drug was approved under FDC Act § 505(c), “the state  of the science is adequate to demonstrate that the active ingredient is the same as the active ingredient of the RLD, and other statutory requirements are met.”  Continuing on, FDA says that with current science highly complex proteins may not be suitable for the ANDA approval pathway:

Because of the complexity of protein molecules and limitations of current analytical methods, it would be difficult for manufacturers of proposed protein products to demonstrate that the active ingredient in their proposed product is identical to the active ingredient in an already approved product.  Therefore, the 505(j) approval pathway, which is predicated on a finding of the “same” active ingredient, will not ordinarily be available for more structurally complex molecules. [(Italics in original)]

Because of the difficulties associated with demonstrating sameness of complex products necessary for ANDA approval, the 505(b)(2) application pathway, which has a “sufficiently similar” standard, may be the better bet, according to FDA.  “The 505(b)(2) approval pathway may be used for a protein or peptide product that is demonstrated to be sufficiently similar to an approved product to permit scientifically justified reliance on certain existing information (e.g., FDA’s finding of safety and/or effectiveness for an approved drug product) to support approval” (italics in original).

FDA’s petition response (like the Agency’s draft guidances) raises a host of unanswered questions.  For example, what series of tests – a la enoxaparin might or might not suffice to demonstrate “sameness” for ANDA purposes for a particular complex protein product during the transition period described in § 7002(e) of the BPCIA (ending on March 23, 2020), and how will FDA handle such products once the transition period ends?  Such questions will likely be addressed in time and on a product-specific basis as sponsors seek FDA’s advice and guidance.