FDA’s House Rules on 505(b)(2) NDA Choice of Listed Drug; How Does it Affect Dealer’s Choice?

By Kurt R. Karst –

FDA’s recent response to two Citizen Petitions (Docket Nos. FDA-2013-P-0995 and FDA-2011-P-0869) helped to shed some additional light on an issue that continues to vex companies considering submitting a 505(b)(2) NDA to FDA for a new drug: When do I have to cite an approved drug as a “listed drug” in my 505(b)(2) application?  After all, the choice of listed drug can have some pretty significant consequences.  If there is patent information listed in the Orange Book for the listed drug, then that raises the prospect of a 30-month stay on approval (pursuant to a Paragraph IV certification) while the parties sort out things in patent infringement litigation.  Then there’s the question of the scope and applicability of any non-patent exclusivity listed in the Orange Book for the listed drug.  And don’t forget issues surrounding intervening NDA approvals and change in listed drug (see here and here).

By way of background, the FDC Act describes a 505(b)(2) NDA as an application that contains full reports of investigations of safety and effectiveness, where at least some of the information required for approval comes from studies not conducted by or for the 505(b)(2) applicant, but instead from published literature reports and/or FDA’s findings of safety and/or effectiveness for one or more listed drugs, and for which the 505(b)(2) applicant has not obtained a right of reference or use.  While there are no FDA regulations governing how a 505(b)(2) applicant should choose a listed drug when various options are present, the Agency has spoken to the issue in guidance and in citizen petition responses.  For example, FDA’s 1999 draft guidance states that “[i]f there is a listed drug that is the pharmaceutical equivalent of the drug proposed in the 505(b)(2) application, the 505(b)(2) applicant should provide patent certifications for the patents listed for the pharmaceutically equivalent drug” (emphasis added).  (FDA’s regulation at 21 C.F.R. § 320.1(c) defines the term “pharmaceutical equivalents.”)  FDA explained in a 2004 Citizen Petition response (Docket No. FDA-2004-P-0089) concerning Fenofibrate (“Fenofibrate CP response”) that citing a pharmaceutical equivalent as a listed drug serves to “ensure that the 505(b)(2) applicant does not use the 505(b)(2) process to end-run patent protections that would have applied had an ANDA been permitted.”  Additionally, FDA commented that these provisions “further ensure that the 505(b)(2) applicant (and FDA) can rely, to the maximum extent possible, on what is already known about a drug without having to re-prove (or re-review) what has already been demonstrated.” 

“When there is no listed drug that is a pharmaceutical equivalent to the drug product proposed in the 505(b)(2) NDA, neither the statute, the regulations, nor the 1999 draft guidance directly addresses how to identify the listed drug or drugs on which a 505(b)(2) applicant is to rely.”  In FDA’s Fenofibrate CP response, however, the Agency stated that:

[I]t follows that the more similar a proposed drug is to the listed drug cited, the smaller the quantity of data that will be needed to support the proposed change.  Accordingly, to avoid unnecessary duplication of research and review, when a section 505(b)(2) application has been submitted and no pharmaceutically equivalent drug product has previously been approved, the 505(b)(2) applicant should choose the listed drug or drugs that are most similar to the drug for which approval is sought.  Similarly, if all the information relied on by FDA for approval . . . is contained in a single previously approved application and that application is a pharmaceutical equivalent or the most similar alternative to the product for which approval is sought, the 505(b)(2) applicant should certify only to the patents for that application.  This is the case even when another application also contains some or all of the same information. [(Emphasis added)]

Based on this stated policy, FDA could reject an applicant’s choice of listed drug if the Agency determines that another (or an additional) drug product is more appropriate (i.e., more similar). 

FDA’s recent response to Citizen Petitions concerning Buprenorphine (“Buprenorphine CP response”) further explains the Agency’s Fenofibrate CP response:

The Fenofibrate CP response describes a suggested approach intended to enhance the efficiency of a prospective 505(b)(2) applicant’s development program.  An applicant choosing to rely on FDA’s finding of safety and/or effectiveness for a listed drug very similar to the proposed product submitted in the 505(b)(2) application would generally need to submit less additional data to support the differences between the proposed product and the listed drug for approval of the 505(b)(2) application.  However, as stated in the Fenofibrate CP response, this suggested approach does not reflect a statutory or regulatory requirement.  Further, the determination of which listed drug is “most similar” to a proposed product may be difficult (except in cases in which a pharmaceutical equivalent previously has been approved) and dependent on the sponsor’s approach to its development program.  Accordingly, a sponsor interested in submitting a 505(b)(2) application that relies upon FDA's finding of safety and/or effectiveness for one or more listed drugs should determine which listed drug(s) is most appropriate for its development program.  If there is a listed drug that is a “pharmaceutical equivalent” to the proposed drug product, the applicant should identify the pharmaceutically equivalent product as a listed drug relied upon and provide patent certifications for the patents listed for the pharmaceutically equivalent drug.

This guidance is certainty useful, as it provides a more fulsome explanation of FDA’s thinking on choice of listed drug; however, it also suggests (at least at first blush) that if there is a listed drug that is a “pharmaceutical equivalent” of the drug proposed in the 505(b)(2) NDA, then that drug must be identified as a listed drug in the application.  But that’s simply not the case.  FDA has a much more nuanced, case-by-case approach to determining whether a 505(b)(2) applicant has identified the appropriate listed drug (or drugs) in its application.  A couple of examples illustrate this approach.

If a 505(b)(2) applicant relies solely on published literature for which it does not have a right of reference and that does not describe an approved drug, then would FDA require the 505(b)(2) applicant to cite an approved pharmaceutical equivalent as a listed drug?  The answer is “No.”  FDA explained this in a May 2011 Citizen Petition response (Docket No. FDA-2010-P-0614) concerning Colchicine.  In that case, the petitioner, Mutual Pharmaceutical Company, Inc., referenced FDA’s 1999 draft guidance and asserted that “even a 505(b)(2) application that relies solely on the literature must identify [a listed drug].”  FDA said that assertion was incorrect:

The 505(b)(2) Draft Guidance states at p. 8: “Even if the 505(b)(2) application is based solely upon literature and does not rely expressly on an Agency finding of safety and effectiveness for a listed drug, the applicant must identify the listed drug(s) on which the studies were conducted, if there are any” (emphasis added).  However, published literature that does not expressly describe studies conducted with Colcrys or ColBenemid (i.e., non-product-specific published literature) may be relied upon by any 505(b)(2) applicant without necessitating citation of Colcrys or ColBenemid as a listed drug.  Similarly, to the extent that portions of the approved product labeling for Colcrys are based on non-product-specific studies of colchicine described in published literature, a subsequent 505(b)(2) applicant that does not cite Colcrys as a listed drug would not be restricted in relying upon those same studies to support approval.

Also consider this scenario: There is an approved pharmaceutical equivalent, but the prospective 505(b)(2) applicant does not need to rely on that approval because, for example, the applicant has completed its own testing, but needs to access FDA’s previous findings with respect to an excipient (e.g., pharm/tox findings) from another drug approval.  Would FDA require the 505(b)(2) applicant to cite an approved pharmaceutical equivalent as a listed drug in this case?  Again, the answer is “No.”  This is because the application is otherwise complete and would be a “full” 505(b)(1) if it were not for the safety information needed on the excipient.  Citing the approved pharmaceutical equivalent would not serve any purpose; that is, it would not inform the approval of the 505(b)(2) application.

Where FDA would apparently require identification of a pharmaceutical equivalent as a listed drug is where reliance on a previous approval is necessary and the Agency somehow determines that a 505(b)(2) applicant’s choice of listed drug is intended to avoid patent or non-patent exclusivities on a pharmaceutical equivalent.