NCE Exclusivity Challenges are hot! Hot! HOT! Ferring Lets Loose with the Latest Lawsuit Challenging Denial of NCE Exclusivity for Colon Cleansing Drug

June 8, 2015

By Kurt R. Karst –     

We thought FDA would be hauled into court after the Agency denied, on October 10, 2014, two Petitions for Reconsideration (here and here) asking the Agency to rethink a February 21, 2014 Consolidated Response Denial to three Citizen Petitions requesting that the Agency interpret the law to award New Chemical Entity Exclusivity (“NCE”) to approved Fixed-Dose Combination Drugs (“FDCs”) containing an NCE and a previously-approved drug – specifically STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets (Docket No. FDA-2013-P-0058); PREPOPIK (sodium picosulfate, magnesium oxide and citric acid) for Oral Solution (Docket No. FDA-2013-P-0119); and NATAZIA (estradiol valerate and estradiol valerate/dienogest) Tablets (Docket No. FDA-2013-P-0471) (see our previous posts here and here).  We just didn’t think it was going to take this long to see a lawsuit (see our previous post here).  Perhaps feeling emboldened after Amarin Pharmaceuticals Ireland Limited’s May 28, 2015 victory in District Court against FDA after the Agency denied NCE exclusivity for VASCEPA (icosapent ethyl) Capsules, 1 gram (see our previous post here), Ferring Pharmaceuticals Inc. (“Ferring”) filed a Complaint against FDA in the U.S. District Court for the District of Columbia last week challenging FDA’s denial of NCE exclusivity for Ferring’s PREPOPIK, which the Agency approved on July 16, 2012 under NDA 202535 for cleansing of the colon as a preparation for colonoscopy in adults.

By way of background, FDC Act § 505(j)(5)(F)(ii) (applicable to ANDAs) (and its sister provision at Section 505(c)(3)(E)(ii) applicable to 505(b)(2) applications) contains both an “eligibility clause” and a “bar clause.”  Under the “eligibility clause,” a drug is eligible for 5-year NCE exclusivity if it is “a drug, no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other [505(b)] application.”  Under the “bar clause,” the submission of any ANDA (or 505(b)(2) application) that “refers to the drug for which the [505(b)] application was submitted” is prevented for 5 years (absent a Paragraph IV certification).  Similarly, FDA’s implementing regulation at 21 C.F.R. § 314.108(b)(2) precludes FDA from accepting ANDAs and 505(b)(2) applications for drugs that contain the same active moiety as in a previously approved NCE for 5 years (absent a Paragraph IV certification). 

If a drug product contains any previously approved active moiety (i.e., it is not composed of all NCEs), then FDA historically denied NCE exclusivity and granted 3-year exclusivity, provided the statutory requirements are met.  This means that order counts, and that to obtain NCE exclusivity for a FDC drug containing new and old actives, the NCE component must be approved first, followed by the combination drug.  In that case, NCE exclusivity granted with respect to the single entity approval would apply to the combination drug under FDA’s so-called “umbrella policy.”  See 54 Fed. Reg. 28,872, 28,897 (July 10, 1989) (“[W]hen exclusivity attaches to an active moiety or to an innovative change in an already approved drug, the submission or effective date of approval of ANDA’s and 505(b)(2) applications for a drug with that active moiety or innovative change will be delayed until the innovator’s exclusivity has expired, whether or not FDA has approved subsequent versions of the drugs entitled to exclusivity, and regardless of the specific listed drug product to which the ANDA or 505(b)(2) application refers.”).

The STRIBILD, PREPOPIK, and NATAZIA petitions argued that FDA’s historical approach of denying NCE exclusivity for a FDC drug containing a new and a previously approved active moiety is contrary to the statute, congressional intent and FDA’s exclusivity regulations, and produces arbitrary outcomes that disfavor FDCs.  Instead, petitioners argued that “the best reading of the statute – and the one that best reflects the agency’s rulemaking choices – is that for a 505(b) application that contains a [FDC] of drugs, the exclusivity must be analyzed and granted as to each drug that is the subject of the application” (emphasis added).  That is, NCE exclusivity should be evaluated on a drug component-by-drug component drug basis, according to the petitioners.

In February 2014, on the same day FDA issued a draft guidance document proposing to reinterpret the FDC Act’s NCE exclusivity provisions to award NCE exclusivity for a newly approved FDC containing an NCE and a previously approved drug, the Agency issued a Consolidated Response denying the three Citizen Petitions referenced above (see our previous post here).  That is, FDA proposed to reinterpret the law, but only prospectively to FDCs approved after finalization of the draft guidance.  FDA explained the Agency’s reasoning for this approach in the Consolidated Response Denial:

Exclusivity runs from the date of approval of a drug product.  At the time of approval of the drug products at issue here (i.e., Stribild, Natazia, and Prepopik), our existing interpretation of the relevant statutory and regulatory provisions was in effect.  We have decided not to recognize 5-year NCE exclusivity based on our new interpretation of these provisions, which we had not announced prior to the approval of these products . . . .

First, although the relevant statutory and regulatory provisions are ambiguous, our existing interpretation of these provisions is longstanding and has been consistently applied in many prior cases presenting similar facts.  Second, the new interpretation we are proposing represents a departure from our past interpretation, and we wish to avoid any unnecessary disruption to regulated industry.  Third, if the new interpretation were to be applied to products for which ANDAs already have been filed, it could impose a burden on the ANDA sponsors, who relied on our existing interpretation in filing their applications.

In addition, we do not believe that applying our new interpretation to the Petitioners’ products would advance the goals of the Hatch-Waxman Amendments.  Although we recognize that the Hatch-Waxman Amendments contain incentives to reward the development an approval of novel drugs, these particular products already have been developed and approved.  Recognizing additional exclusivity in this case is not necessary to encourage the development of novel drugs.  We believe that changing our interpretation going forward will foster Congress’s goal of encouraging the development and approval of novel drugs.  (Emphasis in original.)  

Both Gilead and Ferring submitted Petitions for Reconsideration asking FDA to rethink its position with respect to STRIBILD and PREPOPIK (see our previous posts here and here).  According to Gilead, none of the reasons FDA cites in its petition response fit the circumstances surrounding STRIBILD.  Ferring raised some of the same points in its Petition for Reconsideration.  According to Ferring:

  • The Commissioner’s statutory interpretation of the five-year exclusivity provisions for fixed-combinations with at least one novel drug substance is the only correct interpretation, and must be applied to all relevant applications.  No change in the Agency's regulations is required legally or technically.
  • The Commissioner failed to adequately consider all points raised in the original Citizen Petitions, including wildly inconsistent exclusivity results under its umbrella policy and the support in the legislative history for five-year exclusivity for fixed-combinations with novel ingredients.
  • Due Process and fairness require that five-year exclusivity be recognized for all applicable drug applications with remaining exclusivity, particularly Ferring’s Prepopik.
  • The Commissioner should adopt Petitioners’ statutory interpretation immediately.  The Commissioner’s decision to implement the interpretation prospectively at some indefinite future date (i.e., through final guidance) is arbitrary and capricious action that cannot be considered reasonable when all relevant factors are considered.

Among other things, Ferring highlighted the alleged “irrational and arbitrary nature” of FDA’s application of the Agency’s “old rules” concerning NCE exclusivity for FDCs containing a new and a previously approved drug, and cited FDA’s then-recent approval of NDAs for alogliptin (NESINA, KAZANO, and OSENI) as a prime example (see our previous post here).

On October 10, 2014, FDA released on the Agency’s website a final guidance (see our previous post here).  At that time, FDA also denied the Gilead and Ferring Petitions for Reconsideration and issued a separate denial of a May 30, 2014 Citizen Petition (Docket No. FDA-2014-P-0737) in which Pfizer Inc. says that FDA erred in not granting NCE exclusivity with respect to Pfizer subsidiary Wyeth Pharmaceuticals, Inc.’s DUAVEE (conjugated estrogens/bazedoxifene) Tablets on the basis that FDA never before approved a drug product under FDC Act § 505 containing bazedoxifene as an active moiety. 

Fast-forward almost nine months, and Ferring alleges in a June 1, 2015 Complaint that FDA violated the Administrative Procedure Act (“APA”) and the FDC Act by denying NCE exclusivity after approving PREPOPIK. 

Ferring is seeking, among other things, a declaration that FDA’s decision to deny Ferring NCE exclusivity was arbitrary, capricious, and contrary to law under the APA and the FDC Act, and a temporary, preliminary and/or permanent injunction requiring FDA to rescind its decision to deny Ferring NCE exclusivity.  According to Ferring:

FDA’s decision to continue to apply its erroneous construction of the statute to only a handful of approved drugs, while simultaneously announcing its decision to apply the statute correctly for all pending and future new drug applications, was erroneous, arbitrary, capricious, an abuse of discretion, and not in accordance with law. [(Emphasis in original)]

With respect to FDA’s decision to apply its reinterpretation of the law prospectively, Ferring says that “prospective” should mean as of the date an ANDA or 505(b)(2) application is submitted to FDA citing PREPOPIK:

[E]ven if FDA had adequately justified its decision to apply the correct statutory interpretation of the NCE exclusivity provision only “prospectively,” the agency nevertheless provided no rational justification for applying its “prospective” position only to drug products that had not yet been approved.  The five-year exclusivity period at issue is implicated—if at all—only when an ANDA or 505(b)(2) NDA seeks to rely upon the innovator drug.  After all, it is only when a second sponsor seeks to submit its own application that the statutory and regulatory exclusivity provisions apply.  If no generic application has been submitted—as was the case with PREPOPIK® at the time of FDA’s revised interpretation—then exclusivity remains “prospective.”  Even if the agency believes that it can permissibly apply the correct statutory interpretation only “prospectively,” that “prospective” application should not hinge on the date of approval of the innovator product, but the date of submission of the generic product.

In this case, that could mean May 21, 2014, which is the date identified on FDA’s Paragraph IV Certifications List as the date as of which FDA received the first ANDA for a generic version of PREPOPIK containing a Paragraph IV certification.  In January 2015, Ferring received notice of a Paragraph IV certification stemming from the May 2014 ANDA submission.  Ferring filed a Complaint against Par Pharmaceutical Inc. in February 2015.