FDA Denies 3 Petitions Seeking NCE Exclusivity for Combo Drugs, But Proposes to Reinterpret the Law for New NDAs

By Kurt R. Karst –      

In moves that may displease both brand-name and generic drug manufacturers, and that could lead to litigation from both sides, FDA has with one hand proposed to giveth New Chemical Entity (“NCE”) exclusivity to certain Fixed-Dose Combination Drugs (“FDCs”) and has with the other hand taketh away the possibility of NCE exclusivity for other FDCs. 

Last Friday, FDA announced in a notice that will be published in the Federal Register today the availability of a draft guidance document, titled “New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products,” that, if finalized, would reinterpret the NCE exclusivity provisions of the FDC Act to award NCE exclusivity for a newly approved FDC containing an NCE and a previously approved drug.  One the same day, FDA issued a Consolidated Response denying three Citizen Petitions submitted to the Agency in 2013 requesting that FDA interpret the law to award NCE exclusivity for approved 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).

As we previously reported (here and here), the three petitions take issue with FDA’s long-standing position that in order for a FDC to be eligible for 5-year NCE exclusivity, each of the active moieties in the drug product must be new (i.e., not previously approved).  This interpretation is based on FDA’s reading of the statutory language at FDC Act § 505(j)(5)(F)(ii) (concerning ANDAs) and FDC Act § 505(c)(3)(E)(ii) (concerning 505(b)(2) applications), and application of the Agency’s implementing regulation at 21 C.F.R. § 314.108(b)(2). 

FDC Act § 505(j)(5)(F)(ii) (and its sister provision at Section 505(c)(3)(E)(ii)) 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 compsed of all NCEs), then FDA has 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 combination 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 argue that FDA’s historical approach of denying NCE exclusivity for a FDC drug containing a new and 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 argue 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. 

And, as FDA explains in both its draft guidance and Consolidated Response, the Agency agrees with petitioners: 

In light of the increasing importance of fixed-combination products to treat serious diseases and conditions, and considering the factors discussed above, FDA has concluded that the new interpretation urged by the petitioners would be beneficial to the public health.  Accordingly, FDA is changing its interpretation of the 5-year NCE exclusivity provisions to align the exclusivity incentives more closely with FDA’s public health goals.  Under the revised interpretation, the term drug in the eligibility clause of the statutory provisions, and in the regulatory definition of new chemical entity, refers to drug substance, not drug product.

Accordingly, a 5-year NCE exclusivity determination will be made for each drug substance in a drug product, not for the drug product as a whole.  As a result, an application for a [FDC] submitted under section 505(b) of the FD&C Act will be eligible for 5-year NCE exclusivity if it contains a drug substance, no active moiety of which has been approved in any other application under section 505(b).  For example, a fixed-combination drug product that contains a drug substance with a single, new active moiety would be eligible for 5-year NCE exclusivity, even if the fixed-combination also contains a drug substance with a previously approved active moiety. (Emphasis in original.)

As to the appropriateness of making this change in interpretation through guidance instead of formal notice-and-comment rulemaking, FDA says it has sufficient authority to do so:

The FD&C Act provides FDA with explicity authority to “develop guidance documents . . . [that] present the views of [FDA] on matters under the jurisdiction of [FDA],” and specifies further that for “guidance documents that set forth initial interpretations of s statute or regulation, changes in interpretation or policy that are of more than a minor nature,” among others, FDA “shall ensure public participation.”  Thus, Congress has provided the guidance process as a specific process through which FDA may adopt changes in interpretation or policy, and we believe that it is appropriate in this case to utilize the process in section 701(h) and our implementing Good Guidance Practice regulation to provide for public participation.

There’s a catch, however, with FDA’s proposed interpretation.  As FDA explains in the draft guidance:  “If the new interpretation is adopted, FDA intends to apply the new interpretation prospectively.  Therefore, this guidance does not apply to fixed-combination drug products that were approved prior to adopting the new interpretation.”  That gave the early heads-up that the Agency was denying the STRIBILD, PREPOPIK, and NATAZIA petitions.  (FDA’s Consolidated Response was posted on the Regulations.gov website several hours after the draft guidance was posted.)  FDA further explains its reasoning in the Consolidated Response:

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.)   

In addition to denying 5-year NCE exclusivity for STRIBILD, PREPOPIK, and NATAZIA, FDA’s Consolidated Response seems to foreshadow how the Agency will rule in another case involving NCE exclusivity.  As we previously reported, FDA has been petitioned (Docket Nos. FDA-2013-P-0884 and FDA-2013-P-1397) to conclude that the start date of NCE exclusivity for products that contain a controlled substance and that require a scheduling decision by the Drug Enforcement Administration (“DEA”) under the Controlled Substances Act (“CSA”) is triggered only when FDA-approved labeling incorporating the final DEA CSA scheduling permits commercial marketing of the drug products, and not on the date of NDA approval.  FDA’s Consolidated Response, however, continues to confirm that “[e]xclusivity runs from the date of approval of a drug product.”  In light of this FDA position, there's been talk about amending the law to better accommodate controlled substances (see here).