FDA is Asked to Reconsider Denial of NCE Exclusivity for STRIBILD; Gilead Says FDA Erred in Not Applying the New (and Old) Interpretation

April 9, 2014

By Kurt R. Karst

When FDA announced on February 21, 2014 that the Agency would, upon finalization of a draft guidance document, reinterpret the New Chemical Entity (“NCE”) exclusivity provisions of the FDC Act to award NCE exclusivity for a newly approved Fixed-Dose Combination Drug (“FDC”) containing an NCE and a previously approved drug, FDA also issued a Consolidated Response denying the three Citizen Petitions submitted to the Agency in 2013 that led the Agency to its new interpretation in the first place.  Those petitions concerned 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).  Now one of the petitioners – Gilead Sciences, Inc. (“Gilead”) – is asking FDA in a Petition for Reconsideration to rethink that decision with respect to STRIBILD, and to refuse to accept any ANDA or 505(b)(2) application for a drug product containing either of the two NCEs in STRIBILD – elvitegravir and cobicistat – under the rules governing NCE exclusivity.

As we previously reported, FDA decided to apply its new interpretation prospectively upon finalization of the draft guidance.  FDA explained in the Consolidated Response the Agency’s rationale for this decision and the bases for not granting the three petitions and awarding NCE exclusivity:

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.)   

But according to Gilead, none of these reasons fit the circumstances surrounding STRIBILD.  First, with respect to FDA’s concern that recognizing NCE exclusivity would burden sponsors with pending applications, Gilead says that to its knowledge FDA has not yet even accepted an ANDA or 505(b)(2) application citing STRIBILD as the listed drug relied on for approval.  Second, as to FDA’s rationale that the STRIBILD approval was made when the “old” rules were (and still are) in effect, Gilead says that “the date of approval is not the relevant date . . . because FDA made the decision to defer the exclusivity determination for STRIBILD.”  Moreover, says Gilead, the company “raised the 5-year NCE exclusivity issues early during STRIBILD’s NDA process,” and “requested 5-year NCE exclusivity at the time of submission of the STRIBILD NDA and reiterated its request in a letter submitted to the agency immediately following STRIBILD’s approval.”  Third, FDA’s Hatch-Waxman goals remark misses the mark, says Gilead.  “Gilead developed the new active moieties in STRIBILD with the expectation that they would have 5-year NCE exclusivity,” writes the company.  The STRIBILD NDA was submitted to FDA before the NDAs for elvitegravir and cobicistat because “Gilead recognized during development that pursuing the combination product first would be more beneficial to patients and scientifically feasible.”  Finally, as to FDA’s comment that recognizing NCE exclusivity for an approved FDC would amount to “additional exclusivity,” Gilead says that “nothing additional or gratuitous is being requested,” and that “[a]warding the exclusivity in this instance represents the appropriate statutory recognition for having developed these novel drugs.” 

As to Gilead’s request that FDA refuse to accept any ANDA or 505(b)(2) application for a drug product containing either elvitegravir and cobicistat, the company argues that two key points of interpretation that predate the Consolidated Response require FDA to recognize NCE exclusivity for each active moiety. 

The statutory provisions governing NCE exclusivity – FDC Act § 505(j)(5)(F)(ii) (and its sister provision at Section 505(c)(3)(E)(ii)) – contain 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).  Under FDA’s revised interpretation as described in the Consolidated Response, the term “drug” in the “eligibility clause” of the statute (and in the regulatory definition of NCE at 21 C.F.R. § 314.108) refers to drug substance, not drug product.  But what about the statutory “bar clause”?

According to Gilead, FDA agreed in the Consolidated Response that under the “bar clause” the term “the drug” has historically been interpreted under FDA’s so-called “umbrella policy” to mean a particular active moiety rather than a drug product.  Under that policy, described in various places in the preamble to the 1989 proposed regulations implementing the Hatch-Waxman Amendments, FDA interpretes NCE exclusivity:

to cover any subsequent approval of an application or supplemental application for a different ester, salt, or other noncovalent derivative, or a different dosage form, strength, route of administration, or new use of a drug product with the same active moiety.  Any modification to the product will be protected for the period of exclusivity remaining on the original application, unless the change occurs after or toward the end of the initial 5 years of exclusivity and independently qualifies for exclusivity under another exclusivity provision. [54 Fed. Reg. 28,872, 28,898-99 (July 10, 1989)]

“In light of that clear and appropriate interpretation, it is not plausible that the term ‘a drug’ in the [eligibility] clause . . . could mean something different,” says Gilead.  “Here, the meaning specifically adopted by the agency is that the ‘drug’ at issue in the exclusivity provision is a specific active moiety,” and not a drug product.

Furthermore, FDA long ago incorporated this active moiety-specific interpretation of the “bar clause” into the Agency’s implementing regulation at 21 C.F.R. § 314.108(b)(2), argues Gilead.  That regulation prevents for 5 years (absent a Paragraph IV certification) the submission of an ANDA or 505(b)(2) application that references “a drug product that contains a new chemical entity” (emphasis added).  “A drug product cannot ‘contain’  another drug product; it may contain drug substances and moieties, but not other drug products.”  Thus, argues Gilead, FDA’s bar regulation “is designed to provide the same scope of protection – namely, moiety-specific protection – as the bar clause in the statute, based on FDA’s clear and reasonable interpretation of the statute.”