The “Stable Ester” and New Chemical Entity Exclusivity Eligibility; the Debate Over VERAMYST Exclusivity

By Kurt R. Karst –      

The recent challenge to FDA’s five-year New Chemical Entity (“NCE”) exclusivity determination concerning the ADHD drug VYVANSE (lisdexamfetamine dimesylate) Capsules and the reportedly ongoing debate over whether to grant NCE exclusivity with respect to certain pancreatic enzyme products are not the only NCE exclusivity debates at FDA these days.  FDA is also reportedly considering whether GlaxoSmithKline’s (“GSK’s”) corticosteroid drug VERAMYST (fluticasone furoate) Nasal Spray, which was approved on April 27, 2007 under NDA No. 22-051, is eligible for NCE exclusivity under a narrow exception applicable to certain esters. 

Under the FDC Act (as amended by Title I of the Hatch-Waxman Amendments), five-year exclusivity is available to the sponsor of an application (either a “full” 505(b)(1) NDA or a 505(b)(2) application) for a drug product that does not contain an active moiety previously approved under § 505(b) of the FDC Act.  NCE exclusivity prevents the submission of an ANDA (or a 505(b)(2) application) that “refers to the drug for which the [approved § 505(b) NCE NDA] was submitted before the expiration of five years from the date of the approval” of the NCE NDA.  FDC Act §§ 505(c)(3)(E)(ii) & 505(j)(5)(F)(ii) (emphasis added).  

The FDC Act is ambiguous with regard to the meaning of the term “drug” in §§ 505(c)(3)(E)(ii) and 505(j)(5)(F)(ii).  Neither provision addresses whether “drug” means the particular drug product that is the subject of the approved NCE NDA with five-year exclusivity, or, more generally, the approved active moiety.  FDA identified this ambiguity in the preamble to its proposed rule implementing the exclusivity provisions of the Hatch-Waxman Amendments:

The language of sections 505(c)(3)[(E)] and 505(j)[(5)(F)] of the act is ambiguous as to which ANDA’s or 505(b)(2) applications are affected by an innovator’s exclusivity.  The statutory language allows at least two interpretations.  The narrower interpretation of the protection offered by exclusivity is that exclusivity covers only specific drug products and therefore protects from generic competition only the first approved version of a drug . . . . The broader interpretation of the coverage of exclusivity is that it covers the active moieties in new chemical entities . . . . FDA has concluded that the broader interpretation of the scope of exclusivity should be applied to all types of exclusivity conferred by sections 505(c)(3)[(E)] and 505(j)[(5)(F)] of the act.  Therefore, when 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.

FDA, Proposed Rule, ANDA Regulations, 54 Fed. Reg. 28,872, 28,897 (July 10, 1989) (emphasis added).  This policy, which is known as FDA’s “Umbrella Policy,” effectively replaces the term “drug” in the statutory text with the term “active moiety.”  FDA’s regulations at 21 C.F.R. § 314.108(a) define the term “active moiety” to mean “the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.” 

Although the general rule of thumb is that an ester of an approved drug is not considered a new active moiety eligible for five-year NCE exclusivity – because most ester linkages are rapidly cleaved in vivo to provide the de-esterified molecule circulating in the blood, see Letter from Ronald G. Chesemore, FDA, to John D. Siegfried, M.D., McNeil Pharmaceutical, at 12, n.5 (July 26, 1989) – there is a narrow exception.  FDA has explained in one document that “[a]n ester that is stable, both in vitro and in vivo, is considered to be the active moiety, because the de-esterified molecule is devoid of activity . . . .”

FDA has applied this policy on rare occasion; for example, in the context of organic nitrates.  Specifically, FDA approved ISMO (isosorbide mononitrate) on December 30, 1991 under NDA No. 19-091 and granted NCE exclusivity despite the previous approval of products containing isosorbide dinitrate. 

So what does this all have to do with VERAMYST?  According to documents contained in the VERAMYST Summary Basis of Approval, GSK requested that FDA grant five-year NCE exclusivity for the drug notwithstanding the Agency’s previous approval of drug products containing fluticasone propionate (e.g., FLONASE, FLOVENT, and ADVAIR).  According to GSK, fluticasone furoate “is a unique molecular entity that exhibits distinctive functional characteristics of clinical significance that are directly attributable to the continuing presence of the furoate ester group at the local site of drug action,” and that “the furoate group remains an integral part of this new chemical entity while exerting therapeutic activity at the site of action, and reviewers should appreciate that neither fluticasone furoate nor fluticasone pripionate is ever metabolized to fluticasone.”  GSK goes on to argue that FDA’s decision to grant NCE exclusivity for isosorbide mononitrate “establishes precedent for supporting GSK’s request for a 5-year marketing exclusivity for fluticasone furoate.” 

Although GSK initially requested NCE exclusivity when the company submitted its NDA for VERAMYST in June 2006, and company officials reportedly met with FDA officials in March 2008 to discuss the issue, FDA has apparently not yet – now more than two years after NDA approval – made an exclusivity decision.  The reasons for FDA’s substantial delay in making an exclusivity determination are unclear.  We will continue to follow this developing story.