Function Over Form or Form Over Function? Two Petitions Challenge FDA’s NCE Exclusivity Approach for Combination Drugs

By Kurt R. Karst –  

Two recent citizen petitions submitted to FDA – one from Gilead Sciences, Inc. (“Gilead”) under Docket No. FDA-2013-P-0058, and another from Ferring Pharmaceuticals, Inc. (“Ferring”) under Docket No. FDA-2013-P-0119 – take issue with FDA’s long-standing position that in order for a fixed-dose combination drug to be eligible for 5-year New Chemical Entity (“NCE”) exclusivity, each of the active moieties in the drug product must be new (i.e., not previously approved).  Although there are myriad instances throughout Hatch-Waxman history in which FDA has applied this principle – either to grant or deny NCE exclusivity for a combination drug – the Gilead and Ferring petitions appear to be the first instances in which companies have publicly challenged FDA’s application of the FDC Act in this respect.  Both petitions advance some rather interesting legal and policy arguments in favor of NCE exclusivity, and, provided FDA denies both petitions, arguments that may be raised again in litigation with FDA.

Before we touch on the Gilead and Ferring petitions, we need to first provide the lay of the land.  The statutory 5-year NCE exclusivity provision at FDC Act § 505(j)(5)(F)(ii) applicable to ANDAs states in relevant part:

If an application submitted under [FDC Act § 505(b)] for a drug, no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application under [FDC Act § 505(b)], is approved after the date of the enactment of this subsection, no application may be submitted under this subsection which refers to the drug for which the [FDC Act § 505(b)] application was submitted before the expiration of five years from the date of the approval of the application under [FDC Act § 505(b)], except that such an application may be submitted under this subsection after the expiration of four years from the date of the approval of the [FDC Act § 505(b)] application if it contains a [Paragraph IV certification].

(There is a slightly different corresponding provision at FDC Act § 505(c)(3)(E)(ii) applicable to 505(b)(2) applications.) 

FDA’s regulation at 21 C.F.R. § 314.108(b)(2) implements the statutory 5-year NCE exclusivity provisions and states, in relevant part, that:

If a drug product that contains a [NCE] was approved after September 24, 1984, in an application submitted under [FDC Act § 505(b)], no person may submit a 505(b)(2) application or [ANDA] under [FDC Act § 505(j)] for a drug product that contains the same active moiety as in the [NCE] for a period of 5 years from the date of approval of the first approved [NDA], except that the 505(b)(2) application or [ANDA] may be submitted after 4 years if it contains a [Paragraph IV] certification . . . . 

Thus, the regulation precludes FDA from accepting ANDAs and 505(b)(2) applications for drugs that contain the same active moiety as in a previously approved NCE.  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.”).

Another FDA regulation, 21 CFR § 314.108(a), defines the term “new chemical entity” to mean “a drug that contains no active moiety that has been approved by FDA in any other application submitted under [FDC Act § 505(b)].”  The term “active moiety” is defined in the same regulation 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.

As we previously discussed, FDA has articulated a structure-centric interpretation of “active moiety” (rather than an activity-based interpretation) under which a drug is classified as an NCE regardless of which portions of the active ingredient contribute to the overall therapeutic effect of the drug.  This form over function approach means that relatively small changes to a molecule, such as deuterium analogues of various approved compounds (see here, here, and here), may qualify for NCE exclusivity, while more significant changes that improve the activity of a drug, but that do not change the molecule that is the active moiety, would not result in NCE exclusivity.  Although FDA’s structure-centric interpretation of “active moiety” is not per se at issue in the Gilead and Ferring petitions, the form over function approach that that interpretation embodies is at issue.  

Gilead’s petition concerns STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets, which FDA approved on August 27, 2012 under NDA No. 203100 for the treatment of HIV.  FDA’s Orange Book does not yet reflect an exclusivity determination by the Agency; however, the Gilead petition presumes that if the Agency follows past practice, then NCE exclusivity will be denied on the basis that two of the components in STRIBILD, namely emtricitabine and tenofovir disoproxil fumarate, were previously approved.  The elvitegravir and cobicistat components are NCEs. 

According to Gilead:

FDA’s historical interpretation is not binding. . . . [A] new interpretation of the exclusivity provisions applicable to new active moieties in [fixed-dose combinations] should be adopted and can immediately be put into practice.  A new interpretation is fully justified under the statute; is consistent with the agency’s regulations; and is necessary to keep pace with advances in medical science.

And what is that new interpretation?  Gilead says that the FDC Act is subject to multiple interpretations, but 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 fixed dose combination 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.  Why?  Because it naturally fits with FDA’s regulations and supports Congressional intent to reward the development of new active moieties, says Gilead. 

FDA’s historical approach, writes Gilead, leads to illogical and arbitrary results, such as forcing sponsors to first obtain approval of the NCE (if that is even possible), followed by the combination drug.  Moreover, “rigid application of FDA’s historical interpretation to [fixed dose combinations] also creates inconsistent exclusivity determinations with respect to cross-labeled drug combinations,” such as PREZISTA (darunavir ethanolate), which is an NCE that must be co-administered with ritonavir.  In addition, Gilead points to recent legislation, such as the 2007 FDA Amendments Act, and administrative changes to the NDA review process that support a change in statutory interpretation.

Ferring’s petition concerns PREPOPIK (sodium picosulfate, magnesium oxide and citric acid) for Oral Solution, 10 mg sodium picosulfate/sachet, a colong cleansing drug that FDA approved on July 16, 2012 under NDA No. 202535.  Although the sodium picosulfate component is new, FDA has previously approved drug products containing magnesium oxide and citric acid.  As opposed to STRIBILD, FDA has already make an exclusivity determination with respect to PREPOPIK, granting Ferring 3-year exclusivity instead of 5-year NCE exclusivity.  Another difference is that the sodium picosulfate NCE component in PREPOPIK is not suitable for development as a single-entity drug product, because, according to Ferring, “FDA’s reviews concluded that conducting clinical trials for a single ingredient sodium picosulfate drug would be unethical.”

Ferring advances several arguments in favor of FDA granting NCE exclusivity, including:

(1)  that the intent of the Hatch-Waxman Amendments is to reward sponsors that develop and obtain approval of NCEs, and the denial of NCE exclusivity for PREPOPIK is inconsistent with the legislative history of the law;

(2)  that the need to reduce unnecessary and duplicative research (and avoid unethical research), as evidenced in FDA’s interpretation of FDC Act § 505(b)(2) and policy concerning hybrid New Animal Drug Applications, is consistent with an award of NCE exclusivity for PREPOPIK;

(3)  that FDA’s application of NCE exclusivity to other combination drugs under the Agency’s “umbrella policy” (noted above) shows “that FDA does, in effect, grant five-year exclusivity protection to drugs that are combinations that contain previously approved active ingredients, so long as the single active ingredient drug containing the novel active ingredient is approved first;” and

(4)  that FDA’s so-called “Animal Efficacy Rule,” 21 C.F.R. § 314.610 (drugs), § 601.91 (biologics), under which FDA can rely on evidence from animal studies to provide substantial evidence of effectiveness when it is unethical or unfeasible to conduct human efficacy studies to obtain approval of a countermeasure product, supports “the position that FDA takes public health objectives into consideration when interpreting statutory language.”  Accordingly, says Ferring, because the company “was ethically barred from conducting a study of single ingredient sodium picosulfate without including the other ingredients magnesium oxide and anhydrous,” “FDA should treat Ferring’s situation similar to those cases where FDA approved a drug product and granted exclusivity based on animal studies.”  In each of those cases, FDA presumably granted 3-year exclusivity on the basis of the human safety studies conducted by the NDA sponsor.  See, e.g., FDA Exclusivity Summary for CYANOKIT (hydroxocobalamin for injection), NDA No. 022041 (here).  Under the Animal Efficacy Rule, evaluation of the product for safety in humans is still required and cannot be addressed by animal studies alone.

It is unclear when FDA might respond to both the Gilead and Ferring petitions; however, FDA may be forced to make decisions if a company submits an ANDA in the near future, and before what would otherwise be the “NCE-1” date (i.e., four years after the NCE NDA approval).