Bayer Joins the Combo Drug NCE Challenge Club; Petitions FDA for 5-Year Exclusivity for NATAZIA

By Kurt R. Karst –      

For the third time this year, FDA has been asked to recognize 5-year New Chemical Entity (“NCE”) exclusivity for a fixed-dose combination drug product containing both a never-before-approved active moiety and a previously approved active moiety.  In a Citizen Petition (Docket No. FDA-2013-P-0471) submitted to FDA last month on behalf of Bayer HealthCare Pharmaceuticals Inc. (“Bayer”), the company asks the Agency to effectively erase the award of 3-year new clinical investigation exclusivity for the oral contraceptive NATAZIA (estradiol valerate and estradiol valerate/dienogest) Tablets and instead award a period of NCE exclusivity.  Similar requests for NCE exclusivity recognition were made in petitions submitted to FDA earlier this year concerning STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets (Docket No. FDA-2013-P-0058) and PREPOPIK (sodium picosulfate, magnesium oxide and citric acid) for Oral Solution (Docket No. FDA-2013-P-0119).  Indeed, the STRIBILD petition called out NATAZIA as one example for which NCE exclusivity would be ongoing if FDA had awarded such exclusivity in the first place. 

As we previously reported, FDA’s long-standing position has been that in order for a fixed-dose combination drug 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), which 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 five years (absent a Paragraph IV certification).

FDA approved NATAZIA on May 6, 2010 under NDA No. 022252 and awarded a period of 3-year exclusivity that expired earlier this month.  NATAZIA contains both the previously approved drug estradiol valerate and the new molecular entity dienogest.  Because of the award of 3-year exclusivity instead of NCE exclusivity, FDA was free to accept ANDAs seeking aproval for generic NATAZIA as of the date of approval of the drug.  Indeed, according to FDA’s ANDA Paragraph IV Certification List, the Agency received an ANDA as of October 22, 2010.  FDA has not yet approved or tentatively approved any ANDA for generic NATAZIA, and at least one generic applcant is involved in patent infringement litigation with Bayer over a patent on NATAZIA (see here).

Like the STRIBILD and PREPOPIK petitions, Bayer argues in its NATAZIA petition that FDA’s historical approach of denying NCE exclusivity for a fixed-dose combination drug containing a new and previously approved moiety is contrary to the statute, congressional intent and FDA’s exclusivity regulations, and produces arbitrary outcomes that disfavor fixed-dose combinations.  Thus, Bayer fully endorses the arguments set forth in the STRIBILD and PREPOPIK petitions.  According to Bayer:

There is no plausible reason why FDA should incentivize sponsors to obtain approval for a drug product that contains a single new active moiety prior to obtaining approval for an [fixed-dose combination] that incorporates that active moiety in combination with other active moieties.  There is also no reason why FDA should encourage sponsors to seek separate approvals for each active ingredient of a combination product rather than to seek approval of a [fixed-dose combination].  But these outcomes are precisely what FDA’s interpretation of the 5-year exclusivity provision with respect to FDCs promotes. . . . .  Regardless of whether the [NCE] is first approved as part of a [fixed-dose combination] with a previously approved chemical entity, significant time and effort was undoubtedly invested in developing that [NCE].  Due to the substantial investment required, a 5-year exclusivity period is appropriate.

The NATAZIA petition, like the STRIBILD petition, also argues that FDA need not undergo notice-and-comment rulemaking prior to adopting a new interpretaion resulting in an award of NCE exclusivity for fixed-dose combination containing a new moiety.  “FDA has not given its relevant regulation a ‘definitive interpretation,’” says Bayer.  “Furthermore, even if FDA’s interpretation were considered definitive, there has not been substantial or justifiable reliance on that interpretation.  Accordingly, notice and comment rulemaking is not required prior to FDA’s adoption of the interpretation of 5-year exclusivity proposed in this petition.”

Given the age of the NATAZIA approval and the status of pending ANDAs relative to the STRIBILD and PREPOPIK approvals, FDA may be forced to address the NCE exclusivity issue raised by Bayer and others sooner than the Agency might want to.  A denial of any of the petitions could very well lead to a lawsuit against FDA.  In the meantime, it is possile that other manufacturers may join the petitioning club.  A quick look at products in the drug development pipeline and in the NDA review queue at FDA shows that there are other membership candidates.