By Kurt R. Karst –
Disputes involving non-patent marketing exclusivity available to 505(b)(1) and 505(b)(2) NDA applicants – either 5-year New Chemical Entity (“NCE”) exclusivity, 3-year new clinical investigation exclusivity, or 7-year orphan drug exclusivity – have increased dramatically over the past few years, and there’s no end in sight. Just take a look at the various postings in the “Hatch-Waxman” category on this blog over the past year or two and you’ll see what we mean. We’ve seen numerous lawsuits challenging FDA decisions on the availability of or scope of exclusivity, as well as several citizen petitions requesting that FDA make a particular determination on the appropriate exclusivity period to award an NDA applicant. We’ve also seen several cases in which FDA has inexplicably delayed or failed to make an exclusivity decision after approving an NDA – e.g., AVYCAZ (ceftazidime-avibactam) Injection (NDA 206494; approved on February 25, 2015), AURYXIA (ferric citrate) Tablets (NDA 205874; approved on September 5, 2014), and SURFAXIN (lucinactant) Intratracheal Suspension (NDA 021746; approved on March 6, 2012) – or where FDA “punts” on making an exclusivity determination hoping that the issue will go away with time – e.g., XTAMPZA ER (oxycodone) Extended-release Capsules (NDA 208090), where FDA comments in a November 6, 2015 Tentative Approval letter that “We need not determine at this time whether approval of your 505(b)(2) NDA for XTAMPZA ER would otherwise be blocked by any other drug’s marketing exclusivity expiring before termination of the 30-month stay.”).
The latest exclusivity challenge comes in the form of a Citizen Petition (Docket No. FDA-2016-P-1163) submitted to FDA on behalf of Vifor Fresenius Medical Care Renal Pharma France (“Vifor Fresenius”) requesting that FDA award a period of 5-year NCE exclusivity for Vifor Fresenius’s VELPHORO (sucroferric oxyhydroxide) Chewable Tablets, which FDA approved on November 27, 2013 under NDA 205109 for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis. Although FDA has failed to make an exclusivity decision for another iron-based drug product (AURYXIA, noted above), in the case of VELPHORO it’s not FDA’s failure to act that is being challenged, but rather FDA’s decision to award a period of 3-year exclusivity instead of 5-year NCE exclusivity.
According to Vifor Fresenius, VELPHORO is entitled to 5-year exclusivity under either FDA’s “active moiety standard” or the FDC Act’s “active ingredient standard,” which the U.S. District Court for the District of Columbia recently addressed in Amarin Pharms. Ir. Ltd. v. FDA, 106 F. Supp. 3d 196, 198 (D.D.C. 2015) (see our previous post here), and for which a decision out of FDA seems likely any day now. Vifor Fresenius lays out detailed arguments, including:
- Velphoro is a novel iron-based phosphate binder with a different active moiety from previous iron-based products. The Agency initially rejected five-year exclusivity for Velphoro on the basis of previously approved intravenous iron-carbohydrate iron supplements. But these products do not share an active moiety with Velphoro. Velphoro, a chewable phosphate binder, has as its active moiety a form of insoluble polynuclear iron(III)-oxyhydroxide that is specifically designed to minimize the release of iron: by contrast, the iron supplements are designed to release iron and have a ferric iron (Fe3+) active moiety.
- FDA has agreed that there are significant physicocheinical differences between Velphoro’s iron oxyhydroxide active moiety and the iron oxyhydroxides in Previously approved products. The polynuclear iron(III)-oxyhydroxide moiety in Velphoro is different in significant respects from iron oxyhydroxides in previously approved products, as the Agency itself has concurred. For example, the iron oxyhydroxides in previously approved products contain particles that are billions of times smaller, differ in their iron release properties, and differ in their structure and chloride content.
- Velphoro does not contain a previously approved active ingredient. The FDCA requires that the Agency assess approved active ingredients as a whole, rather than focus narrowly on active moieties. This approach is also consistent with FDA’s approach to active ingredient sameness in the ANDA approval context. Here, the approved active ingredients in other iron-carbohydrate drugs differ in activity, differ in particle size, differ in iron release and solubility, contain different carbohydrates and other components, and contain significantly higher stoichiometric ratios of carbohydrates, resulting in dramatic differences in therapeutic effect.
- Velphoro’s physicochemical differences are essential for the desired therapeutic indication, not minor differences that the Agency can ignore. The Agency agrees that Velphoro has physicochemical differences from intravenous iron supplements that it also concurs are “essential for the desired therapeutic indication.” Velphoro is a solid that binds phosphate for purposes of excretion, and is designed so that it causes only minimal iron absorption into the body. By contrast, the iron-carbohydrate anemia drugs are injectables introduced into the bloodstream and designed for the purpose of delivering iron into the body. In evaluating active ingredients, the Agency should not ignore differences that are essential to activity.
Until FDA makes a decison on NCE exclusivity, Vifor Fresenius wants FDA to stay the acceptance of any new ANDAs or 505(b)(2) NDAs that reference VELPHORO, and any action on a previously-submitted ANDA or 505(b)(2) NDA that references VELPHORO. A single patent is listed in the Orange Book for VELPHORO that expires on December 19, 2016, so it’s possible that an application is pending at FDA with a Paragraph III patent certification.
Metal-containing products have historically been difficult for FDA to evaluate for active moiety and exclusivity purposes. Consider, for example, the September 2003 memorandum FDA included in NDA 021626 for RADIOGARDASE (insoluble Prussian Blue) Capsules evaluating whether different ferric(III) hexacyanoferrate(II) compounds are different active moieties. There’s also FDA’s recent Manual of Policies and Procedures (“MAPP”) on NDA Classification Codes (MAPP 5018.2). As we noted in a previous post, the MAPP specifically addresses the active moiety in metal-containing substances.
We’re not entirely certain where FDA will land on the VELPHORO petition, but we note that it’s not very often that FDA changes an exclusivity decision . . . . at least not absent litigation. So we may be headed down that path once again.