Briefing in Appeal Over Colchicine 505(b)(2) Approval Wraps Up; Oral Argument and a Decision are Patiently Awaited

January 11, 2016

By Kurt R. Karst

A few months have passed since the appeals Takeda Pharmaceuticals U.S.A., Inc. (“Takeda”) and Elliott Associates, L.P., Elliott International, L.P. and Knollwood Investments, L.P. (collectively “Elliott”) filed with the U.S. Court of Appeals for the District of Columbia Circuit after District Court Judge Ketanji Brown Jackson issued a lengthy Opinion (and an Order) in January 2015 upholding FDA’s September 26, 2014 approval of a 505(b)(2) application (NDA 204820) submitted by Hikma Pharmaceuticals LLC (“Hikma”) and its U.S. partner West-Ward Pharmaceutical Corp. (“West-Ward”) for MITIGARE (colchicine) Capsules, 0.6 mg, for prophylaxis of gout flares.  There’s been a decent amount of activity on the court docket since our last post, so an update is in order.

As you might recall, The MITIGARE 505(b)(2) NDA did not cite Takeda’s COLCRYS (colchicine) Tablets, 0.6 mg (NDA 022352), as a listed drug relied on for approval. Instead, the 505(b)(2) NDA cites a different drug – COL-PROBENECID, a fixed-dose combination drug product containing probenecid (500 mg) and colchicine (0.5 mg) that FDA approved on November 23, 1976 under ANDA 084279 – and also relies on published literature on colchicine.  COL-PROBENECID is not listed in the Orange Book with any protections.  In contrast, COLCRYS is listed with information on several patents.  Takeda sued FDA alleging that the Agency’s approval of MITIGARE violates the FDC Act and the Administrative Procedure Act (“APA”) in several respects, including that FDA approved MITIGARE without requiring Hikma to reference COLCRYS and to make patent certifications, and that MITIGARE was approved without certain labeling information FDA required be included in the labeling of COLCRYS (see our previous posts (here, , and ).

Takeda and Elliott, in their Opening Briefs (here and here) filed in the D.C. Circuit, pitched their appeals as presenting issues that, if not resolved with a reversal of Judge Jackson’s decision, would upset the balance Congress intended to create with the passage of the Hatch-Waxman Amendments: the balance between brand-name incentives, on the one hand, and for prompt approval of high quality and lower-cost generic drugs, on the other hand. The Pharmaceutical and Research Manufacturers of America (“PhRMA”) filed an amicus brief that falls in line with the “upending Hatch-Waxman” theme in the Takeda and Elliott briefs, but PhRMA also addressed Judge Jackson’s interpretation of FDC Act § 505(b)(2) in a more general and overarching sense (see our previous post ). 

Since our last update, FDA and Hikma (along with West-Ward) filed their Opening Briefs (here and here), and the Generic Pharmaceutical Association (“GPhA”) filed an amicus brief.

Both FDA and Hikma (West-Ward) argue that the Takeda and Elliott appeals are meritless and pointless, because the statute is clear and FDA is owed deference. As Hikma argues:

Appellants primarily ask this Court to rescind Hikma’s application to allow Takeda “to litigate any patent claims promptly, before FDA approves” the product. But Hikma did not invoke the Hatch-Waxman provision that triggers this pre-approval, patent resolution process. . . .  [U]nder the “quid pro quo” process established by Hatch-Waxman, Hikma owes no quid (a patent certification) for Takeda’s quo (the Colcrys® data).

For its part, Elliott advances an argument eschewed by Takeda—namely, that Hatch-Waxman does not even require such a quid pro quo. But as the district court recognized, “Elliott’s reading is a distortion of the statutory text, rather than a statement of its unambiguous plain meaning.” . . .

Aware of this difficulty, Takeda argues that even though Hikma did not rely on any Colcrys® data, FDA did—noting that the administrative record references Colcrys® “246 times.” But these references simply confirm that FDA diligently studied whether Hikma needed to rely on the Colcrys® data and, after thorough analysis, properly concluded that Hikma did not need to do so. . . .

Takeda alternatively asks the Court to rescind FDA approval on the ground that FDA failed to explain, in light of a prior citizen petition ruling, how the Mitigare® label safely omits the specific dose adjustments referenced in the Colcrys® labeling. But as the district court explained, this argument is “puzzling” given “the agency’s clear and convincing record statements about why it permitted the Mitigare label to differ from that of Colcrys.”  Appellants’ efforts to second-guess FDA’s approval are particularly misplaced given the high level of deference accorded to agencies’ safety-related scientific determinations.  [(Internal citations omitted)]

GPhA’s brief focuses on two arguments raised by Takeda and/or Elliott, and that PhRMA also commented on in its brief: (1) that FDA must require that a 505(b)(2) applicant identify as its listed drug, and therefore certify to patents claiming, the approved drug “most similar” to its test product; and (2) that Hikma/West-Ward was required to certify to the COLCRYS method-of-use patents listed in the Orange Book because a 505(b)(2) applicant is required to certify to any patents that claim the same use as the test product, including use patents for drug products other than the listed drug cited in a 505(b)(2) NDA.  (According to GPhA, PhRMA’s amicus brief “varies this argument slightly to claim that a 505(b)(2) applicant must certify to any patent for a product that is ‘essential’ to the test product’s approval, whether or not the patent was for the listed drug.)

As to the first issue, GPhA says that:

FDA has never adopted Takeda’s “most similar” test. The inflexible standard Takeda seeks conflicts with the text of section 505(b)(2) and FDA’s consistent interpretation that it is the responsibility of the 505(b)(2) applicant to determine which listed drug to reference and how best to combine FDA’s prior approval of the listed drug with new studies to secure a determination of safety and effectiveness from the agency.  By congressional design, the 505(b)(2) approach for listed drugs differs from the more defined and narrow “reference listed drug” (“RLD”) requirements [ANDAs] . . . . Takeda and [PhRMA] seek to impose a parallel RLD requirement for 505(b)(2) products that ignores these differences.

As to the second issue, GPhA says that:

Elliott’s and PhRMA’s interpretations fundamentally distort the basic Hatch-Waxman quid pro quo. The statute requires an applicant to certify to patents for a listed drug product as a price for being able to rely on FDA’s prior approval of that same product.  Elliott’s and PhRMA’s readings would grant brand companies windfall opportunities to delay competition through litigation on patents claimed for products that were not actually relied on by the 505(b)(2) applicant.

Both of Appellants’ statutory arguments, if accepted, would have far-reaching implications for 505(b)(2) products by expanding an applicant’s certification obligations—and, therefore, the ability of brand companies to delay competition from 505(b)(2) products through patent litigation—well beyond the parameters established by Congress and applied by FDA. The district court rejected Appellants’ construction of the FDCA and FDA regulations, and so too should this Court. [(Emphasis in original)]

In Reply Briefs (here and here) Takeda and Elliott press their respective arguments, saying that Appellees are practicing revisionist history when it comes to MITIGARE’s approval, and that FDA ignores the clear statutory mandate about patent certifications. The bottom line in the case when it comes to 505(b)(2) reliance, says Takeda, “is whether Colcrys data was necessary to FDA’s approval of Mitigare.”  “Although FDA claims in the alternative that it was not, the record belies that claim,” says Takeda.  

Although Oral Argument was initially set for February 12, 2016, that date was removed from the Court’s calendar. We’re still waiting on a date agreeable to the parties.