In Appeal Over Colchicine 505(b)(2) Approval, Plaintiffs-Appellants and PhRMA Allege Lower Court Decision Upsets Hatch-Waxman Scheme

September 10, 2015

By Kurt R. Karst –   

It’s been a while since we peeked in on 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 an Opinion and 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 some recent court docket activity to report on . . . and there’s more activity on the way in October. 

As we previously posted (here, , and ), Takeda is the holder of NDA 022352 for COLCRYS (colchicine) Tablets, 0.6 mg, which FDA approved to prevent and treat gout flares, and that is listed in the Orange Book with several unexpired patents.  The MITIGARE 505(b)(2) NDA did not cite COLCRYS as a listed drug relied on for approval, but rather a different drug: COLBENEMID, a fixed-dose combination drug product containing probenecid (500 mg) and colchicine (0.5 mg) FDA approved under NDA 012383 on July 27, 1961, that is no longer marketed, and for which no patents are listed in the Orange Book.  Takeda sued FDA alleging that the Agency’s approval of MITIGARE violates the FDC Act and the Administrative Procedure Act (“APA”) in several respects:

First, FDA acted arbitrarily and capriciously in approving Hikma’s Section 505(b)(2) application for Mitigare without requiring the label to contain critical safety information that FDA previously stated was necessary for single-ingredient oral colchicine products.  Second, FDA’s approval of Hikma’s application for Mitigare was unlawful, arbitrary and capricious because, as approved, Mitigare is not safe in light of the defects in its label.  And third, FDA’s failure to require Hikma to reference Takeda’s own colchicine drug, Colcrys®, in its application interfered with Takeda’s rights to participate in the administrative process, including the Paragraph IV certification process under the Hatch-Waxman Act and the Citizen Petition process.  [(Emphasis in original)]

Later, Elliott, which has investment interests in COLCRYS, filed a separate Complaint alleging that FDA’s approval of the MITIGARE NDA violated the FDC Act and the APA because Hikma was required to certify to patents listed in the Orange Book for COLCRYS.

Judge Jackson dismissed each of the allegations and ruled for FDA (and Intervenor-Defendants Hikma and West-Ward).  She nicely summarized her ruling on pages 31-32 of her 80-page Opinion:

[T]his Court concludes that Plaintiffs are wrong to characterize FDA’s actions with respect to Mitigare as unauthorized, unsafe, or unreasoned; to the contrary, it is clear on the record presented that FDA’s approval of Mitigare was consistent with the FDCA, the regulations the agency has promulgated pursuant to the FDCA, the Citizen Petition Responses FDA has issued, and the policies and practices under which the agency operates.  Furthermore, the record clearly reveals the reasonableness of FDA’s expert determination that Mitigare is safe and effective as labeled, and it supports the agency’s conclusion that Mitigare’s labeling best reflects current scientific information regarding the risks and benefits of Mitigare—a conclusion that, in any event, is entitled to a high degree of deference.  Consequently, Plaintiffs have failed to establish that summary judgment should be entered in their favor on their APA claims, and this Court finds that Defendants are entitled to summary judgment as a matter of law.

For more in-depth commentary and analysis of Judge Jackson’s decision and the issues presented in the case, see our previous post here.

In their Opening Briefs (here and here) filed in the D.C. Circuit, Takeda and Elliott pitch 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. 

Springboarding from Judge Jackson’s explanation that it’s not FDA’s reliance on the investigations underlying another drug product that triggers the 505(b)(2) patent certification requirement, but only a 505(b)(2) applicant’s reliance, Takeda frames FDA’s approval of the MITIGARE NDA as violating the APA in at least two ways:

First, FDA approved Hikma’s 505(b)(2) application without requiring Hikma to reference Colcrys and to make the Paragraph IV certifications required by statute.  Under Hatch-Waxman, a 505(b)(2) applicant must certify to patents for each previously approved drug “relied upon by the applicant for approval of the application.”  FDA emptied the statute of effect by permitting an applicant to certify only to those drugs expressly named in its application—even if FDA uses an unnamed drug’s data to approve the application.  That is inconsistent with the statutory text, with common sense, and with FDA’s longstanding interpretation that an applicant must certify to any drugs without which “the application cannot be approved.” . . .  And it is clear that Colcrys was necessary to Mitigare’s approval, despite Hikma’s gerrymandering of its application to avoid mentioning Colcrys. . . .

Second, FDA acted arbitrarily and capriciously in approving Hikma’s 505(b)(2) application without requiring the Mitigare label to include critical safety information it had previously deemed essential.  After Mutual’s groundbreaking studies, FDA determined that information about dose adjustments and a low-dose colchicine regimen was mandatory for all single-ingredient oral colchicine products’ labels.  The Mitigare label omits both types of information.  FDA gave no reasoned explanation for allowing those omissions.  [(Emphasis in original; citations omitted)]

Elliott’s arguments on appeal are more straightforward:

FDA’s approval of Mitigare without requiring certification to the Colcrys® use patents was arbitrary and capricious because it violated FDA’s own binding regulation.  21 C.F.R. § 314.50(i)(1)(iii)(B) requires a 505(b)(2) applicant to file “an applicable certification” if “the labeling of the drug product for which the applicant is seeking approval includes an indication that” according to the Orange Book “is claimed by a use patent.” Mitigare’s label contained an indication for “prophylaxis of gout flares.”  Takeda’s Colcrys® use patents are listed in the Orange Book as claiming that very indication.  FDA’s binding regulation accordingly required Hikma to certify whichever of the following was “applicable”: that Takeda had not submitted patent information to FDA, that the patents were expired, or that they were “invalid, unenforceable, or will not be infringed.”  Hikma filed no certification, and FDA’s acquiescence was an unlawful violation of its own regulation. . . .

FDA’s approval of Mitigare without requiring certification to the Colcrys® use patents also violated Section 505(b)(2) itself.  The plain language of the statute requires a 505(b)(2) applicant to certify to “each patent … which claims a use for such drug for which the applicant is seeking approval under this subsection.”  The Colcrys® use patents claim the use of colchicine for prophylaxis of gout flares, the precise use of colchicine for which Hikma sought approval.

The Pharmaceutical and Research Manufacturers of America (“PhRMA”), in an amicus brief filed late last month, falls in line with the “upending Hatch-Waxman” theme in the Takeda and Elliott briefs, but PhRMA also addresses Judge Jackson’s interpretation of FDC Act § 505(b)(2) in a more general and overarching sense:

The district court’s decision undermines Hatch-Waxman’s grand bargain by permitting section 505(b)(2) applicants to obtain the Act’s benefits without shouldering any of the corresponding burdens.  Specifically, the district court concluded that a section 505(b)(2) applicant may obtain approval of a follow-on drug—without providing the required patent certification—by omitting any mention of the pioneer drug in its application and relying on FDA to fill in the blanks.  That interpretation cannot be squared with the Act’s structure and purpose. . . . 

The decision below also conflicts with FDA’s regulations and guidance.  First, the district court assumed that a section 505(b)(2) applicant “relie[s] upon” one and only one pioneer drug, but FDA has made clear that section 505(b)(2) applications may rely on more than one drug.  Second, the district court incorrectly concluded that a section 505(b)(2) applicant faces no constraints in deciding which pioneer drug (or drugs) it will “rel[y] upon.”  While applicants have some freedom of choice, FDA has limited that flexibility by concluding that a section 505(b)(2) application may implicitly rely upon a similar pioneer drug.  Third, the district court failed to observe the rule that a section 505(b)(2) applicant may rely on the fact of a pioneer drug’s approval, but not the confidential data underlying that approval. 

FDA’s Opening Brief is due to the D.C. Circuit on October 16, 2015, as is the brief of Hikma/West-Ward.  Takeda and Elliott Reply Briefs are due on October 30, 2015.  We’ll be particularly interested in any discussion from FDA of the Agency’s February 6, 2015 proposed rule implementing certain provisions of the 2003 Medicare Modernization Act (see our previous post here), and specifically FDA’s proposal “to require a 505(b)(2) applicant to identify a pharmaceutically equivalent product, if already approved, as a listed drug relied upon, and comply with applicable regulatory requirements.”