District Court Tackles Sticky 505(b)(2) Application Issues in an Extensive Memorandum Opinion Involving Colchicine

By Kurt R. Karst –      

When Judge Ketanji Brown Jackson of the U.S. District Court for the District of Columbia noted in a January 12, 2015 Minute Order that the Court filed under seal a “lengthy opinion” on January 9, 2015 denying Motions for Summary Judgment from Takeda Pharmaceuticals U.S.A., Inc. (“Takeda”), the holder of NDA 022352 for COLCRYS (colchicine) Tablets, 0.6 mg, and Elliott Associates, L.P., Elliott International, L.P., and Knollwood Investments, L.P. (collectively “Elliott”), entities with investment interests in COLCRYS, in a dispute stemming from FDA’s September 26, 2014 approval of a 505(b)(2) application (NDA 204820) submitted by Hikma Pharmaceuticals LLC (“Hikma”) and its partner, West-Ward Pharmaceutical Corp. (“West-Ward”), for MITIGARE (colchicine) Capsules, 0.6 mg, for prophylaxis of gout flares, she wasn’t kidding.  Judge Jackson’s decision, which was unsealed earlier this week, comes in at 80 pages long, including a table of contents.  It’s one of those must-read opinions for Hatch-Waxman practitioners.  Not only is the decision well written, but it’s the first ever court decision to attempt to untangle some of the knotty issues involving 505(b)(2) applications, including FDA statements concerning the “choice of listed drug” for 505(b)(2) applicants.  And Judge Jackson’s opinion is unlikely to be the last word on the issue.  On January 20, 2015, Takeda and Elliott each filed a Notice of Appeal (here and here) to the U.S. Court of Appeals for the District of Columbia Circuit.

We previously discussed the colchicine dispute in a post last October when Takeda first filed suit (), and again earlier this month () when Judge Jackson issued her January 9th Order denying Motions for Summary Judgment from Takeda and Elliott and granting Cross-Motions for Summary Judgment from FDA and Hikma/West-Ward.  This post focuses on Judge Jackson’s Memorandum Opinion, which is summed up as follows (pages 31-32):

[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 [Administrative Procedure Act] (APA)] claims, and this Court finds that Defendants are entitled to summary judgment as a matter of law.

The Issues 

Both Takeda and Elliott make myriad arguments challenging the propriety of FDA’s approval of the MITIGARE 505(b)(2) application.  Here’s how Judge Jackson characterizes those issues in her Opinion: 

First, both Takeda and Elliott steadfastly maintain that FDA should not have approved Mitigare without requiring West-Ward to certify to the Colcrys patents that cover the use of colchicine for the prophylaxis of gout flares, with Takeda asserting that the agency relied on Colcrys’s data to approve Mitigare and thus FDA’s failure to require West-Ward to reference Colcrys and certify to the Colcrys patents violated the agency’s own procedural rules, and Elliott arguing additionally that the agency’s failure to require West-Ward to certify to the Colcrys patents without regard to any reliance on Colcrys contravened both the agency’s longstanding policies and the FDCA itself.  In addition, Takeda takes issue with Mitigare’s label, arguing that “[t]he Mitigare label contains neither the FDA-approved low-dose-treatment notation for acute gout nor the drug-drug interaction dosing adjustments, both of which FDA expressly required in light of the severe safety concerns it identified during the Colcrys review process.”  Consequently, Takeda contends that Mitigare is unsafe as labeled, and also that FDA’s approval of Mitigare constitutes an unreasoned change in the agency’s position regarding the requirements for the labeling of single-ingredient oral colchicine products.  Takeda also argues that “FDA’s failure to enforce its own labeling requirements allowed [West-Ward] to circumvent the statutory directive that it file a Paragraph IV certification to Takeda’s patents[.]” [(Internal citations omitted)]

Judge Jackson’s handling of each of these issues is discussed separately below.

Do FDA’s procedural rules require West-Ward to reference COLCRYS even though the West-Ward did not rely on COLCRYS data?

As an initial matter, Takeda’s assertion that FDA should have required West-Ward to cite COLCRYS as a listed drug and certify to relevant Orange Book patents is generally the same argument that Takeda’s predecessor in the COLCRYS NDA, Mutual Pharmaceutical Company, Inc. (“Mutual”), made to FDA in a 2010 Citizen Petition (Docket No. FDA-2010-P-0614).  There, Mutual asked FDA to refrain from approving any future 505(b)(2) application for a single-ingredient oral colchicine drug product that does not reference COLCRYS. 

FDA largely denied Mutual’s petition in a May 2011 response.  In doing so, FDA stated that a 505(b)(2) application for a single-ingredient oral colchicine product might not need to cite COLCRYS as its listed drug, regardless of similarities in strength, pharmacokinetic profile, or other characteristics (such as dosage form or conditions of use).  FDA also emphasized in the petition response that “[w]hether another 505(b)(2) application for a single-ingredient colchicine product that does not cite Colcrys as a listed drug could ever be appropriate will depend on the facts and circumstances of the particular application. . . .”

“Plaintiffs argue now that the facts and circumstances of Mitigare’s approval are such that the agency should have required a Colcrys reference and patent certifications, and that FDA arbitrarily and capriciously failed to do so,” wrote Judge Jackson.  Specifically:

Takeda asserts that FDA’s refusal to make West-Ward reference Colcrys and certify to the Colcrys patents violated two of the agency’s “procedural requirements”: (1) the requirement that a Section 505(b)(2) applicant reference another product if the agency itself relies on studies or data relating to that other product in approving the applicant’s application, and (2) the requirement that a Section 505(b)(2) applicant choose the “most appropriate” listed drug to be its reference drug.  Elliott makes the slightly different argument that FDA not only violated the agency’s own policies, its actions also breached the FDCA itself, which, according to Elliott, requires a Section 505(b)(2) applicant to certify to all method-of-use patents that claim a use for the drug substance for which the applicant is seeking approval.  [(Internal citations omitted)]

But Judge Jackson was unconvinced, and refused to accept Plaintiffs' argument that FDA arbitrarily and capriciously violated any requirements when the Agency approved the MITIGARE 505(b)(2) application.  “[T]his Court discerns no basis in law or fact for Plaintiffs’ insistence that FDA was legally required to force West-Ward to reference Colcrys and to certify to the Colcrys patents under the circumstances presented here,” wrote Judge Jackson.

Turning to the alleged procedural requirement that a 505(b)(2) applicant cite in its application as a listed drug relied on for approval an approved drug if FDA (but not the 505(b)(2) sponsor) relies on data or information from that approved drug in approving the 505(b)(2) application, Judge Jackson boiled Takeda’s reliance argument down to major corollaries:

(1) that, under FDA’s rules, “[t]he ultimate reference and certification obligations depend on whether FDA relies on other drug studies or data” regardless of whether the Section 505(b)(2) applicant does so, and

(2) that the instant administrative record shows that “FDA explicitly referenced and relied on the Colcrys data—over and over and over again—in approving Mitigare.”  [(Internal citation omitted; emphasis in original)]

Judge Jackson found Takeda wrong on both counts.  With respect to whether or not FDA reliance counts for 505(b)(2) listed drug purposes, Judge Jackson wrote:

[T]he contention that, under established agency policy, the patent certification requirement is triggered by the agency’s reliance on the investigations underlying another drug product is entirely unsupported. . . .  The key to understanding why Takeda’s agency-reliance argument fails is recognizing its linchpin: the proposition that, without “a right of reference or use,” FDA lacks the authority to review or access third-party data from a previously approved new drug application when it is evaluating a Section 505(b)(2) new drug application.

Her opinion goes on to note that Congress used the phrase “right of reference or use” in passing FDC Act § 505(b)(2) to “expressly appl[y] only to the Section 505(b)(2) applicant,” and that it “pertains only to what application materials such sponsor is required to submit.”  “And just as the statute says nothing about the circumstances under which FDA can, or cannot, consult third-party data when it makes a scientific determination regarding whether or not to approve a Section 505(b)(2) application, the ‘right of reference’ definition that the agency provides in 21 C.F.R. § 314.3 is similarly silent on the issue of whether the agency itself needs such a ‘right’ before it can” reference data in a previously approved NDA when acting on another applicant’s 505(b)(2) application. 

Moreover, wrote Judge Jackson:

Surely the prior applicant’s voluntary submission of its proprietary data to FDA waived any right that applicant may have had to prohibit FDA from “open[ing] th[e] locked file drawer” to access the applicant’s data in the future.  And to extent that a drug sponsor’s proprietary data contributes to the general body of scientific knowledge about what a particular pharmacological agent is or does, it is not at all clear that it would even be feasible to prevent FDA’s scientists from applying that knowledge when other new drug applications are considered in the future.  [(Internal citation omitted; emphasis in original)]

That first sentence might raise some eyebrows among those in the brand-name industry, particularly given previous FDA statements on the matter (see, e.g., here).

In any case, and notwithstanding Judge Jackson’s conclusions about FDA versus 505(b)(2) applicant reliance, she says that “[e]ven if one were to accept Takeda’s legal argument that the agency’s reliance on third-party studies and data gives rise to an obligation on the part of the agency to require the applicant to reference the relied-upon drug product and certify to its patents, this Court concludes that the record here does not demonstrate FDA ‘reliance’ on Colcrys” in the Agency’s approval of the MITIGARE 505(b)(2) application “in the relevant sense.”

Does a 505(b)(2) applicant have a right to choose which approved drug is (or is not) most appropriate or most similar to cite (or not) as a listed drug relied on for approval?

Turning to Plaintiffs’ next alleged “procedural requirement” argument – that FDA violated a “choice of listed drug” requirement in approving MITIGARE without requiring a reference (and patent certifications) to COLCRYS because it is most similar to MITIGARE – Judge Jackson analyzes various FDA responses to relevant Citizen Petitions and uses them to pick apart Plaintiffs’ argument:

[T]heir argument hinges on the existence of an FDA drug reference policy that does not exist. . . .  When all of the agency’s statements are read in context, [] it is clear that FDA’s policy is to view the “most appropriate” drug to be whatever drug fills in the gaps in the data the drug sponsor submits to support the sponsor’s contention that the drug is safe and effective, and not whatever listed drug is most similar in nature to the one the applicant proffers. . . . 

The bottom line is this: FDA’s prior statements confirm that, other than where duplicate drug products are involved, a Section 505(b)(2) applicant has the discretion to select a reference drug, and to make that selection in relation to the scope of the materials the applicant desires to submit.  Thus, to the extent that the agency has any “policy” about what drug should be referenced in a Section 505(b)(2) application, FDA has decided to leave it up to the drug sponsor to determine whether the sponsor would like to do less work and rely on a very similar drug, or do more work and rely on a dissimilar drug.  [(Internal citations omitted; emphasis in original)]

FDA’s “choice of listed drug” policy is one that we’ve commented on before in our post “FDA’s House Rules on 505(b)(2) NDA Choice of Listed Drug; How Does it Affect Dealer’s Choice?”  As noted there, we think there’s room in the 505(b)(2) space for an applicant to argue that even where there is an approved pharmaceutical equivalent, such drug does not necessarly have to be cited by a 505(b)(2) applicant as a listed drug relied on for approval.  The policy is also at issue in a recent Citizen Petition (Docket No. FDA-2014-P-2188) concerning abuse-deterrent immediate-release oxycodone tablets.

Does the FDC Act unambiguously require a 505(b)(2) applicant to certify only to patents associated with the RLD?

“Yes,” says Judge Jackson in response to Elliott’s argument that the text of the FDC Act required West-Ward to certify to the various patents listed in the Orange Book for COLCRYS regardless of whether or not West-Ward did relied on COLCRYS for the MITIGARE approval.  In revisiting the debate as to whether the word “drug” in the statute means a particular drug product, or, more generally, a drug substance, Judge Jackson sets up the issue as follows:

The statutory question that Elliott raises here is, in essence, whether 21 U.S.C. § 355(b)(2)(A) requires not only certification to those patents that claim the drug product on whose investigations the 505(b)(2) applicant relied (i.e., the reference listed drug), but also certification to all patents that claim a method of using the drug substance (i.e., the active ingredient) in the new drug product that the applicant has proffered for approval.  [(Emphasis in original)]

Her Chevron analysis ends at Step One:

[T]his Court finds that Congress’ intent regarding the scope of a Section 505(b)(2) applicant’s patent certification obligation is clear on the face of the statute: such applicant need only certify to the product patents or the method-of-use patents that are associated with the reference listed drug (i.e., the drug product on whose investigations the 505(b)(2) applicant relies).

We’ll leave it to you to go through the sepcifics of Judge Jackson’s analysis on pages 52-65 of the opinion. 

Is the MITIGARE approval an unreasoned change of FDA policy concerning single-ingredient oral colchicine drug products, and do certain safety-related labeling differences call into question FDA”s approval of MITIGARE?

In the final two sections of her decision, Judge Jackson moves out of the listed drug/patent certification space and into the drug labeling space.  First, Takeda questioned FDA’s approval of MITIGARE with labeling that differs from COLCRYS with respect to certain drug-drug interactions, and in light of certain FDA statements in the Agency May 2011 Citizen Petition response.  Judge Jackson didn’t bite:

Given that FDA never promised in the Colchicine Citizen Petition Response to require that Colcrys’s drug-drug interaction table appear on all future products, and also that the agency did engage in precisely the kind of individualized assessment of Mitigare’s label that the Colchicine Citizen Petition Response said would be required regarding single-ingredient oral colchicine products in the future, FDA’s conclusion that Mitigare did not need to include the same low-dose requirements as appear on Colcrys’s label was hardly a change of FDA’s position, much less an “arbitrary” or “capricious” deviation from its prior policy.

Although a closer question was presented in the context of certin FDA statements and “the extent to which the labels of future single-ingredient oral colchicine products approved for the prophylaxis of gout flares must provide information about the use of the product for the treatment of acute gout flares,” Judge Jackson concluded that “[t]o the extent that FDA’s decision to approve Mitigare without a label that included Colcrys’s AGREE trial regimen can be viewed as a departure from the agency’s prior position, this Court concludes that it was not an unreasoned change in position in violation of the APA, because the record clearly reflects the agency’s well-reasoned and well-supported rationale for reaching this conclusion.”  (Internal citation omitted.) 

Second, Takeda argued that the MITIGARE approval was arbitrary and capricious because the drug product is not safe in light of certain labeling deficiencies.  Judge Jackson quickly dispensed with this matter by deferring to FDA’s scientific judgment:

[FDA’s] scientific determination that Mitigare is safe and effective as labeled is entitled to the highest degree of deference, meaning that, even if this Court had the expertise to reevaluate FDA’s safety and efficacy decision, it could not freely supplant the agency’s scientific judgments about what a drug product’s label must include in order to ensure safe use of that product, any more than it could roll up its sleeves and dig into the data or run its own clinical experiments in order to determine whether FDA was wrong to conclude that such drug product was, in fact, safe.

We anticipate a lively debate as this case moves on to the D.C. Circuit.  And we’ll be keeping a close eye on it.