KETANJI BROWN JACKSON, United States District Judge.
A. Colchicine: A Drug For The Treatment Of Gout . . . 69
B. FDA's Drug Approval Framework: The Hatch-Waxman Amendments . . . 71
1. NDAs, ANDAs, and 505(b)(2) NDAs. . . 71
2. The Patent Certification Requirement. . . 72
3. The Labeling Requirements . . . 73
C. FDA's Approval Of Colcrys (A Colchicine Tablet) . . . 74
1. Mutual Relies On ColBenemid, Published Literature, And Its Own Clinical Studies To Support The Colcrys Application For Acute Flares Of Gout . . . 74
2. Mutual Relies on ColBenemid and Published Literature To Support The Colcrys Application For Prophylactic Treatment of Gout . . . 76
3. FDA Takes Enforcement Action Against Unapproved Oral Colchicine Products Because Their Labels Do Not Reflect The Most Current Data . . . 76
D. FDA's Approval Of Mitigare (A Colchicine Capsule) . . . 77
1. Mutual Files A Citizen Petition Protesting West-Ward's Application And FDA Responds . . . 77
2. FDA Approves Mitigare Capsule For Prophylaxis Of Gout Flares Based On Col-Probenecid, Published Literature, and West-Ward's Own Studies . . . 79
3. West-Ward Launches Mitigare, Alerting Takeda To The Existence Of Mitigare. . . 80
E. Procedural History . . . 80
A. FDA's Approval Of Mitigare Without A Colcrys Reference And Related Certifications To The Colcrys Patents Did Not Violate The Agency's Rules Or The FDCA. . . 84
1. FDA's Procedural Rules Did Not Require West-Ward To Reference Colcrys Because West-Ward Did Not Rely On Colcrys Data To Support West-Ward's Application For FDA Approval Of Mitigare . . . 85
a. No FDA Policy Establishes That FDA's Reliance—As Opposed To That Of The Section 505(b)(2) Applicant—Gives Rise To Patent Certification Obligations. . . 86
2. Under FDA's Procedural Rules, An Applicant—Not FDA—Has The Right To Choose The "Most Appropriate" Or "Most Similar" Reference Drug For Its 505(b)(2) Application . . . 92
3. The FDCA Unambiguously Requires A Section 505(b)(2) Applicant To Certify Only To Patents Associated With The Reference Listed Drug . . . 95
B. FDA's Approval Of Mitigare Was Not An Unreasoned Change Of The Agency's Prior Position Regarding Single-Ingredient Oral Colchicine Products . . . 103
C. FDA's Decision To Approve Mitigare With A Label That Contains Safety Information That Differs From Colcrys Was Not Arbitrary And Capricious . . . 107
IV. CONCLUSION . . . 108
The Hatch-Waxman Amendments to the Food, Drug, and Cosmetic Act ("FDCA"), Pub. L. No. 98-417, 98 Stat. 1585 (1984), "balance two competing interests in the pharmaceutical industry: (1) inducing pioneering research and development of new drugs and (2) enabling competitors to bring low-cost, generic copies of those drugs to market." Janssen Pharmaceutica, N.V. v. Apotex, Inc., 540 F.3d 1353, 1355 (Fed.Cir.2008) (internal quotation marks and citation omitted). Hatch-Waxman achieves this balance, in part, by allowing new applicants for drug approval to rely on research and data that an innovator company generates so long as the new applicant "references" the innovator's drug and "certifies" to the innovator's patents. See infra Part I.B.2; see also 21 U.S.C. § 355(b)(2)(A). Plaintiffs Takeda Pharmaceuticals U.S.A., Inc. ("Takeda") and Elliott Associates, L.P., Elliott International, L.P., and Knollwood Investments, L.P. (collectively, "Elliott") allege that the Food and Drug Administration ("FDA") upset Hatch-Waxman's careful balance when the agency approved an application that Hikma Pharmaceuticals PLC ("Hikma") submitted through its U.S. agent West-Ward Pharmaceuticals Corp. ("West-Ward") for a gout medication named Mitigare. Mitigare is a single-ingredient 0.6 milligram ("mg") oral colchicine drug product that is substantially similar to Plaintiffs' colchicine drug, Colcrys, which FDA approved five years prior to Mitigare based in part on research studies that Takeda's predecessor Mutual Pharmaceutical Company, Inc. ("Mutual") conducted. In seeking approval for Mitigare, West-Ward neither referenced Colcrys nor certified to the Colcrys patents, and Hikma has now authorized West-Ward to market a generic version of Mitigare that will compete with—and cost less than—Plaintiffs' Colcrys.
In the separate but consolidated complaints that Takeda and Elliott have filed in this Court against Defendants Sylvia Mathews Burwell (in her official capacity as Secretary of the Department of Health and Human Services) and Margaret Hamburg (in her official capacity as head of the FDA), Plaintiffs maintain that FDA's approval of Mitigare without a Colcrys reference or the related patent certifications violates the Administrative Procedure Act ("APA") because that approval was inconsistent with the agency's procedural rules and the certification provisions of the FDCA. Plaintiffs also claim that FDA's approval of Mitigare was arbitrary and capricious because Mitigare's label lacks certain safety information that is on the Colcrys label—information that is related to Mutual's research and that FDA previously suggested should be on the label of future colchicine drug products. The lawsuits
Before this Court at present are four cross-motions for summary judgment that the Plaintiffs, the Defendants, and the Defendant-Intervenors have submitted in the context of the two pending actions.
The instant dispute involves two drug products, both of which have the active ingredient colchicine, which is a pharmacological substance that has been used historically for the treatment of gout.
Doctors have used colchicine—an agent derived from the Colchicum Autumnale plant—to treat gout for centuries. (See Admin. R. (hereinafter, "AR") at 3 ("The
Consistent with colchicine's long history, drug manufacturers in the United States marketed a variety of forms and dosages of colchicine for decades prior to Congress's 1962 enactment of amendments to the FDCA that required FDA to "approve" a drug—i.e., to make findings that a drug is safe, effective, and properly labeled—prior to marketing. (See AR at 50, 255); see also Peter Barton Hutt, et al., Food and Drug Law 577 (3rd ed.2007).
Just as combination colchicine products were legally marketed and sold for many years in the pre-approval era, "[s]ingle-ingredient colchicine tablets"—tablets that contain only colchicine and are not combined with another drug—"were available for decades as marketed but unapproved products, in 0.6 mg strength." (Id. at 668.) The practice of marketing single-ingredient colchicine products as an unapproved drug continued even after Congress required premarket approval of drugs (see id. at 421), and it persisted until at least 2006, when "FDA announced a new drug safety initiative to remove unapproved marketed drugs from the market" (id. at 349). FDA undertook this initiative with
In brief, Hatch-Waxman requires drug manufacturers seeking to market a new drug to first obtain FDA approval via one of three different application pathways: (1) a full New Drug Application ("NDA"); (2) an Abbreviated New Drug Application ("ANDA"); or (3) an intermediate process known as a Section 505(b)(2) NDA. See 21 U.S.C. § 355; see also, e.g., Ethypharm S.A. France v. Abbott Labs., 707 F.3d 223, 226-27 (3d Cir.2013) (describing the three different approval methods).
The full NDA process, see 21 U.S.C. § 355(b)(1), requires the manufacturer to submit detailed safety and efficacy data for the drug, including, among other things, "full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use" (i.e., clinical trials); all components of the drug; the methods used for the drug's manufacture, processing, and packing; examples for proposed labeling for the drug; and any patents claimed in relation to the drug. See 21 U.S.C. §§ 355(b)(1)(A), (B), (D), (F), (G). This path is used by drug manufacturers for "new branded drug[s]," Ethypharm S.A. France, 707 F.3d at 226, which are sometimes called "pioneer" or "innovator" drugs.
A drug manufacturer may also choose to file an Abbreviated New Drug Application ("ANDA") pursuant to 21 U.S.C. § 355(j). The ANDA process facilitates efficient approval of generic versions of pioneer drug products that have already been determined to be safe and effective. Rather than requiring generic manufacturers to conduct expensive and time consuming clinical trials, the ANDA process allows the manufacturer to rely on the clinical trials already performed in connection with the approval of the previously approved drug, provided that the generic manufacturer can show that its drug has the same relevant characteristics (including, inter alia, the same labeling, active ingredient, route of administration, dosage form, strength, and bioequivalency). See 21 U.S.C. § 355(j)(2)(A). In other words, an ANDA does not attempt to demonstrate safety or effectiveness; instead, the applicant's only goal is to establish that the generic product is equivalent to another drug that is already known to be safe and effective. Thus, this path is used by drug manufacturers "for the introduction of generic versions of previously approved branded drugs." Ethypharm S.A. France, 707 F.3d at 227.
The Section 505(b)(2) NDA is a sort of hybrid of the other two pathways.
Because development of a new drug product is notoriously "expensive and time-consuming[,]" Pfizer Inc. v. Shalala, 182 F.3d 975, 976 (D.C.Cir.1999), Congress has concluded that the statutory scheme should include effective incentives for innovation such as patent protection for the substantial "investments necessary to research and develop new drug products" that pioneering companies undertake, Mylan Pharm., Inc. v. FDA, 454 F.3d 270, 272 (4th Cir.2006) (internal quotation marks omitted). With property rights comes the potential for price manipulation, however; and Congress is also perpetually concerned about drug manufacturer monopolies and the rising prices of prescription drugs. The Hatch-Waxman Amendments to the FDCA are aimed at "strik[ing] a balance between [creating] incentives. . . for innovation," on the one hand, and "quickly getting lower-cost generic drugs to market[,]" on the other. Teva Pharm. Indus. Ltd. v. Crawford, 410 F.3d 51, 54 (D.C.Cir.2005). This balance is reflected in statutory process for the FDA's approval of new drugs.
Specifically, the Hatch-Waxman Amendments mandate that the FDA must record patent information about approved drug products in a publication entitled "Approved Drug Products with Therapeutic Equivalence Evaluations," which is generally called the "Orange Book," after the color of its cover.
Notably, patent certifications are essentially promises that relate to the status of the drug product's patents, as known or understood by the applicant: (I) no such patents exist, (II) any such patents have expired, (III) the proposed drug will not be marketed before the patents expire, or (IV) any such patents are invalid or will not be infringed by the proposed drug. See id. § 355(b)(2)(A)(i)-(iv). This last requirement—often referred to as a "Paragraph IV certification"—is particularly relevant here because Mutual and its affiliates received numerous patents directed to colchicine. Seventeen of these patents are listed in FDA's Orange Book for Colcrys, and the earliest of the Colcrys patents expires on October 6, 2028.
In addition to the obligation to reference the drug upon which the 505(b)(2) application relies and certify to its patents, a 505(b)(2) applicant must also provide notice of any Paragraph IV certification to owner of the RLD and each patent owner, explaining the factual and legal basis for the applicant's opinion that the patent is invalid or not infringed. See 21 U.S.C. § 355(b)(3)(C)-(D). This notice enables the owners of the RLD and its related patents to litigate the patent issue before FDA approves the 505(b)(2) NDA applicant's new drug product.
Thus, Congress has permitted new drug applicants to piggyback on the approved research of prior drug manufacturers—and thus forgo costly and time-consuming studies aimed at proving the safety and effectiveness of drug substances that have already been approved—in exchange for requiring those applicants to notify the owners of the drug that the new applicant relies upon so that the drug owner has an opportunity to take steps to protect its patent rights. See Abbott Labs. v. Young, 920 F.2d 984, 985 (D.C.Cir.1990) ("Facing the classic question of the appropriate trade-off between greater incentives for the invention of new products and greater affordability of those products, Congress struck a balance [in the Hatch-Waxman Amendments] between expediting generic drug applications and protecting the interests of the original drug manufacturers.").
In addition to selecting an approval path, as part of the Hatch-Waxman drug approval process drug sponsors must submit to FDA for approval the "proposed text of labeling," 21 C.F.R. § 314.50(c)(2)(i); see also 21 U.S.C. § 355(b), including "adequate directions for use," 21 U.S.C. § 352(f)(1). The labeling must contain all material facts and adequate warnings, and the product must be safe for the uses indicated in the labeling. Id. §§ 321(n), 352(f), and 352(p). FDA evaluates the information included in the text of the proposed labeling and has
When FDA finally undertook vigorous enforcement of Hatch-Waxman's drug approval protocol in 2006, colchicine drug products that had previously been marketed as prescription drugs but had not gone through the new approval process were among the many types of pharmaceuticals that were forced to exit the market. (See AR at 5, 349.) The two drug companies that are at odds in the instant dispute—Takeda (previously Mutual) and Hikma (in conjunction with its U.S. agent West-Ward)—had both previously marketed colchicine products as prescription drugs in the U.S., and both companies sought to have those products approved for re-entry into the marketplace.
On July 31, 2006, Mutual met with FDA to discuss the new regulatory requirements and to get information regarding what would be necessary to bring Mutual's colchicine drug product into compliance with the statutory and regulatory scheme. (See id. at 5.) Because of the wealth of pre-existing information concerning the use of colchicine for the treatment of gout and FDA's prior approval of combination colchicine products like ColBenemid and Col-Probenecid, Mutual discovered that it did not need to submit full NDAs supporting the safety and effectiveness of Colcrys for the treatment of gout. (See id. at 5-9.) Instead, Mutual submitted two successive 505(b)(2) NDAs in order to have its 0.6 mg single-ingredient oral colchicine tablet Colcrys approved for two indications: the treatment of acute gout flares and the prophylaxis of gout flares. (See id. at 668.)
Mutual's first Section 505(b)(2) application for Colcrys, which requested approval of a 0.6 mg single-ingredient oral colchicine tablet for treatment of acute gout flares, identified the combination drug product ColBenemid as the reference listed drug. (See id at 7.) In addition, Mutual's application cited FDA's earlier finding that ColBenemid is effective for the chronic treatment of gout, and also relied on published literature about the use of colchicine. Mutual also conducted its own research; specifically, it sponsored two sets of studies that contributed to the existing body of knowledge about the potential toxicity of colchicine.
Mutual's Acute Gout Flare Receiving Colchicine Evaluation trial ("the AGREE trial") was a "randomized, double-blind,
Mutual also conducted certain drug-drug interaction studies ("DDI studies") comparing colchicine administered alone with colchicine administered in conjunction with other drugs. (Id.) Such drugs included cytochrome P4503 ("CYP3A4") inhibitors and Pglycoprotein ("P-gp") inhibitors—pharmaceuticals that can affect the mechanisms that the body uses to metabolize colchicine, and thus were already known to have the potential of leading to toxic colchicine blood levels. (Id. at 50, 58-60, 668.) As a result of its DDI studies, Mutual developed a new dosing regimen for concomitant use of Colcrys with certain CYP3A4 inhibitors and P-gp inhibitors. Thus, although the potential for adverse reactions from the interaction of certain drugs with colchicine was already well-known prior to Mutual's research, Mutual's DDI studies "allowed for a more precise quantitative assessment of the interactions." (Id. at 668; see also id. at 50 (summarizing dose modifications developed by Mutual).)
FDA approved Mutual's 505(b)(2) NDA for Colcrys for the treatment of acute gout flares on July 30, 2009. (See AR at 6.) On that same day, based on Mutual's AGREE trial and DDI studies, FDA issued a related drug safety communication for healthcare providers (an "FDA Alert"). See FDA, Information for Healthcare Professionals: New Safety Information for Colchicine (marketed as Colcrys) (July 30, 2009).
Approximately three months after the FDA Alert was issued, on October 16, 2009, FDA approved a second Colcrys application, this time for the prophylaxis of gout flares. (See id. at 8.) Unlike Mutual's application for approval of Colcrys for the treatment of acute gout flares, Mutual's application for Colcrys for the prophylaxis of gout flares did not include new studies in support of the safety and efficacy of the drug product. (Id.) Instead, Mutual's assertion that Colcrys is a safe treatment for the prophylaxis of gout flares was based on "an assessment of adverse events from the worldwide literature and postmarketing adverse event databases" and "cross-reference to Mutual's earlier colchicine NDAs." (Id.) Mutual's assertion that Colcrys is an effective treatment for the prophylaxis of gout flares "was based entirely on the published literature, including published reports of two randomized, controlled trials of colchicine for this indication and the DESI finding for ColBenemid" (id. at 22-23 (footnote omitted)).
On September 30, 2010—nearly one year after Colcrys was approved for prophylaxis of gout flares—"FDA announced its intention to take enforcement action against unapproved single-ingredient oral colchicine products and persons who manufacture or cause the manufacture of such products or their shipment in interstate commerce." (Id. at 9.) This action was part of the broader initiative that the agency had launched in 2006 against unapproved marketed drugs generally, and with respect to colchicine products in particular, FDA remarked that "the labeling for unapproved single-ingredient oral colchicine products listed with FDA . . . does not reflect the most current data regarding the safety and effectiveness of single-ingredient oral colchicine." See Single-Ingredient Oral Colchicine Products; Enforcement Action Dates; Notice, 75 Fed. Reg. 60768 at 60769-70 (effective October 1, 2010); see also FDA News Release, "FDA orders halt to marketing of unapproved single-ingredient oral colchicine" (Sept. 30, 2010).
Notably, the agency expressed a particular concern with how the labels of unapproved colchicine products dealt with the use of colchicine for the treatment of acute gout flares and potential drug-drug interactions—the two areas that Mutual had studied and had specifically addressed in the Colcrys label. Unlike Colcrys, the labels of unapproved colchicine products generally used vague warnings suggesting "avoidance when possible and caution when necessary, with vigilant monitoring of clinical signs of toxicity." (AR at 668.) By contrast, consistent with the findings of Mutual's DDI studies and AGREE trial, the Colcrys label contained both: (1) a two-page table of dose modifications intended to help mitigate the risk of colchicine toxicity for patients taking Colcrys in combination with the drug products listed in the table (see Compl. Ex. 5 at 5-6), and (2) a low dose regimen of colchicine for treatment of acute gout flares that occur while colchicine is already being used to
West-Ward removed its unapproved single-ingredient 0.6 mg colchicine tablet from the market in response to FDA's enforcement announcement, just as Mutual had done. (AR at 50.) West-Ward had been marketing its 0.6 mg single-ingredient oral colchicine tablet since the early 1970s. (Id.) In an attempt to comply FDA's new approval scheme and announced enforcement measures, West-Ward submitted a Section 505(b)(2) application to FDA for approval of its pre-existing colchicine tablet. (Id. at 50-51.) Before filing its application, however, West-Ward specifically inquired of FDA whether the agency would entertain a 505(b)(2) application for a colchicine tablet that referenced and relied upon Col-Probenecid, rather than Mutual's recently-approved Colcrys, and the agency answered in the affirmative. (See id. at 6.) It is undisputed that West-Ward wanted to cite Col-Probenecid instead of Colcrys because, unlike Colcrys, Col-Probenecid is not tied to any patents that would require West-Ward to submit a Paragraph IV certification that would delay the approval and re-marketing of West-Ward's colchicine product.
West-Ward filed the aforementioned Section 505(b)(2) application for approval of a colchicine tablet that referenced Col-Probenecid in August 2010. (See AR at 50.) Although FDA's new drug approval process is confidential, Mutual learned of West-Ward's application through public sources while approval was pending. (Compl., Takeda Pharms. U.S.A., Inc. v. Burwell, No. 14-1668-KBJ (D.D.C. Oct. 6, 2014), ECF No. 1, ¶ 35.)
On November 26, 2010, Mutual filed a "citizen petition" with FDA regarding the agency's requirements for ANDAs and Section 505(b)(2) NDAs for colchicine tablets.
(1) "[r]efrain from filing or approving any application for a 0.6 mg oral colchicine tablet with a proposed indication already approved for Colcrys (i.e., a "duplicate" of Colcrys) that is not submitted as an ANDA";
(2) "[r]efrain from filing or approving any ANDA or 505(b)(2) application for a single-ingredient oral colchicine product that does not reference Colcrys and include certifications to the patents listed in FDA's [Orange Book] for Colcrys;" and
(3) "[r]equire the labeling for any single-ingredient oral colchicine product to include all information related to drug-drug interactions that is in the Colcrys labeling, including relevant dose adjustments needed to prevent unnecessary toxicity[.]" (AR at 1.) In other words, Mutual asked FDA to mandate that every
On May 25, 2011, FDA responded to Mutual's Citizen Petition, granting the petition in part and denying it in part. (See id. at 2.) For present purposes, FDA made three significant decisions. First, the Colchicine Citizen Petition Response sustained Mutual's objections to West-Ward's 505(b)(2) application for a 0.6 mg single-ingredient colchicine tablet that was identical to Colcrys. FDA acknowledged that it had previously advised West-Ward that West-Ward could submit an application for its 0.6 mg single-ingredient colchicine tablet via the 505(b)(2) pathway and without referencing Colcrys, but admitted in the Response that the agency had been "incorrect" about that, and added that "FDA regrets that [] advice to West-Ward." (Id. at 17.) Thus, FDA granted Mutual's request that the agency require any application for a single-ingredient oral colchicine product that was identical to Colcrys "be submitted as an ANDA that cites Colcrys as the RLD and complies with applicable regulatory requirements." (Id. at 2-3.) FDA also stated that the West-Ward application needed to be withdrawn and resubmitted as an ANDA (see id. at 11-16).
Second, FDA's Citizen Petition Response addressed Mutual's broader contention that any single-ingredient colchicine product—not just a 0.6 mg tablet such as the one submitted by West-Ward—"must necessarily cite Colcrys as its listed drug, irrespective of whether the proposed product shares the same strength, pharmacokinetic (PK) profile, or other characteristics such as dosage form or conditions of use." (Id. at 3.) FDA denied this request. (See id.) The agency explained that a drug product that differs from Colcrys in one of the above listed ways is not a "duplicate" of Colcrys and therefore presents a different set of circumstances than West-Ward's admittedly incorrect 505(b)(2) application for a 0.6 mg single-ingredient oral colchicine tablet that did not reference Colcrys.
Third, FDA's Citizen Petition Response described what type of information FDA would require for the label of a single-ingredient oral colchicine product. With respect to label information about concomitant use of colchicine with other drugs, FDA commented that "Mutual's drug-drug interaction studies [had] provided new, quantitative information about the extent of changes in exposure that can occur with co-administration of certain drugs with colchicine." (Id. at 19.) Thus, the label "for any single-ingredient oral colchicine product needs to include adequate information on drug-drug interactions, including relevant dose adjustments needed to prevent unnecessary toxicity." (Id. at 3.) As for the use of colchicine to treat the acute flares of patients who were already taking colchicine for prophylaxis, FDA stated that "the labeling for a single-ingredient colchicine product seeking approval for prophylaxis of gout flares must inform healthcare providers that the lower dose colchicine regimen evaluated in the AGREE trial is adequate to treat an acute gout flare that may occur during chronic colchicine use[.]" (Id. at 3.)
After FDA determined that it was unacceptable for West-Ward to submit a Section 505(b)(2) application for a colchicine tablet that was a duplicate of Colcrys, as explained above, West-Ward reformulated its product, and submitted a new 505(b)(2) application for a colchicine capsule named Mitigare. West-Ward's application for Mitigare relied on published literature about colchicine, FDA's findings of safety and effectiveness from Col-Probenecid, and new clinical pharmacology studies West-Ward conducted. (See AR at 108.) This application differed from West-Ward's earlier application for a single-ingredient colchicine product in at least two significant ways.
First, Mitigare is a capsule, not a tablet. Like Colcrys, Mitigare contains 0.6 mg of colchicine administered orally, but the difference in dosage form means that Mitigare is not a duplicate of Colcrys, and as a result, FDA permitted West-Ward to file its application for Mitigare using the 505(b)(2) pathway rather than the ANDA pathway. (See Ex. 11 to Takeda Compl., ECF No. 1-1, at 217-32, FDA Ctr. for Drug Evaluation & Research, Guidance for Indus.: Appls. Covered By Sec. 505(b)(2), Draft Guidance (Oct. 1999) at 6 (noting that "[a]n application that is a duplicate of a listed drug and eligible for approval under section 505(j)" "can't be submitted as 505(b)(2) application").)
Second, West-Ward conducted new DDI studies to support its application. In an effort to produce a single-ingredient oral colchicine product that did not reference Colcrys or rely upon Mutual's data, West-Ward commenced a development program that FDA recommended in which West-Ward sponsored DDI studies similar to Mutual's but involving a different set of CYP3A4 and P-gp inhibitor drugs. (AR at 118, 669.) Per FDA's advice, West-Ward chose to study the same classifications of drugs that Mutual studied; however, contrary to expectations, the results of West-Ward's studies differed substantially from the results of Mutual's studies. (See id. at 669-70.) Mutual's studies had indicated that colchicine dosing regimens should be modified when colchicine is co-administered
FDA ultimately reached the conclusion that Mitigare is safe and effective for the prophylaxis of gout, and approved West-Ward's 505(b)(2) application on September 26, 2014. (See id. at 28.) As approved, Mitigare not only differs from Colcrys in dosage form, it also has a substantially different label than Colcrys. In contrast to the Colcrys label, the Mitigare label does not include the lower dose colchicine regime for the treatment of acute gout flares that Mutual evaluated in its AGREE trial; rather, the Mitigare label states under the "[l]imitations of use" section that "[t]he safety and effectiveness of Mitigare for acute treatment of gout flares during prophylaxis has not been studied." (id. at 32 (Mitigare label)). Furthermore, instead of the detailed dose modifications for preventing drug-drug interaction toxicity that the Colcrys label contains, the Mitigare label warns generally that patients taking certain drugs in combination with Mitigare should avoid the combination entirely, or if avoidance is not possible, adjust the dose of Mitigare "by either reducing the daily dose or reducing the dose frequency, and the patient should be monitored carefully for colchicine toxicity." (AR at 141 (citation omitted).)
FDA's evaluation of West-Ward's application for Mitigare was undertaken confidentially, in accordance with FDA rules and regulations. See 21 C.F.R. § 314.430(b) ("FDA will not publicly disclose the existence of an application or abbreviated application before an approval letter is sent to the applicant under § 314.105 or tentative approval letter is sent to the applicant under § 314.107[.]"). Moreover, because West-Ward neither cited Colcrys as the RLD nor certified to any Colcrys patents in West-Ward's 505(b)(2) application for Mitigare, West-Ward did not inform Takeda of West-Ward's application for Mitigare. Consequently, Plaintiffs did not know about West-Ward's application for Mitigare until September 30, 2014, when West-Ward issued a press release regarding FDA's approval of its new single-ingredient colchicine product. (See Confidential Decl. Matthew Woods, Takeda Pharms. U.S.A., Inc. v. Burwell, No. 14-1668-KBJ, ECF No. 3-6 ¶ 33.) Moreover, Takeda only discovered that West-Ward intended to market an authorized generic version of Mitigare that will compete with—and cost less than—Takeda's Colcrys, on October 1, 2014. (See id. ¶ 34.)
On October 6, 2014, Takeda filed a two-count complaint and a Motion for a Preliminary Injunction against Defendants Burwell and Hamburg. (See Compl., Takeda Pharms. U.S.A., Inc. v. Burwell, No. 14-1668-KBJ (D.D.C. Oct. 6, 2014), ECF No. 1 ("Takeda Compl."); Mot. for TRO or Prelim. Inj., Takeda Pharms. U.S.A., Inc. v. Burwell, No. 14-1668-KBJ (D.D.C. Oct. 8, 2014), ECF No. 9, see also Mem. Supp. Pl.'s Confidential Mot. for TRO or Prelim. Inj., Takeda Pharms. U.S.A., Inc. v. Burwell, No. 14-1668-KBJ (D.D.C. Oct. 8, 2014), ECF No. 10 ("Takeda PI Mem.").) In its complaint, Takeda alleges that FDA acted wrongfully in three respects: (1)
Takeda initiated a patent infringement action against West-Ward in the United States District Court for the District of Delaware shortly before it brought this action against FDA. (See Compl., Takeda Pharms. U.S.A., Inc. v. West-Ward Pharm. Corp., No. 14-1268-SLR, 2014 WL 5241780 (D.Del. Oct. 3, 2014), ECF No. 1.) On October 9, 2014, the Delaware court entered a Temporary Restraining Order enjoining West-Ward from marketing Mitigare pending further proceedings in the patent litigation. (See Memorandum Order, Takeda Pharms. U.S.A., Inc. v. West-Ward Pharm. Corp., No. 14-1268-SLR, 2014 WL 5088690 (D.Del. Oct. 9, 2014, ECF No. 21.) The Delaware court eventually denied Takeda's Motion for a Preliminary Injunction, but "given the significance of this dispute to both parties" issued an order maintaining the status quo—that is, prohibiting West-Ward from marketing Mitigare—pending Takeda's appeal of that court's decision regarding the preliminary injunction. (Memorandum Opinion at 16, Takeda Pharms. U.S.A., Inc. v. West-Ward Pharm. Corp., No. 14-1268-SLR, 72 F.Supp.3d 539, 2014 WL 5780611 (D.Del. Nov. 4, 2014), ECF No. 78, 2014 WL 5088690; see also Order, Takeda Pharms. U.S.A., Inc. v. West-Ward Pharm. Corp., No. 14-1268-SLR, 72 F.Supp.3d 539, 2014 WL 5780611 (D.Del. Nov. 4, 2014), ECF No. 79.)
Meanwhile, in the instant District of Columbia case, West-Ward moved to intervene in Takeda's suit against FDA, and this Court granted that request. (See Unopposed Mot. to Intervene, Takeda Pharms. U.S.A., Inc. v. Burwell, No. 14-1668-KBJ (D.D.C. Oct. 9, 2014), ECF No. 11; Minute Entry dated Oct. 9, 2014, Takeda Pharms. U.S.A., Inc. v. Burwell, No. 14-1668-KBJ.) West-Ward and the Government then filed oppositions to Takeda's Motion for a Preliminary Injunction. (See Hikma and West-Ward's Opp'n to Mot. for TRO ("West-Ward Opp. Mem."), Takeda Pharms. U.S.A., Inc. v. Burwell, No. 14-1668-KBJ (D.D.C. Oct. 17, 2014), ECF No. 16; Burwell and Hamburg's Resp. to Mot. for TRO ("FDA Opp. Mem."), Takeda Pharms. U.S.A., Inc. v. Burwell, No. 14-1668-KBJ (D.D.C. Oct. 17, 2014), ECF No. 15.) Takeda field a reply on October 20, 2014. (See Reply to Opp'n to Mot. for TRO ("Takeda Reply Mem."), Takeda Pharms. U.S.A., Inc. v. Burwell, No. 14-1668-KBJ (D.D.C. Oct. 20, 2014), ECF No. 21.)
On November 4, 2014, this Court heard argument from Takeda, FDA, and West-Ward on Takeda's Motion for a Preliminary Injunction. (See Minute Entry dated Nov. 4, 2014, Takeda Pharms. U.S.A., Inc. v. Burwell, No. 14-1668-KBJ). However, in light of the stay that was issued in the Delaware patent litigation, this Court consolidated Takeda's Motion for a Preliminary Injunction with the resolution of the merits of Takeda's complaint and, with Takeda's consent, construed the merits arguments in Takeda's preliminary injunction motion as a motion for summary judgment.
On the same day that this Court heard argument on Takeda's then-pending preliminary injunction motion (November 4, 2014), Elliott Associates, L.P., Elliott International, L.P., and Knollwood Investments, L.P. (collectively, "Elliott") filed a two-count complaint against Defendants Burwell and Hamburg that is substantially similar to Takeda's action. (See Compl. Elliott Assocs. v. Burwell, No. 14-1850-KBJ (D.D.C. Nov. 4, 2014), ECF No. 1 ("Elliott Compl.").) Elliott "owns a legally-enforceable right tied to the Colcrys patents to receive a percentage of the royalties from the sale of Colcrys," and because Elliott expects that Mitigare will compete directly with Colcrys, these plaintiffs allege that FDA's failure to require West-Ward to certify to the Colcrys patents has injured them. (Elliott Compl. ¶ 7.) The Elliott complaint specifically alleges that FDA acted wrongfully in two respects: (1) that "FDA's decision to approve Mitigare without requiring that [West-Ward] certify to the patents covering the use of colchicine for the prophylaxis of gout flares violates the plain text of Section 505(b)(2)(A) of the FDCA[;]" and (2) that "FDA acted in an arbitrary and capricious manner by approving [West-Ward's] 505(b)(2) application without requiring a certification as to the Colcrys patents." (Id. ¶ 9-11.) Elliott filed a motion for summary judgment on November 17, 2014. (See Mot. for Summ. J, Elliott Assocs. v. Burwell, No. 14-1850-KBJ (D.D.C. Nov. 17, 2014), ECF No. 14, see also Pl.'s Mem. Supp. Mot. for Summ. J., Elliott Assocs. v. Burwell, No. 14-1850-KBJ (D.D.C. Nov. 17, 2014), ECF No. 14-1 ("Elliott MSJ Mem.").) Just as they had in Takeda v. Burwell, Hikma and West-Ward moved to intervene in Elliott v. Burwell. (See Consent Mot. to Intervene, Elliott Assocs. v. Burwell, No. 14-1850-KBJ (D.D.C. Nov. 18, 2014), ECF No. 47.) This Court granted the motion. (See Minute Entry dated Nov. 21, 2014, Elliott Assocs. v. Burwell, No. 14-1850-KBJ.)
In light of the overlap between the parties, facts, and allegations in Takeda v. Burwell and Elliott v. Burwell, this Court that the two cases should be considered in tandem. (See Minute Entry dated Nov. 18, 2014, Elliott Assocs. v. Burwell, No. 14-1850-KBJ.) On November 19, 2014, this Court held a second motions hearing in which the parties in both cases participated. (See Minute Entry dated Nov. 19, 2014, Takeda Pharms. U.S.A., Inc. v. Burwell, No. 14-1668-KBJ.) After the hearing, West-Ward and FDA filed cross-motions for summary judgment in Elliott v. Burwell. (See Cross Mot. for Summ. J. by Hikma and West-Ward, Elliott Assocs. v. Burwell, No. 14-1850-KBJ (D.D.C. Dec. 9, 2014), ECF No. 60; Mem. in Opp. by Hikma and West-Ward, Elliott Assocs. v. Burwell, No. 14-1850-KBJ (D.D.C. Dec. 9, 2014), ECF No. 61 ("West-Ward XMSJ Mem."); Cross Mot. for Summ. J. by Burwell and Hamburg ("FDA XMSJ Mem."), Elliott Assocs. v. Burwell, No. 14-1850-KBJ (D.D.C. Dec. 9, 2014), ECF No. 62; Mem. in Opp by Burwell and Hamburg,
Under Federal Rule of Civil Procedure 56, summary judgment is appropriate when the moving party demonstrates "that there is no genuine dispute as to any material fact and the movant is entitled to judgment as a matter of law." Fed. R.Civ.P. 56. However, in a case involving review of final administrative action—such as FDA's approval of a new drug—the standard set forth in Rule 56 does not apply. See, e.g., ViroPharma, Inc. v. Hamburg, 916 F.Supp.2d 76, 79 (D.D.C. 2013). Instead, "FDA's administrative decisions are subject to review under the Administrative Procedure Act (`APA'), 5 U.S.C. § 706, which requires the reviewing court to set aside an agency action that is `arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law.'" ISTA Pharm., Inc. v. FDA, 898 F.Supp.2d 227, 230 (D.D.C.2012). "Summary judgment thus serves as a mechanism for deciding, as a matter of law, whether the agency action is supported by the administrative record and is otherwise consistent with the APA standard of review." Hill Dermaceuticals, Inc. v. FDA, No. 11-1950, 2012 WL 5914516, at *7 (D.D.C. May 18, 2012) (citing Richards v. INS, 554 F.2d 1173, 1177 & n. 28 (D.C.Cir. 1977)); see also Am. Bioscience, Inc. v. Thompson, 269 F.3d 1077, 1083-84 (D.C.Cir.2001) (collecting cases).
In reviewing agency action, a court must be mindful of the division of labor between the court and the agency. "Under the APA, it is the role of the agency to resolve factual issues to arrive at a decision that is supported by the administrative record, whereas the function of the district court is to determine whether or not as a matter of law the evidence in the administrative record permitted the agency to make the decision it did." Hi-Tech Pharmacal Co. v. FDA, 587 F.Supp.2d 13, 18 (D.D.C.2008) (internal quotation marks and citation omitted). Accordingly, a reviewing court cannot "substitute its judgment for that of the agency," Motor Vehicle Mfrs. Ass'n v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29, 43, 103 S.Ct. 2856, 77 L.Ed.2d 443 (1983), especially when the agency's scientific expertise informs its judgment. See Balt. Gas & Elec. Co. v. Natural Res. Def. Council, Inc., 462 U.S. 87, 103, 103 S.Ct. 2246, 76 L.Ed.2d 437 (1983) (holding that "[w]hen examining . . . [a] scientific determination. . . a reviewing court must generally be at its most deferential"). Moreover, given that "[t]he scope of review under the `arbitrary and capricious' standard is narrow[,]" State Farm, 463 U.S. at 43, 103 S.Ct. 2856, the agency action under review is "entitled to a presumption of regularity[,]" Citizens to Preserve Overton Park, Inc. v. Volpe, 401 U.S. 402, 415, 91 S.Ct. 814, 28 L.Ed.2d 136 (1971), overruled on other grounds by Califano v. Sanders, 430 U.S. 99, 97 S.Ct. 980, 51 L.Ed.2d 192 (1977). In sum, the court performs "only the limited, albeit important, task of reviewing agency action to determine whether the agency conformed with controlling statutes[,]" Balt. Gas, 462 U.S. at 97, 103 S.Ct. 2246, and/or whether the agency has committed "a clear error of judgment[,]" Overton Park, 401 U.S. at 416, 91 S.Ct. 814.
Although the instant cross-motions for summary judgment focus on the alleged impropriety of one agency action—FDA's approval of Mitigare—Plaintiffs make myriad arguments in an attempt to support their claim that FDA's approval of that drug product was wrongful and should be rescinded. 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 (see Takeda Reply Mem. at 19-22; Takeda Suppl. Mem. at 6-13), 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 (see Elliott MSJ Mem. at 23-46).
For the reasons explained below, this 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.
Both Plaintiffs contend that, when FDA approved Mitigare without a Paragraph IV certification to the Colcrys patents, FDA permitted West-Ward to "circumvent" the agency's own Hatch-Waxman directives
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. To be specific, 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. (Takeda Reply Mem. at 17; see also id. at 16-22.) 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. (See Elliott MSJ Mem. at 23-46). As explained below, this 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. Consequently, this Court cannot accept Plaintiffs' arguments that FDA arbitrarily and capriciously violated any such requirements when it approved West-Ward's application for Mitigare.
Takeda appears to accept that reliance on the studies of another drug product is a necessary prerequisite to the obligation of a Section 505(b)(2) applicant to certify to that product's patents, and it vigorously asserts that the obligation to certify to the Colcrys patents was triggered here under FDA's own rules because "FDA relied repeatedly and extensively upon Colcrys's safety and efficacy data in approving Mitigare." (Takeda Suppl. Mem. at 5.) As
First of all, the 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. (See Takeda Suppl. Mem. at 7 (maintaining that "[i]f FDA relied on Colcrys to support the approval of Mitigare, [West-Ward] was required to reference Colcrys and certify to its patents").) Takeda does not cite to any one regulation or clearly applicable agency statement to bolster its assertions in this regard; instead, Takeda points to various sources—e.g., section 505(b)(2) of the FDCA, a few lines from FDA's implementing regulations, a case that settled, and selective quotations from Citizen Petition Responses (see Takeda Suppl. Mem. at 8-9)—to cobble together a legal argument that, in essence, asks this Court to apply its own logic to conclude that FDA's reliance matters, when, as explained below, this conclusion is hardly logical.
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. (See Takeda Suppl. Mem. at 9 ("FDA's use of third-party data [to consider and approve a 505(b)(2) application] without a right of reference would trigger the 505(b)(2) obligations." (emphasis added)); see also id. ("If there is no right of reference or use, FDA does not have carte blanche to consult or rely on third-party data that might be relevant to an application without requiring the applicant to reference and certify to the relevant patents." (emphasis altered)).) As Takeda explains it, in the absence of a right of reference or use, FDA is not entitled "to refer to data from a previously approved application during the review of another party's 505(b)(2) application" (id. at 9), and it is precisely because of the agency's limited authority to access such data that, if the agency does undertake to consult third-party data as part of its evaluation of a Section 505(b)(2) application, the agency must require the applicant to certify to the data owner's patents. (See id. at 10 (asserting that, "where the [505(b)(2)] applicant fails in its duty to identify a referenced
Specifically, although Congress uses the phrase "right of reference or use" in 21 U.S.C. § 355(b)(2), that statutory section expressly applies only to the Section 505(b)(2) applicant, and pertains only to what application materials such sponsor is required to submit; Takeda fails entirely to explain its suggestion that this statutory language can somehow be read to bind FDA in its consideration of data pertinent to a submitted application. (See Takeda Suppl. Mem. 8.) 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 "refer to data from a previously approved application during the review of another party's 505(b)(2) application[,]" as Takeda maintains. (Takeda Suppl. Mem. at 9.)
Pfizer Inc. v. FDA, No. 03-2346 (D.D.C. filed Nov. 13, 2003) also fails to shed any light on the subject. Takeda cites Pfizer as an example of a circumstance in which "FDA was sued for improperly referencing third-party data to approve a 505(b)(2) application submitted by Dr. Reddy's Labs for the drug amlodipine maleate." (Takeda Suppl. Mem. at 9.) What Takeda does not explain in its brief is that the court in Pfizer never reached any legal conclusion regarding whether the agency has a blanket policy of prohibiting its employees from consulting third-party data without a right of reference or use—the case was ultimately dismissed—and, indeed, it is highly likely that FDA requested the stay and dismissal based on doubts about the particular studies its reviewer relied upon in that case and not on the basis of some unstated agency policy prohibiting unauthorized reliance on third-party studies entirely. See Pfizer Inc. v. FDA, No. 03-2346 (D.D.C. Nov. 13, 2003), ECF No. 1, Compl. ¶ 15-37, see also id. ¶ 36 (alleging that "there could be no reasonable scientific basis to rely on data contained in Pfizer's NDA for Norvasc to approve Reddy's drug" (emphasis added)). In other words, although FDA may have seen fit, under the circumstances presented in Pfizer, to "reevaluate whether the approval of the NDA . . . was based upon data from appropriate sources" (Takeda Suppl. Mem. at 9 (alteration in original) (internal quotation marks and citation omitted)), that case by
This Court is also at a loss to ascertain how any supposed "right of reference or use" requirement for the agency's consideration of third-party data (the flip side of Takeda's assertion that the agency cannot proceed to rely on third-party data without such a right) would work, as a practical matter. Given the confidential nature of the Section 505(b)(2) application process, it makes little sense to suggest, as Takeda does, that FDA cannot consider the previously-submitted safety and effectiveness data of third-party drug sponsors as part of its review of a Section 505(b)(2) application without securing the data owner's permission. (Cf. MSJ Mot. Hr'g Tr. at 23:22-24:17 (arguing that, "when FDA looks at [a 505(b)(2)] application and concludes that it is going to need to go to a different file and pull a different file out of the drawer and consult those studies and those data in that file in order to make its decision," the agency must not do so without taking further action). 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. (Id. at 28:13.) 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. Moreover, and in any event, any agency effort to secure a "right of reference or use" from a prior applicant with respect to proprietary data such applicant previously submitted would almost certainly alert that prior applicant to the possibility of a potential new competitor, obviating any need for Hatch-Waxman's patent certification and notice process. Thus, Takeda's contention that FDA cannot consult or rely upon third-party data in the absence of a right of reference, or conversely, that it must secure such right if it desires to access third-party data, has practical implications that render the assertion manifestly inconsistent with the Hatch-Waxman scheme, which is perhaps why no such limitation on FDA authority is articulated anywhere in the FDCA or the agency's regulations—Takeda cites none, and as far as this Court can tell, the contention that "FDA had no right to use [proprietary third-party data] to approve a competing product" (Takeda Suppl. Mem. at 8; see also id. at 8-10) has been crafted entirely out of whole cloth.
Nor will it do for Takeda to insist that (fear not!) FDA actually can do what the
Takeda also plainly struggles to reconcile its agency-reliance argument with what the agency has said repeatedly about when the patent certification obligation is triggered. For example, Takeda points to a Citizen Petition Response to Abbott Labs dated November 30, 2004, in which the agency stated that "[e]ach application will certify only to patents listed for drugs on whose finding of safety and effectiveness FDA relies for approval (including patents for pharmaceutical equivalents or, if there is no pharmaceutical equivalent, for the most similar alternative), not to patents submitted for applications on which FDA could have relied but did not." (Takeda Suppl. Mem. at 7 (emphasis in the original) (citing Ltr. from Steven K. Galson, Acting Dir., FDA Ctr. for Drug Evaluation and Research, FDA, to Donald O. Beers, Arnold & Porter LLP and William F. Cavanaugh, Jr., Patterson, Belknap, Webb & Tyler LLP at 10 (Nov. 30, 2004) (hereinafter "Fenofibrate Citizen Petition Response") (responding to Docket No. 2004P-0386/CP1 & RC1)).) But FDA made this statement in the context of a letter that rejects Abbott Labs's broad proposition that a Section 505(b)(2) applicant must certify "not only to the patents for the listed drug that [the] 505(b)(2) application references and on which it relies for approval, but also to all patents on all other later-approved [products in the same product line] that were approved based, in part, on some or all of the same underlying investigations[.]" (Id. at 1.) Read in context, FDA's use of the phrase "[e]ach application will certify only to patents listed for drugs on whose finding of safety and effectiveness FDA relies for approval" merely clarifies the limited scope of the applicant's patent certification obligation as far as the universe of drug products that may share the same underlying investigations are concerned, and it is by no means addressed to the question of whether the agency's own reliance on data outside that which is submitted or referred to in the 505(b)(2) application triggers the patent certification obligation.
Furthermore, in the course of pulling FDA's quotation out of context, Takeda has deftly sidestepped numerous instances in this same petition response in which FDA clearly explains that its policy regarding a Section 505(b)(2) applicant's patent certification obligations relates solely to the applicant's reliance, to wit:
(Id. at 8 (emphasis added) (footnote omitted).) Thus, contrary to Takeda's argument, FDA makes clear in this Citizen Petition Response that the agency's own reliance on third-party data is not even relevant to a Section 505(b)(2) applicant's obligation to reference a drug and file a related patent certification, much less "the triggering event" for that obligation. (Takeda Suppl. Mem. at 6.)
In the final analysis then, this Court finds no basis for Takeda's contention that, as a matter of FDA policy, "[t]he ultimate reference and certification obligations depend on whether FDA relies on other studies or data." (Takeda Suppl. Mem. at 6 (emphasis in original).) Moreover, when Takeda makes the assertion that FDA's reliance on third-party data triggers the Section 505(b)(2) patent certification obligation under the Hatch-Waxman Act, it presents a puzzling conundrum: for all of Takeda's efforts to convince this Court that Congress intended for FDA itself to be a party to the Hatch-Waxman exchange—prohibited from consulting proprietary third-party data and information to approve a 505(b)(2) application unless it forces the applicant to certify to the owner's patents—it not only fails to identify any statutory or regulatory provision that says this, it also has failed to articulate any benefit that would redound to the agency (or the public) as a result of that supposed bargain. It is beyond dispute that Congress has entrusted FDA with the responsibility of making scientific determinations regarding the safety and effectiveness of marketed drug products—which, in and of itself, strongly indicates that Congress intended for the agency to have more data and information at its disposal, rather than less—and there can be no question that making science-based safety decisions is FDA's core function. Consequently, there is no reasonable explanation for the view that Congress somehow also intended for the privilege that it has given FDA to access proprietary data and information in the fulfillment of its core responsibilities to be linked to, and potentially hampered by, a duty to protect third-party patent rights. (See MSJ Mot. Hr'g Tr. at 26:7-29:3.) Put another way, if Takeda is correct that, under the statutory scheme, "[t]he critical [patent certification] issue is whether third-party data were used [by FDA] to support the approval of a 505(b)(2) application" (Takeda Suppl. Mem. at 10), then another crucial question remains unanswered: why would Congress require the federal agency that is tasked with determining the safety and efficacy of new drugs to "lock" an agency file drawer that contains scientific data pertinent to the evaluation of a new drug marketing application (MSJ Mot. Hr'g Tr. at 28:13), and to access that information for the purpose of the agency's own review only if the agency first forces the applicant to certify to the data owner's patents?
Even 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"
Takeda strongly suggests that every mention of—or reference to—Colcrys that the agency made during its consideration of the Mitigare application counts as an instance of "reliance" for the purpose of the patent certification obligation, and certainly that the combined 246 times that the agency refers to Colcrys in the instant administrative record is sufficient to satisfy the reliance threshold for the purpose of the patent certification requirement. (See, e.g., Takeda Suppl. Mem. at 3 ("[T]he agency repeatedly consulted and referred to Colcrys data in considering whether and how to approve Mitigare."); MSJ Mot. Hr'g Tr. at 6 (emphasizing "the number 246," as the number of Colcrys references in the record).) In this regard, however, Takeda is employing a "reliance" concept that is much broader than what Congress envisioned when it developed the Hatch-Waxman patent-certification scheme.
As will be discussed fully below in Part III.A.3, with the Hatch-Waxman Amendments to the FDCA, Congress established a drug approval system in which a Section 505(b)(2) applicant can satisfy the clinical research requirement by using the results of research studies that were not conducted by the applicant and "for which the applicant has not obtained a right of reference." 21 U.S.C. § 355(b)(1), (2). Here, West-Ward conducted its own drug-drug interaction studies, and it also relied on published literature about colchicine and FDA's safety and efficacy findings for the drug Col-Probenecid. The fact that FDA considered the differences between what West-Ward's clinical studies found and what Mutual's clinical studies had concluded does not necessarily mean that West-Ward's own submissions had failed to show that Mitigare is safe and effective for the prophylaxis of gout independently of the Colcrys data. In fact, FDA specifically stated that, based on West-Ward's submissions alone, the agency had come to the conclusion that Mitigare is safe and should be approved. (See, e.g., AR at 28-30 (Mitigare approval letter); id. at 162 (noting that "the clinical pharmacology data submitted by the applicant are sufficient for approval of this application for colchicine, and a product label can be written based on case reports described in the published literature and the specific clinical pharmacology studies conducted by the applicant"); id. at 170 ("No clinical pharmacology/biopharmaceutics deficiencies were identified in the original application for [Mitigare.]").) Thus, from the standpoint of the type of reliance that Section 505(b)(2) requires and that Congress clearly cares about, FDA did not "rely" on Mutual's Colcrys studies to fill in an identified gap in the safety and effectiveness
Nevertheless, Takeda confidently maintains that sufficient reliance was achieved for the purpose of the Section 505(b)(2) patent certification obligations because FDA made repeated substantive references to Colcrys data during its review of the Mitigare application (Takeda Suppl. Mem. at 5)—in stark contrast to the scant number of times that Col-Probenecid was referenced (MSJ Mot. Hr'g Tr. at 22:3-13)—and because "Mitigare's labeling . . . would make no sense if they hadn't looked at Colcrys' studies." (Id. at 62:10-12.) But, given the nature of the Section 505(b)(2) application process, Takeda's certitude that FDA's repeated references to the Colcrys data triggered the patent certification requirement seems unwarranted. In Takeda's world view, it might be the case that the type of reliance necessary to give rise to patent certification when an agency actively consults third-party studies and data can be different in nature from the applicant reliance that the Section 505(b)(2) process requires—i.e., the fill-in-the gap variety—but Takeda has provided no basis upon which this Court can conclude that Congress intended any such distinction, and of course, that determination would be for Congress, not this Court, to make. In the meantime, even if this Court agreed with Takeda that a Section 505(b)(2) applicant's patent certification obligations are tied to the data that FDA consults when reviewing a Section 505(b)(2) application as a matter of law and FDA policy, Takeda has fallen short of making a persuasive argument that FDA's actions here—including its repeated "substantive references to Colcrys data" (Takeda Suppl. Mem. at 5)—qualify as the type of reliance that Congress intended to give rise to the patent certification obligation.
The second "procedural requirement" that Takeda and Elliott argue FDA violated when it approved Mitigare without requiring a reference to Colcrys and certifications to the Colcrys patents has to do with the drug that a Section 505(b)(2) applicant selects as its reference listed drug. (See Takeda Suppl. Mem. at 13-18.) Takeda cites a Citizen Petition Response in which FDA states that a "505(b)(2) applicant should determine which listed drug(s) is most appropriate for its development program[,]" (id. at 13-14 (citing Ltr. from Janet Woodcock, Dir., Ctr. for
Both Plaintiffs are mistaken. Put bluntly, their argument hinges on the existence of an FDA drug reference policy that does not exist. First, the Citizen Petition Response that Takeda says shows that an applicant must select the reference drug that is "most appropriate" contains the clear disclaimer that "this suggested approach does not reflect a statutory or regulatory requirement." (Suboxone Citizen Petition Response at 7). Then, when one actually reads that document, FDA clearly states that "a sponsor interested in submitting a 505(b)(2) application that relies upon FDA's finding of safety and/or effectiveness for one or more listed drugs should determine which listed drug is most appropriate for its development program." (Id. (emphasis added).). FDA also provides a clear explanation as to why the agency has chosen to cede the reference determination to the applicant in this way: because, under the Section 505(b)(2) scheme, the applicant uses the reference listed drug to supply safety and effectiveness data in total or partial fulfillment of the applicant's obligation to prove that its drug is safe and effective—meaning that there is a direct correlation between the drug the applicant chooses to reference and the applicant's burden of proof. (See id. ("An applicant choosing to rely on FDA's finding of safety and/or effectiveness for a listed drug very similar to the proposed product submitted in the 505(b)(2) application would generally need to submit less additional data to support the differences between the proposed product and the listed drug for approval of the 505(b)(2) application.").) Thus, it is FDA policy that, "so long as a sponsor provides the necessary data and information to support the difference(s) between the reference drug and its proposed drug, and so long as the proposed drug is not an exact duplicate of the reference drug, a sponsor is free to choose the listed drug that it deems `most appropriate' for reliance in its 505(b)(2) application." (FDA Suppl. Mem. at 3; see also Fenofibrate Citizen Petition Response at 9 ("[B]ecause, under 21 CFR 3 14.54(a), a 505(b)(2) applicant seeking approval for a change to a listed drug need only supply information sufficient to support the change proposed, it follows that the more similar a proposed drug is to the listed drug cited, the smaller the quantity of data that will be needed to support the proposed change.").)
To be sure, in the Suboxone Citizen Petition Response, FDA states that "the applicant should identify the pharmaceutically equivalent product as a listed drug relied upon[,]" and "should determine which listed drug(s) is most appropriate
Elliott's attempt to craft a mandatory reference policy out of the agency's supposed "most similar drug" requirement fares no better. (Elliott MSJ Mem. at 38-42 (citing Fenofibrate Citizen Petition Response).) In essence, Elliott argues that FDA has a long-standing policy of "prohibiting 505(b)(2) applicants from circumventing the FDCA's patent certification requirements" (id. at 38), and that the requirement that an applicant reference the "most similar drug" in its Section 505(b)(2) application (Fenofibrate Citizen Petition Response at 9) does the work of enforcing this objective insofar as it constrains sponsors who select the 505(b)(2) pathway as a means of "shirk[ing]" their patent certification obligations. (Elliott MSJ Mem. at 38.) But Elliott provides no evidence that FDA actually monitors or mandates a "most similar drug" requirement within the 505(b)(2) context (see id. at 38-39 (providing only examples of ANDAs)), much less that the agency views this alleged requirement as a mechanism for keeping applicants who approach the agency with a questionable Section 505(b)(2) application in line. Nor has Elliott explained how any supposed FDA policy of restraining a Section 505(b)(2) applicant's discretion regarding the reference drug jibes with the agency's well-established reasons for permitting the applicant itself to make the reference determination. (See FDA Suppl. Mem. at 2-3; FDA XMSJ Mem. at 1516.)
This Court also notes that, in addition to the lack of any policy on the part of FDA regarding which drug must be referenced
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. (See Fenofibrate Citizen Petition Response at 8-10; Suboxone Citizen Petition Response at 8-10; AR at 12-14 (Colchicine Citizen Petition Response).) 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. (See id.) Given that policy choice—which is the opposite of Elliott's ANDA-related assertion that "[u]nder longstanding FDA policy, applicants do not have unfettered discretion to choose any prior drug as the reference listed drug" (Elliott MSJ Mem. at 41)—neither the agency nor West-Ward needs to provide any explanation as to "why Col-Probenecid was more similar or more appropriate for [West-Ward] to cite than Colcrys" (Takeda Reply Mem. at 17). Regardless, it is clear that Plaintiffs' argument that FDA violated its own procedural rules when it refused to force West-Ward to reference the obviously most similar/appropriate drug (Colcrys) fails.
Whereas Takeda's patent certification argument is primarily about whether, and to what the extent, FDA's approval process for Mitigare relied on Colcrys data, Elliott maintains that FDA should have required West-Ward to certify to the Colcrys patents regardless. Elliott's contention is primarily a statutory one: that the text of the FDCA required West-Ward to file a certification to the Colcrys method-of-use patents when it sought FDA approval for Mitigare, even if West-Ward did not rely on the investigations or data underlying Colcrys in its application for approval. (See Elliott MSJ Mem. at 2328.) In this regard, Elliott homes in on language in subdivision (A) of 21 U.S.C. § 355(b)(2); specifically, the statement that a Section 505(b)(2) application must include "a certification . . . with respect to each patent which claims the drug for which such investigations were conducted or which claims a use for such drug for
As a threshold matter, Elliott is correct that the APA requires a reviewing court to set aside FDA's final action in approving a drug product for marketing if the court finds that that approval violates limitations that a federal statute imposes. See 5 U.S.C. § 706(2)(C); see, e.g., Am. Bioscience, Inc. v. Thompson, 269 F.3d 1077 (D.C.Cir.2001) (holding that FDA improperly approved an ANDA for a generic form of a patented drug because FDA had arbitrarily and capriciously removed a new patent from the Orange Book listing and approved the ANDA without requiring the competitor to address the de-listed patent); Bayer HealthCare, LLC v. FDA, 942 F.Supp.2d 17 (D.D.C.2013) (suspending FDA's approval of an ANDA where FDA had approved the application for a generic version of plaintiff patent owner's drug without responding to plaintiff's Citizen Petition for years and without providing a reasoned basis for rejecting the petition). Courts review FDA's own interpretation of what the FDCA (the agency's organic statute) permits under the two-step framework of Chevron, U.S.A., Inc. v. Natural Res. Def. Council, Inc., 467 U.S. 837, 104 S.Ct.2778, 81 L.Ed.2d 694 (1984), see, e.g.,
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. To determine whether Congress has spoken directly this issue under the first step of the Chevron analysis, this Court must use the traditional tools of statutory construction, which include an examination of the statute's text, structure, purpose, and legislative history. See, e.g., Stat-Trade Inc. v. FDA, 869 F.Supp.2d 95, 102 (D.D.C. 2012); Serono Labs., Inc. v. Shalala, 158 F.3d 1313, 1319 (D.C.Cir.1998)); Eagle Broad. Grp., Ltd. v. FCC, 563 F.3d 543, 552 (D.C.Cir.2009). Notably, after wielding these standard implements in the context of this case, the parties here not only have competing interpretations of subsection (b)(2)(A)'s plain text, they also differ as to whether this statutory subsection is ambiguous.
Examining the text of the statute, one must begin at the beginning, recognizing that the language of section 355 of Title 21 opens with an unmistakably clear mandate to sponsors of new drugs: before any new drug can be marketed, the sponsor must seek FDA approval for the drug by filing an application with FDA that includes certain specified components. See 21 U.S.C. § 355(a) ("No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application filed pursuant to subsection (b) or (j) of this section is effective with respect to such drug."). Subsection (b)(1), which clarifies that "[a]ny person may file with the [agency]
21 U.S.C. § 355(b)(1) (emphasis added).
The dispute at issue here involves new drug applications that seek to satisfy the clause (A) "investigations" requirement by relying on studies that "were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted[.]" Id. § 355(b)(2). Congress specifically addresses this circumstance in subsection (b)(2). Pursuant to that subsection, when an applicant wishes to rely on the safety and efficacy investigations that were conducted with respect to another drug and the applicant has not secured the right to reference those studies, additional application materials must be submitted. Specifically, the statute requires the applicant to make certain patent-related representations: "(A) a certification . . . with respect to each patent which claims the drug for which such investigations were conducted or which claims a use for such drug for which the applicant is seeking approval[,]" id. § 355(b)(2)(A), and also, if applicable, (B) "a statement" that confirms that an existing method-of-use patent "with respect to the drug for which investigations . . . were conducted" "does not claim a use for which the applicant is seeking approval under this subsection," id. § 355(b)(2)(B). In this Court's view, the plain text of subdivision (b)(2) unambiguously evidences Congress' intent to require a patent certification to be filed only with respect to patents that either claim the drug product that is the basis for the investigations upon which the applicant is relying (the reference listed drug), or that claim a method of using the reference listed drug for which the applicant is seeking approval.
The textual support for this conclusion is abundant. First, Congress lists the patents for which certifications are required in a single sentence—without break or numerical delineation—indicating that the categories of patents being referred to in this single run-on statement are generally of the same type and bear some relationship to one another, i.e., both relate to the reference-listed drug, as opposed to being of an entirely different species. See DeNaples v. Office of Comptroller of Currency, 706 F.3d 481, 490 (D.C.Cir.2013). Second, the disputed clause uses the word "drug" twice when identifying the patents that require certification: every patent "which claims the drug for which such investigations were conducted or which claims a use for such drug for which the applicant is seeking approval under this subsection[.]" 21 U.S.C. § 355(b)(2)(A). Although the term "drug," as used in the FDCA, can refer to both the finished drug product and also its active ingredient, see 21 U.S.C. § 321(g)(1), the fact that Congress repeated the word "drug" twice within such a short span of text strongly suggests that it intended the same definition
The fact that Congress uses the phrase "such drug" after the conjunction further indicates its intent to reference only one drug—the drug for which the relied-upon investigations were conducted—in section (b)(2)(A). The term "such," when used as an adjective, is an inclusive term, showing that the word it modifies is part of a larger group. See, e.g., Black's Law Dictionary 1446 (7th ed. 1999) (defining "such" as "[o]f this or that kind," or "[t]hat or those; having just been mentioned"); Am. Heritage Dictionary of the English Language 1285 (New College ed. 1976) (defining "such" as "[b]eing the same as that which has been last mentioned or implied"). Relatedly, and even more important, "such" nearly always operates as a reference back to something previously discussed. See United States v. Ashurov, 726 F.3d 395, 398-99 (3d Cir.2013) (citation, internal quotation marks, and alterations omitted) (noting that it is "a commonly recognized rule in American jurisprudence that the word `such' naturally, by grammatical usage, refers to the last precedent"); United States v. Chi Tong Kuok, 671 F.3d 931, 945 n. 8 (9th Cir.2012) ("`Such' in this context means `of the sort or degree previously indicated or implied.'") (quoting Webster's Third New Int'l Dictionary 2283 (2002); Nieves v. United States, 160 F.2d 11, 12 (D.C.Cir.1947) ("The word `such' is restrictive in its effect and obviously relates to an antecedent.").
Thus, in accordance with its plain meaning, the term "such drug" unambiguously refers back to the "the drug for which such investigations were conducted"; much like "such investigations" plainly refers back to "the investigations . . . relied upon by the applicant for approval of the application[.]" 21 U.S.C. § 355(b)(2)(A). By contrast, Elliott's reading of subsection (b)(2)(A) ignores "such" entirely, and essentially replaces it with "the," so that the statute requires an applicant to submit a certification "with respect to each patent which claims the drug for which such investigations were conducted or which claims a use for [such the] drug for which the applicant is seeking approval." As much as Elliott may wish that Congress had employed another article in the method-of-use clause of subsection (b)(2)(A), Congress selected "such," and this Court is required to take Congress at its word. See Am. Meat Inst. v. USDA, 968 F.Supp.2d 38, 56 (D.D.C. 2013) ("Plaintiffs . . . cannot escape the fact that the North Star of any exercise of statutory interpretation is the intent of Congress, as expressed in the words it uses.").
Turning to an examination of the overall structure of the statute, this Court finds that its view of the plain meaning of § 355(b)(2)(A) is only reinforced. This is because the certification subsection is clearly embedded in a section of the statute that mandates reliance upon another drug's investigations as a non-negotiable prerequisite to any additional action on the
Adding to the structural difficulty with Elliott's proposition is the fact that the subsection (b)(2)(A) certification requirement—which, according to Elliott, Congress intended to be completely unmoored from the essential reliance underpinnings of the Section 505(b)(2) process—is followed by a subsection that concerns itself expressly with the method-of-use patents "with respect to the drug for which investigations. . . were conducted." 21 U.S.C. § 355(b)(2)(B). This subsection requires an applicant to file a "statement" in lieu of a certification, when the method-of-use patents for the referenced and relied-upon drug cover uses that are not the same as the uses for which the applicant seeks approval. (Id.) Thus, as FDA explains, this subsection clearly works in conjunction with subsection (b)(2)(A), to address all method-of-use patents for the reference listed drug, whether or not the 505(b)(2) applicant is seeking approval for a patented use.
It is also clear that the fundamental purpose of the Hatch-Waxman Amendments themselves confirms this Court's reading of subsection (b)(2)(A). As has been stated repeatedly above, Congress intentionally designed Hatch-Waxman to balance two important and potentially conflicting objectives: incentivizing investment in the innovation of new drugs, and encouraging the production of less-costly alternative drug products. Janssen Pharmaceutica, N.V., 540 F.3d at 1355. To ensure that both of these goals are achieved, Congress constructed a system in which having to certify to patents and provide the patent owners with notice (protecting the innovator's work product) is the price that a new drug applicant pays for being able to rely on work already approved (promoting efficient drug development). See 21 U.S.C. § 355(b)(2). (See
For all these reasons, this Court is convinced that subsection (b)(2)(A) must be read in accordance with the plain meaning of its terms, and that those terms unambiguously describe two related types of patents that require certification when an applicant files a Section 505(b)(2) application in reliance on another drug's safety and efficacy studies: patents that claim the reference listed drug and patents that claim a method of using the reference listed drug, so long as the applicant is seeking approval for that patented use. In this regard, the phrase "for which the applicant is seeking approval" plainly relates to the term "use"—as in, "which claims a use for such drug for which the applicant is seeking approval"—and not, as Elliott argues, the term "drug"—as in "which claims a use for such drug for which the applicant is seeking approval" (see Elliott MSJ Mem. at 26-28). As a practical matter, this means that the statute requires certification
In short, Elliott has cast aside all of the very clear textual indications that Congress intended a Section 505(b)(2) applicant to certify only to the patents that are associated with the drug that the applicant referenced and relied upon and, nevertheless, insists that, where method-of-use patents are concerned, Congress meant to jettison the reference listed drug product entirely and to require certification with respect to all patents that claim a use for the active ingredient that is in the applicant's new drug. This Court has little doubt that Elliott's reading is a distortion of the statutory text, rather than a statement of its unambiguous plain meaning. But even if there were any ambiguity in statute, and it thus became necessary to proceed to the second step of the Chevron analysis, this Court believes that it is entirely reasonable for FDA to interpret the certification provision in subsection (b)(2)(A) to require a Section 505(b)(2) applicant to certify only to the product and use patents that claim the reference listed drug, which, according to FDA, has been its long-held view of the statute. (See FDA XMSJ Mem. at 11.)
Shifting away from the patent certification issue that is at the heart of the instant action, Takeda also trains its focus on the extent to which FDA has permitted Mitigare's label to differ from Colcrys. The basis for this attack on FDA's approval of Mitigare is the fact that the agency previously and specifically addressed the labeling of single-ingredient oral colchicine products in a response to a Citizen Petition that Mutual filed in 2010. (See AR at 18-20, 24.) As explained above (see supra Part I.D.1), when Mutual learned that West-Ward had submitted an application for a single-ingredient oral colchicine product that was identical to Colcrys, Mutual filed a petition that asked that the agency to restrict the marketing of such products in the future, by, among other things: (1) "[r]equir[ing] labeling for any single-ingredient oral colchicine product to include all information related to drug-drug interactions that is in the Colcrys labeling including relevant dose adjustments needed to prevent unnecessary toxicity;" (AR at 1), and (2) "not allow[ing] an applicant to carve-out the protected gout flares labeling information because the information is essential to prophylaxis." (Id. at 22.) Takeda now reads FDA's written response to this request, which the agency filed in 2011, as establishing "two specific labeling requirements" that Takeda says the agency arbitrarily and capriciously "abandoned" three years later with the approval of Mitigare: "one pertaining to the low-dose regimen for treating gout flares that occur during prophylaxis, and one pertaining to specific safety data showing drug-drug interactions." (Takeda Suppl. Mem. at 18.) As this Court reads the record, however, FDA did no such thing.
Accordingly, when it came time for FDA to evaluate the proposed label for Mitigare, and, in particular, to make a determination regarding what dose instructions would adequately inform patients taking Pg-p and CYP3A4 inhibitors how to use the product safely for prophylaxis of gout, FDA engaged in an extensive analysis of this very issue. Among other things, the agency looked at the drug-drug interaction instructions on the Colcrys label and the studies Mutual had conducted regarding the interaction of colchicine with certain prescription drug products. (See id. at 681-82.) It also looked at the drug-drug interaction studies that West-Ward submitted with its Mitigare approval application—studies that, quite surprisingly, had come to the opposite conclusion about whether health problems were likely to arise when a person taking certain inhibitor medications also takes colchicine for the prophylaxis of gout. (See id. at 668, 692-94). Ultimately, in a memo entitled "The Curious Case of Colchicine: What to Do About Conflicting Drug Interaction Study Results for the Same Molecular Entity" (id. at 667-672), Michelle Garner, who was the Senior Regulatory Management Officer, represented the conclusion of a "regulatory briefing panel" of FDA research scientists about what information needs to be conveyed regarding drug-drug interactions: the panel determined both that "in light of the new information provided by the West-Ward DDI studies, and the questions about the generalizability of dose modification recommendations, . . . it was reasonable to forego detailed dose modification recommendations," and also that "a general precaution to reduce the daily dose and monitor closely for colchicine toxicity is reasonable[.]" (Id. at 672).
A closer question is presented when one considers a statement that FDA made in the Colchicine Citizen Petition Response regarding Mutual's AGREE Trial results 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. In the Citizen Petition Response, FDA considered whether the labels of single-ingredient oral colchicine products must alert health care providers to the possibility that a low-dose regimen of oral colchicine could be safely added to treat the acute gout flares of a person who is regularly taking oral colchicine for prophylaxis of gout. As explained in Part I.C.1, supra, Mutual had studied precisely how much additional colchicine could be added to a regular oral colchicine regimen to treat an acute gout flare in its AGREE Trial, and Colcrys was specifically approved for the treatment of acute gout flares on the basis of the AGREE Trial data. FDA did specifically state in the Colchicine Citizen Petition Response that "labeling for a single-ingredient colchicine product seeking approval for prophylaxis of gout flares must inform healthcare providers that the lower dose colchicine regimen evaluated in the AGREE trial is adequate to treat an acute gout flare that may occur during chronic colchicine use" (AR at 3); yet, as Takeda points out, FDA did not require the AGREE trial information to appear on Mitigare's label. (Takeda PI Mem. at 27-28.) To 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 (see Takeda PI Mem. at 26-29), because the record clearly reflects the agency's well-reasoned and well-supported rationale for reaching this conclusion.
Specifically, it is clear that FDA focused primarily on the undisputed fact that West-Ward had submitted an application for approval of its colchicine capsule solely for prophylaxis of gout. In fact, West-Ward expressly disclaimed that Mitigare should be indicated for the treatment of acute gout flares. (See AR at 28, 51). With this in mind, when the agency considered whether the product's packaging nevertheless needed to include the specific lower-dose regimen instructing patients
(AR at 113 (emphasis added).) Thus, as approved, the Mitigare label proclaims that "[t]he safety and effectiveness of Mitigare for acute treatment of gout flares during prophylaxis has not been studied" (id. at 32), and the Mitigare Medication Guides instructs patients that "[i]f you have a gout flare while taking Mitigare, tell your healthcare provider" (id. at 43).
In light of the agency's clear and convincing record statements about why it permitted the Mitigare label to differ from that of Colcrys, it is puzzling that Takeda puts so much stock into trying to persuade the Court that FDA somehow failed to explain its decisions regarding Mitigare's label adequately. To this end, Takeda complains that FDA has not sufficiently articulated its reasons for approving a Mitigare label that omitted specific, known information about the drugs that Takeda had studied (see Takeda Reply Mem. at 11-12), and it suggests that the agency was not justified in refusing to require inclusion of Mutual's findings in addition to West-Ward's, along with an explanatory statement that the Colcrys research findings might not be generalizable (see id.). Takeda also presses the argument that FDA needed to say more than it did regarding its decision to jettison the AGREE trial's lower dose regimen for the treatment of acute gout flares, which, according to Takeda, was a must-have item for Mitigare's label in light of the agency's "own regulations, which specifically acknowledge that risk information related to common `off label uses' may be required in labeling." (Takeda Reply Mem. at 9 (citing 21 C.F.R. § 201.57(c)(6)). Of course, by the plain terms of these same regulations (specifically, the "may") the agency has discretion regarding whether or not to require a product's label to include information related to off-label uses. See 21 C.F.R. § 201.57(c)(6) (providing that "[a] specific warning relating to a use not provided for under the `Indications and Usage' section may be required by FDA in accordance with sections 201(n) and 502(a)
In any event, under the relevant review standard, this Court has no choice but to defer to "the agency['s] . . . choice between rational alternatives." Rempfer v. Von Eschenbach, 535 F.Supp.2d 99, 107 (D.D.C. 2008) (citing Alliance for Bio-Integrity v. Shalala, 116 F.Supp.2d 166, 177 (D.D.C. 2000) aff'd sub nom. Rempfer v. Sharfstein, 583 F.3d 860 (D.C.Cir.2009)). Here, FDA determined that the recent scientific research about the interaction between colchicine and certain classes of inhibitor drugs cast doubt on the generalizability of Mutual's drug-drug interaction studies, so the agency thought it best not to require that the detailed Colcrys tables be included on Mitigare's label. In addition, the agency made the entirely rational decision that instructions about the additional lowdose amounts that a user might take for the treatment of gout flares were inappropriate for Mitigare, given that Mitigare was being approved solely for the prophylaxis of gout flares.
Finally, Takeda attempts to cast the dissimilarity between the Mitigare and Colcrys labels in a slightly different light, by arguing that FDA's approval of Mitigare was arbitrary and capricious because, "[a]s approved, Mitigare is not safe in light of the significant deficiencies in its labeling." (PI Takeda Mem. at 30 (citing Food and Drug Admin. v. Brown & Williamson Tobacco Corp., 529 U.S. 120, 133, 120 S.Ct. 1291, 146 L.Ed.2d 121 (2000).) On its face, this contention suggests that Takeda believes FDA was mistaken in its ultimate determination that Mitigare is safe and effective (a hard contention to make for a drug manufacturer that also maintains that its own drug product is substantively identical to the drug it challenges); as it turns out, however, Takeda's actual argument appears to be that, in light of the long history of adverse events related to colchicine toxicity, a 0.6 milligram single-ingredient oral colchicine product simply cannot be safe and effective without a label that contains the low-dose regimen
That request will not be honored. As explained above, on this record, Takeda cannot reasonably maintain that FDA made a "clear error" of administrative judgment when it decided to permit Mitigare to be marketed with a label that differs from Colcrys. Overton Park, 401 U.S. at 416, 91 S.Ct. 814. Furthermore, the agency'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. FDA is the administrative body that has both the expertise and the authority to evaluate the safety and efficacy of drugs, and its conclusion that a drug product submitted to it for approval—including a product with a label that differs substantially from one that is already on the market—is safe and effective must be respected. See Sanofi-Aventis U.S. LLC v. FDA, 842 F.Supp.2d 195, 209 (D.D.C.2012) ("[D]eference is particularly appropriate when FDA approval of drugs is involved") (citing Serono Labs., Inc. v. Shalala, 158 F.3d 1313, 1324 (D.C.Cir.1998)); see also Am. Wildlands v. Kempthorne, 530 F.3d 991, 1000 (D.C.Cir.2008) ("The rationale for deference is particularly strong when the [agency] is evaluating scientific data within its technical expertise") (citing Int'l Fabricare Inst. v. EPA, 972 F.2d 384, 389 (D.C.Cir.1992)); Troy Corp. v. Browner, 120 F.3d 277, 283 (D.C.Cir.1997) (courts "review scientific judgments of the agency `not as the chemist, biologist, or statistician that [they] are qualified neither by training nor experience to be, but as a reviewing court exercising [its] narrowly defined duty of holding agencies to certain minimal standards of rationality.'") (quoting Ethyl Corp. v. EPA, 541 F.2d 1, 36 (D.C.Cir. 1976)); Schering Corp. v. FDA 51 F.3d 390, 399 (3d Cir.1995) ("[FDA's] judgments as to what is required to ascertain the safety and efficacy of drugs falls squarely within the ambit of the FDA's expertise and merit deference from us."); Henley v. FDA, 77 F.3d 616, 621 (2d Cir.1996) ("FDA possesses the requisite know-how to conduct such [scientific] analyses, by sifting through the scientific evidence to determine the most accurate and up-to-date information regarding a particular drug. . . . We therefore defer to its reasonable findings.").
Applying the necessary deference here, this Court adopts its own findings about the rationality of FDA's decisions regarding Mitigare's label that are the discussion in the previous section, and the bases for them (i.e., it concludes that Takeda's challenge fails because FDA fully explained its conclusion that Mitigare meets the applicable safety standards as labeled, and that explanation appears to be reasonable).
When it established the Section 505(b)(2) new drug approval process as part of the Hatch-Waxman Amendments to the FDCA, Congress placed the burden
Accordingly, as set forth in the separate order that was issued on January 9, 2015, the Plaintiff Takeda Pharmaceuticals U.S.A., Inc.'s Motion for Summary Judgment in Takeda Pharms. U.S.A., Inc. v. Burwell, et al., Civ. No. 14-1668-KBJ (D.D.C. Oct. 6, 2014) is
21 U.S.C. § 355(b)(2)(A).
