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Amgen Inc. v. Hargan

United States District Court, District of Columbia

January 26, 2018

AMGEN INC., Plaintiff,
ERIC D. HARGAN, Acting Secretary, Department of Health and Human Services, et al., Defendants, and TEVA PHARMACEUTICALS USA, INC., et al., Intervenor-Defendants.



         To encourage pharmaceutical companies to study the safety and effectiveness of pediatric uses of drugs approved for adults, the Federal Food, Drug, and Cosmetic Act (“FFDCA”) grants six months of “pediatric exclusivity” to the sponsor of a brand-name drug if the sponsor conducts studies that “fairly respond” to a “written request” from the Food and Drug Administration (“FDA”). 21 U.S.C. § 355a(d)(4). At the urging of Plaintiff Amgen Inc., the FDA issued a written request asking that Amgen conduct pediatric studies of its drug Sensipar (cinacalcet hydrochloride), and Amgen endeavored to fulfill the request. Ultimately, however, the FDA found that Amgen had failed to complete a study on the safety of cinacalcet hydrochloride in children ages 28 days to < 6 years and concluded that Amgen's studies did not “fairly respond” to the written request. The FDA, accordingly, denied Amgen's request for pediatric exclusivity. Subsequently, the FDA denied both Amgen's request for reconsideration and its appeal of that decision.

         Amgen challenges the FDA's decision as well as the agency's underlying interpretation of the “fairly respond” requirement. The matter is now before the Court on Amgen's motion for summary judgment, Dkt. 60, and cross-motions for summary judgment filed by the FDA, Dkt. 65, and four intervenor-defendants, Dkt. 63. For the reasons that follow, the Court will DENY in part and GRANT in part Amgen's motion and will DENY in part and GRANT in part the FDA's and the intervenor-defendants' cross-motions for summary judgment.

         I. BACKGROUND

         A. Statutory Background

         A manufacturer seeking to market a new drug in the United States must first obtain approval from the FDA. The approval process is both time-consuming and expensive. Among other things, the applicant-or “sponsor”-must submit a new drug application (“NDA”) containing the extensive data and information necessary to demonstrate that the new-or “pioneer”-drug is “safe” and “effective, ” 21 U.S.C. § 355(b)(1), as well as a “certification” relating to each patent that claims the drug or a use of the drug, 21 U.S.C. § 355(b)(2).

         The Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98- 417, 98 Stat. 1585-popularly known as the Hatch-Waxman Act-created an alternative path for manufacturers of generic drugs. Instead of submitting its own clinical data on safety and efficacy, a generic manufacturer may submit an abbreviated new drug application (“ANDA”) showing that the generic version of the drug contains the same active ingredient as the pioneer drug and is “bioequivalent” to that drug. 21 U.S.C. § 355(j); see AstraZeneca Pharm. LP v. FDA, 713 F.3d 1134, 1136 (D.C. Cir. 2013) (“ANDAs need not include new clinical studies demonstrating . . . safety or efficacy, but must propose the same basic labeling as approved for the pioneer drug.”). In creating this shortcut, Congress sought to encourage “the development of generic drugs to increase competition and lower prices.” Amarin Pharm. Ireland Ltd. v. FDA, 106 F.Supp.3d 196, 198 (D.D.C. 2015). But, at the same time, Congress recognized that it needed to maintain “incentives for pharmaceutical companies to invest in innovation and the creation of new drugs.” Id. Accordingly, Congress “provided increased intellectual property rights and periods of market exclusivity for those pioneer manufacturers that invent new drugs.” Id.; see also 21 U.S.C. § 355(j)(5)(F); AstraZeneca, 713 F.3d at 1136. After the period of marketing exclusivity ends, however, the FDA may ordinarily approve ANDAs, thus authorizing the marketing of competing, generic versions of the pioneer drug. AstraZeneca, 713 F.3d at 1136; see 21 U.S.C. § 355(j).

         Although this statutory scheme proved successful in encouraging generic competition while maintaining the impetus to innovate, it failed to provide sufficient incentives for drug companies to conduct research on the effects of new drugs on children. In 1997, Congress found that the pharmaceutical industry had “studied and labeled for use in children” only a small portion of the drugs on the market, even though “children suffer from many of the same diseases as adults and are often treated with the same medicines.” S. Rep. No. 107-79, at 3-4 (2001). After looking for the cause of this lack of pediatric research, Congress concluded that “there [was] little incentive for drug sponsors to perform studies for medications which they intend to market primarily for adults and [the] use [of which] in children is expected to generate little additional revenue.” Id. at 4 (quoting S. Rep. No. 104-284 (1996)). The absence of information on pediatric drug safety and efficacy, moreover, exposed children to a number of unique risks:

Dosing children based merely on their lower weight is often imprecise, since their bodies can metabolize medicines differently than adults. Some drugs may have different adverse side effects or toxicities in children than in adults, so estimating dosages for children from dosages found to be safe and effective in adults may not be appropriate. The lack of pediatric studies and labeling information may lead to unintended medical errors and place children at risk of being under-dosed or overdosed with medication. The lack of age-appropriate formulations (e.g., liquid form) can also make it difficult to give children and infants prescribed amounts of a needed medication.

Id. at 3.

         To address this problem, Congress enacted a “pediatric exclusivity” statute. See Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, § 111, 111 Stat. 2296, 2305-09; Best Pharmaceuticals for Children Act, Pub. L. No. 107-109, 115 Stat. 1408 (2002); see also Mylan Labs., Inc. v. Thompson, 389 F.3d 1272, 1276 (D.C. Cir. 2004). Under that law, a drug sponsor that receives “pediatric exclusivity” is entitled to an additional six months of market exclusivity. AR 1390. This protection, moreover, is sweeping; it applies to all “products containing the active moiety that has existing patent protection or exclusivity, ”[1] and it applies both to patent rights and to the FDA's authority to approve ANDAs for competing products. Id.

         Five events must occur for a sponsor to qualify for pediatric exclusivity: (1) the FDA must determine “that information relating to the use of [the] drug in the pediatric population may produce health benefits in that population;” (2) the FDA must make a “written request for pediatric studies;” (3) the applicant must agree to that request; (4) the studies must be “completed using appropriate formulations for each age group for which the study is requested within [the specified] timeframe;” and-most importantly for present purposes-(5) the reports from those studies must be “submitted [to] and accepted” by the FDA. 21 U.S.C. § 355a(b)(1) (emphasis added). A sponsor may ask the FDA to issue a written request by filing “a proposed pediatric study request” (“PPSR”). 21 U.S.C. § 355a(d)(3). Before issuing the written request, the FDA must consult with the sponsor, 21 U.S.C. § 355a(d)(1)(A), and submit the request for review by the Pediatric Review Committee, 21 U.S.C. § 355a(f)(1), (2). That committee includes experts in, among other fields, pediatrics, biopharmacology, chemistry, and “the appropriate expertise pertaining to the pediatric product under review.” 21 U.S.C. § 355d. When issued, the written request asks the sponsor to “conduct pediatric studies” within a certain timeframe and to “propose pediatric labeling resulting from such studies.” 21 U.S.C. § 355a(d)(1)(A).

         The written request “serves as a yardstick against which the sponsor's eligibility for pediatric exclusivity is later measured.” Dkt. 65-1 at 16. As the FDA explains, “[g]iven the breadth of the benefit available to sponsors who qualify for pediatric exclusivity, the agency generally asks for a full range of studies designed to provide meaningful information regarding use of the drug in all of the pediatric populations in which the drug is likely to be used.” Id. at 15-16. The written request also includes “specific details regarding study design and endpoints, [the] number of patients to be studied, and study duration.” Id. at 16.

         After the sponsor completes the studies and submits its reports, the FDA is required to decide within 180 days whether to “accept or reject such reports.” 21 U.S.C. § 355a(d)(4). The FDA must accept the reports if the sponsor's studies satisfy the three exclusive conditions set forth in the statute. In the words of the statute:

The Secretary's only responsibility in accepting or rejecting the reports shall be to determine, within the 180-day period, whether the studies [1] fairly respond to the written request, [2] have been conducted in accordance with commonly accepted scientific principles and protocols, and [3] have been reported in accordance with the requirements of the Secretary for filing.

Id. (emphasis added). The Pediatric Review Committee may review the studies for purposes of making a recommendation on whether the FDA should accept or reject the reports, but it is not required to do so. 21 U.S.C. § 355a(f)(3).

         B. Regulatory Background

         This case turns on the meaning of the “fairly respond” requirement, and, it is fair to say, the FDA's approach to this statutory language has “[e]volv[ed]” over the years. Dkt. 60-1 at 13. Prior to 2001, the FDA apparently required that the sponsor satisfy each and every term of the written request. In Merck & Co. v. FDA, 148 F.Supp.2d 27 (D.D.C. 2001), a drug sponsor challenged that interpretation after the FDA denied its request for pediatric exclusivity. Id. at 30. Judge Robertson concluded that denying pediatric exclusivity “for failure to meet a single term of a written request would not be in accordance” with the statute. Id. The statute, he explained, “plainly does not require compliance with every single provision of a written request, but requires only that a pediatric study ‘fairly respond' to a written request.” Id. The Court, accordingly, extended its earlier temporary restraining order, which had “stayed the effectiveness . . . of the FDA's refusal” of pediatric exclusivity. Id. at 31.

         The FDA's most recent interpretation of the statute is set forth in a letter decision issued by the Deputy Director for Clinical Science, Center for Drug Evaluation and Research on August 2, 2017, resolving Amgen's administrative appeal. See AR 1632-50. Under the interpretation set forth in that letter, the “fairly respond” requirement can be satisfied in two ways. First, “[w]hen a sponsor meets the terms” of the written request, “the resulting studies” will “fairly respond” to the request because “studies that are carried out in accordance with the trial's plans and objectives, as expressed in the [written request], will generally satisfy the statutory goal of obtaining pediatric use information.” AR 1637. Neither party disputes this aspect of the FDA's interpretation. The parties' disagreement, instead, centers on the second prong of the test. Under that prong, even where “specific terms” of the written request are not met, the FDA will nonetheless “generally consider the sponsor's studies to have ‘fairly responded'” to the written request if the agency, “apply[ing] its scientific expertise, ” determines that the underlying “objectives of the [written request] have . . . been met.” Id. That is, the studies will be accepted if the FDA determines that the studies yielded information that is “clinically meaningful across all age groups and uses cited in the” written request. Id.

         C. Factual Background

         In March 2004, the FDA approved Amgen's drug Sensipar, or cinacalcet hydrochloride, for secondary hyperparathyroidism (“HPT”) in adult patients with chronic kidney disease on dialysis, hypercalcemia in adult patients with parathyroid carcinoma, and hypercalcemia in adult patients with primary HPT who are unable to undergo parathyroidectomy. AR 1403. Several of Amgen's patents claim Sensipar, one of which expires on March 8, 2018. Dkt. 65-1 at 17.

         Amgen, believing that there was “an unmet medical need for the treatment of secondary HPT” in children, submitted a Proposed Pediatric Study Request to the FDA in May 2007. AR 18, 38-42. At that time, cinacalcet's “safety [and] effectiveness in pediatric patients had not been established.” Dkt. 65-1 at 17 (citing AR 14). Amgen, then, submitted a new Proposed Pediatric Study Request in December 2009, stressing that there was a need for pediatric studies because cinacalcet was “already being used off-label in a significant portion of the pediatric dialysis patient population.” AR 1633-34. In May 2010, after “several years of discussions and a pre-clinical study, ” Dkt. 60-1 at 14, the FDA issued a written request to Amgen, see AR 647. As the agency explained, pediatric studies on cinacalcet were necessary because its efficacy in adults “cannot be extrapolated to the pediatric population”: secondary HPT progresses differently in children, and cinacalcet poses unique risks to pediatric patients, whose “skeletal and vascular system[s]” are still developing. AR 648. The written request, accordingly, proposed that Amgen conduct two pediatric studies on “the potential use of cinacalcet hydrochloride in the treatment of secondary hyperparathyroidism” in children “with chronic kidney disease . . . receiving dialysis.” AR 647. The objective of the written request was to obtain information on cinacalcet's efficacy, safety, and tolerability in pediatric patients, including “pediatric patients ages 28 days to < 6 years.” AR 647-48.

         Over the next several years, the written request was amended five times to relax the study parameters, reduce the scope of the studies, or expand the ways in which the requested information could be obtained. See AR 730-48, 755-68, 990-1007, 1035-51, 1076-90; see also Dkt. 60-1 at 14-15; Dkt. 65-1 at 18-19. The final-and operative-version of the written request asked Amgen to complete four clinical studies:

Study 1: A single dose [pharmacokinetics/pharmacodynamics (“PK/PD”)] study in pediatric patients ages 28 days to < 6 years with chronic kidney disease and secondary hyperparathyroidism receiving dialysis.
Study 2: A 30-week, randomized, double-blind, placebo-controlled, safety and efficacy study with a 30-week, open-label, safety extension in pediatric patients ages 6 years to < 18 years with chronic kidney disease and secondary hyperparathyroidism receiving dialysis. This study will include an assessment of pharmacokinetic (PK) parameters using a sparse sampling design. Study 2 has been terminated early and will be analyzed with available data.
Study 3: A 26-week or time-until-transplantation (whichever comes first), open-label, safety study in pediatric patients ages 28 days to < 6 years. . . .
Study 4: A 20-week, randomized, open-label, controlled study in pediatric subjects between the ages of 6 and < 18 years, with secondary hyperparathyroidism and chronic kidney disease who are receiving either hemodialysis or peritoneal dialysis.

AR 1080 (emphasis added). Although Study 1 and Study 3 both involved pediatric patients ages 28 days to < 6 years, they focused on different questions. Study 1 examined cinacalcet's pharmacokinetics (the drug's “movement . . . within the body” such as “absorption, distribution, [and] metabolism”) and pharmacodynamics (“the characteristics of the action of” the drug). Dkt. 60-1 at 15 n.4 (internal quotation marks and citation omitted). Study 3, in contrast, focused on the drug's safety in the youngest pediatric patients. Compared to Study 2, which also examined safety but in older pediatric patients, Study 3 was “shorter, smaller[, ] [and] of limited scope” with a minimum of only 15 completers. Dkt. 65-1 at 19-20; see AR 1063. For a variety of reasons, Amgen struggled to locate an adequate number of patients for Study 3, AR 664-66, but eventually enrolled 18, AR 1159.

         In December 2012, a patient enrolled in Study 2 died. AR 840. Following standard protocol, the FDA issued a partial clinical hold, or a temporary suspension, on further testing on pediatric patients with secondary HPT. Id. While the hold was in effect, Amgen and the agency discussed potential next steps. See AR 858-64. Amgen opted to continue the studies, AR 862, and the FDA replaced Study 2 with Study 4, AR 991-92. The hold, however, affected Amgen's ability to complete Study 3. As Amgen explains, “enrolled patients were not receiving treatment, and five of the eight patients then[-]enrolled in Study 3 discontinued their participation.” Dkt. 60-1 at 17. Amgen and the FDA continued to correspond regarding Amgen's efforts to complete Study 3. See AR 1391-95.

         In late 2015, the FDA rejected Amgen's request for a sixth amendment, which would have lowered the minimum number of completers in Study 3 from fifteen patients to four patients-“the number of completers in the study available at the time.” AR 1338. The agency “did not agree that [four] completers . . . would allow for an adequate characterization of safety for the intended use” and “was not willing to further amend” the written request to lower the study parameters to fit “the amount of data collected.” AR 1138-39. Amgen also sought a meeting with the FDA to discuss Study 3 and the submission of Amgen's supplemental NDA. AR 1099. The FDA denied Amgen's request, asserting that it would “not have any more discussion on” Study 3 and indicating that Amgen's request to meet regarding Amgen's supplemental NDA was premature. AR 1102. The agency eventually met with Amgen on September 21, 2016, “to discuss the overall cinacalcet pediatric development program.” AR 1116.

         On November 23, 2016, Amgen submitted its study reports to the FDA, requested pediatric exclusivity, and sought approval for a pediatric indication for Sensipar. AR 1152. The “only discrepancy” between Amgen's studies and the written request was “the number of completers” for Study 3. AR 1159. The written request required a minimum of 15 patients; Amgen enrolled 18. Id. But only 11 patients exceeded 12 weeks of treatment, and even fewer- just 4 patients-completed the full 26-week study. Id. Nevertheless, Amgen reported, it had collected “sufficient data” to “satisfy the primary objectives” of Study 3, which were to “evaluate the safety and tolerability” of cinacalcet in pediatric patients ages 28 days to < 6 years. AR 1160. In Amgen's opinion, its data was “sufficient . . . to support an indication” in that pediatric population. Id.

         On May 22, 2017, the FDA denied Amgen's request for pediatric exclusivity in a letter decision. AR 1389-98. The agency explained that, in issuing the written request, it sought to “characterize the risks” of using cinacalcet to treat secondary HPT in children with chronic kidney disease on dialysis. AR 1391. But the FDA found that it could not draw “any conclusions about the safety” of the drug in a key age group-patients ages 28 days to < 6 years-because of “Amgen's failure to provide sufficient safety data.” AR 1398. This conclusion was based on the “totality of safety information” Amgen provided, not merely the data generated in Study 3. Id. As the FDA explained, Amgen's reports “could [have] be[en] considered a fair response to the [written request] as a whole” if the company's findings in the aggregate “provided an appropriate safety assessment in younger children.” Id. Instead, the “lack of sufficient safety data” on pediatric patients ages 28 days to < 6 years “led to the inability to clearly establish the safety profile of the drug . . . in accordance with [the] objectives of the amended [written request].” Id.

         D. Procedural History

         Three days after the FDA issued its decision, Amgen filed this action “to compel the FDA” to accept Amgen's reports and to grant pediatric exclusivity for Sensipar. Dkt. 1 at 2 (Compl. ¶ 1). Amgen claimed that the FDA's interpretation of “fairly respond” was contrary to the pediatric exclusivity statute under the Administrative Procedure Act (“APA”), 5 U.S.C. § 701 et seq., Dkt. 1 at 21-23 (Compl. ¶¶ 50-56); that its denial of pediatric exclusivity for Sensipar was arbitrary and capricious, id. at 29-31 (Compl. ¶¶ 76-88); and that its application of its standard violated Amgen's due process rights, id. at 31 (Compl. ¶¶ 89-90). On the same day, Amgen moved for a temporary restraining order or preliminary injunction, arguing that it might “lose the full benefit of its pediatric exclusivity” absent injunctive relief. Dkt. 3 at 10. The Court held a hearing on Amgen's motion on June 2, 2017. Minute Entry (June 2, 2017). After the hearing, however, the parties agreed that Amgen would seek reconsideration and administrative dispute resolution before the FDA and that the proceedings before the Court would be stayed. Dkt. 14. Based on the parties' stipulation, the Court denied Amgen's motion for preliminary relief as moot and stayed the case pending completion of the renewed administrative process. Dkt. 15.

         On remand, the FDA denied both Amgen's request for reconsideration, AR 1484, as well as its appeal of that decision in the FDA's administrative dispute resolution process, AR 1632. During those proceedings, Amgen “pressed the same arguments it makes here”-that the FDA's interpretation of “fairly respond” is foreclosed by the statute and that FDA's application of that standard to Amgen “violated foundational principles of administrative law and due process.” Dkt. 60-1 at 22. In a final letter decision denying Amgen's administrative appeal, the agency set forth the interpretation of “fairly respond” described above. See supra Part I.B. Applying that standard, the FDA affirmed its earlier conclusions that Amgen's studies did not “fairly respond” to the written request because (1) Amgen “fail[ed] to carry out Study 3 in accordance with the [written request]” and (2) Amgen failed to provide “meaningful pediatric use information in children 28 days to < 6 years of age.” AR 1648.

         The dispute then returned to this Court, where the parties jointly proposed an expedited briefing schedule. Dkt. 24. Before either side moved for summary judgment, four generic drug companies-Teva Pharmaceuticals USA, Inc., Barr Laboratories, Inc., Watson Laboratories, Inc., and Amneal Pharmaceuticals LLC-moved to intervene as defendants, Dkt. 26; Dkt. 33, and the Court granted their motions, see Minute Order (Aug. 15, 2017); Dkt. 61. In addition, Amgen moved to complete or supplement the administrative record with several sets of documents that Amgen asserted were considered by the FDA in denying Amgen pediatric exclusivity. Dkt. 38. The Court denied Amgen's motion in part from the bench at a hearing held on September 20, 2017, and directed that the parties meet and confer regarding the remaining portion of Amgen's motion. See Minute Entry (Sept. 20, 2017). After the parties were unable to reach an agreement, they set forth their respective positions in a further filing, Dkt. 53, and the Court denied the remainder of Amgen's request, see Minute Order (Oct. 11, 2017); Dkt. 61.

         Three motions are now before the Court: Amgen's motion for summary judgment, Dkt. 60, the FDA's cross-motion, Dkt. 65, and the intervenor-defendants' joint cross-motion, Dkt. 63. The Court held a hearing on those motions on January 11, 2018. See Minute Entry (Jan. 11, 2018). Because Amgen has represented that a “key patent[] covering Sensipar” is due to expire on March 8, 2018, Dkt. 1 at 4-5 (Compl. ¶ 9), the Court has expedited its resolution of the pending motions.


&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Under Federal Rule of Civil Procedure 56, summary judgment is ordinarily available if the movant demonstrates &ldquo;that there is no genuine dispute as to any material fact&rdquo; and that, based on the uncontested facts, &ldquo;the movant is entitled to judgment as a matter of law.&rdquo; Fed.R.Civ.P. 56(a). In the unique context of a case brought under the APA, however, the district court &ldquo;sit[s] as an appellate tribunal, &rdquo; Marshall Cty. Health Care Auth. v. Shalala, 988 F.2d 1221, 1222-23 (D.C. Cir. 1993), to decide &ldquo;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, &rdquo; Coal. for Common Sense in Gov&#39;t Procurement v. United States, 821 F.Supp.2d 275, 280 (D.D.C. 2011); see also Citizens to Preserve Overton Park, Inc. v. Volpe, 401 U.S. 402, 415 (1971); Sw. Merch. Corp. v. NLRB, 53 F.3d 1334, 1341 (D.C. Cir. 1995). In short, it is the role of the administrative agency to “resolve factual issues” and to “arrive at a decision that is supported by the ...

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