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Astrazeneca Pharmaceuticals Lp v. Food and Drug

July 5, 2012


The opinion of the court was delivered by: Judge Beryl A. Howell


Plaintiff AstraZeneca Pharmaceuticals LP ("AstraZeneca") has manufactured the drug quetiapine fumarate ("quetiapine") under the brand name Seroquel® ("Seroquel") since 1997 without generic competition. AstraZeneca brought this lawsuit, which presents a question of statutory interpretation, against the Food and Drug Administration, Margaret A. Hamburg, M.D., Commissioner of Food and Drugs, and Kathleen Sebelius, Secretary of Health and Human Services (collectively, "the FDA"), to challenge the FDA's approval, on March 27, 2012, of generic versions of Seroquel. See Complaint, ECF No. 1 ("Compl."), ¶ 3.

AstraZeneca believes that, under the plain language of 21 U.S.C. § 355(j)(5)(F)(iv), codifying Section 505(j)(5)(F)(iv) of the Federal Food, Drug, and Cosmetic Act ("FDCA"), it is entitled to total market exclusivity until December 2, 2012 for the safety information encapsulated in "Table 2," which was approved for all Seroquel labels on December 2, 2009 and must be included on the labels of all generic versions of quetiapine. Based upon this belief, AstraZeneca seeks a judgment that the FDA's recent approval of generic versions of quetiapine, while AstraZeneca retains exclusivity over Table 2, violated AstraZeneca's exclusivity rights and was arbitrary, capricious, and contrary to law.

Pending before the Court are Cross-Motions for Summary Judgment filed by AstraZeneca, ECF No. 21, and the FDA, ECF No. 26. For the reasons explained below, the Court denies AstraZeneca's Motion for Summary Judgment and grants the FDA's Motion for Summary Judgment.



1. New Drug Applications

The pharmaceutical drug approval process for both new and generic drugs is governed by the FDCA, as amended by, inter alia, the Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585 ("Hatch-Waxman Amendments") (codified at 21 U.S.C. §§ 355, 360cc (2000), and 35 U.S.C. §§ 156, 271, and 282 (2000)).*fn2 The FDA is the agency charged with approving all new and generic drugs for market. See 21 U.S.C. § 355(a).

Under the FDCA, pharmaceutical drug manufacturers interested in marketing a new pharmaceutical drug (otherwise known as an "innovator" or "pioneer" drug), such as Seroquel, must file a new drug application ("NDA") with the FDA as required by 21 U.S.C. § 355(b)(1), and must demonstrate, inter alia, the safety and efficacy of the drug. See id.; Compl. ¶ 29. Pioneer drug companies must file with the FDA "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,"

21 U.S.C. § 355(b)(1)(A), and other information, including "a full statement of the composition of such drug," 21 U.S.C. § 355(b)(1)(C), and "specimens of the labeling proposed to be used for such drug," 21 U.S.C. § 355(b)(1)(F). "Once the drug is approved, it is referred to as a 'listed drug.'" Sanofi-Aventis U.S. LLC v. FDA, No. 10-1255, 2012 WL 373214, at *1 (D.D.C. Feb. 7, 2012) (citing 21 C.F.R. § 314.3(b)).

The FDA publishes listed drugs in the "Orange Book," which includes information about applicable patents and periods of exclusivity. See Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, available at ("Orange Book"). The Orange Book provides notice to generic drug applicants about when drug patents and periods of exclusivity expire, and when there will be openings to market generic versions of pioneer drugs. See Defs.' Mem. in Supp. of Mot. for Summ. J. ("Defs.' Mem.") at 4.

2. Abbreviated New Drug Applications

The Hatch-Waxman Amendments to the FDCA allowed manufacturers to seek approval from the FDA to market generic drugs by filing an abbreviated new drug application ("ANDA"). See 21 U.S.C. § 355(j). The significance of the Hatch-Waxman Amendments has been aptly noted by other Judges in this Circuit:

Prior to 1984, all applicants seeking to market pioneer drugs or generic non-antibiotic drugs had to file [a new drug application ("NDA")] containing, inter alia, extensive scientific data demonstrating the safety and effectiveness of the drug. See 21 U.S.C. § 355(a)-(b); 21 C.F.R. § 314.50. As a result, few generic non-antibiotic drugs were approved by [the] FDA. See [Glaxo, Inc. v. Heckler, 623 F. Supp. 69, 72 (E.D.N.C. 1985)]. Hatch-Waxman created an abbreviated approval process for generic non-antibiotic drugs, while retaining incentives for pioneer drugs, such as marketing exclusivity and patent protections. See 21 U.S.C. § 355(j). The abbreviated new drug application ("ANDA") process shortens the time and effort needed for approval of a generic drug by allowing the applicant to merely demonstrate its product's bioequivalence to the NDA drug, without reproducing the entirety of the NDA's extensive scientific research. See Eli Lilly and Co. v. Medtronic, Inc., 496 U.S. 661, 676, 110 S. Ct. 2683, 110 L. Ed. 2d 605 (1990) (describing the ANDA process).

ViroPharma, Inc. v. Hamburg, No. 12-0584, 2012 U.S. Dist. LEXIS 56128, at *6-7 (D.D.C. Apr. 23, 2012) (quoting Allergan, Inc. v. Crawford, 398 F. Supp. 2d 13, 16-17 (D.D.C. 2005)).

Unlike applicants for pioneer drugs, applicants for generic drugs are not required to submit clinical data to demonstrate the safety and efficacy of their product. Instead, according to the FDA, "if an ANDA applicant establishes that its proposed drug product has the same active ingredient, strength, dosage form, route of administration, labeling (with certain permissible differences), and conditions of use as a listed drug, and that it is bioequivalent to that drug, the applicant" may rely on the FDA's earlier findings of safety and efficacy for the drug when it was approved as an NDA. Defs.' Mem. at 5; see also 21 U.S.C. § 355(j); Compl. ¶ 34.

FDA-approved generic versions of a drug must utilize the "same" labeling as the labeling approved for the reference-listed drug, except for labeling differences "based on a suitability petition or because the generic drug and the reference drug are produced or distributed by different manufacturers." Compl. ¶ 35; 21 U.S.C. § 355(j)(2)(A)(v) (an ANDA must include "information to show that the labeling proposed for the new drug is the same as the labeling approved for the listed drug referred to in clause (i) . . . ."). FDA regulations require that, when a manufacturer submits an ANDA, "[l]abeling (including the container label, package insert, and, if applicable, Medication Guide) proposed for the drug product must be the same as the labeling approved for the reference listed drug," with certain exceptions not applicable here. 21 C.F.R. § 314.94(a)(8)(iv); see AR 294, 305 (FDA Letter, dated Mar. 27, 2012, to AstraZeneca, explaining that the "FDA concurs that these portions of the labeling are essential to safe use of a generic quetiapine product referencing Seroquel for any indication, and the agency would not approve a quetiapine ANDA referencing Seroquel that omitted them"); Defs.' Mem. at 3 (noting that "the safety information in Table 2 is necessary for safe use of the product and therefore cannot be carved out . . . ").

3. Exclusivity Periods

Since "Congress still wanted to provide incentives for new drug development, alongside the ANDA process that eased the marketing of generic drugs, Hatch-Waxman entitles an NDA applicant to a period of market exclusivity (3 or 5 years, depending on the degree of innovation reflected in the NDA) . . . ." ViroPharma, 2012 U.S. Dist. LEXIS 56128, at *7 (quoting Allergan, Inc., 398 F. Supp. 2d at 17). During an exclusivity period, the FDA is barred from approving a generic ANDA for the NDA product. See id. (citing 21 U.S.C. §§ 355(c)(3)(D)(ii)-(iv), (j)(5)(D)(ii)-(iv)). In this case, for example, following Seroquel's approval on September 26, 1997, the FDA granted AstraZeneca a five-year period of "new chemical entity" exclusivity for Seroquel. Defs.' Mem. at 8.

Pioneer drugs may also be eligible under statutorily prescribed circumstances for additional periods of exclusivity on the basis of medical studies completed after the drug approval process. These additional exclusivity periods "provide incentives to pioneer companies to conduct new clinical investigations [for] previously approved NDAs, including through 'supplemental' NDAs ('sNDAs')." Compl. ¶ 32 (citation omitted).

The statutory provision at issue in this case, 21 U.S.C. § 355(j)(5)(F)(iv), describes one such circumstance, for new indications or uses of the already approved pioneer drug. This section provides:

If a supplement to an application approved under subsection (b) is approved after the date of enactment of this subsection [enacted Sept. 24, 1984] and the supplement contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the supplement and conducted or sponsored by the person submitting the supplement, the Secretary may not make the approval of an [ANDA] . . . for a change approved in the supplement effective before the expiration of three years from the date of the approval of the supplement under subsection (b).

21 U.S.C. § 355(j)(5)(F)(iv).*fn3

Three-year exclusivity under this statutory provision is sometimes referred to as "new indication exclusivity" or "new patient population exclusivity" because it often applies to applications for approval of the use of an already-approved drug for a new medical indication, such as to treat a different disorder, or a new population of patients, such as a new age group. See Defs.' Mem. at 6 (citation omitted); ViroPharma, 2012 U.S. Dist. LEXIS 56128, at *8-9. Under FDA regulations, the FDA will not approve an ANDA for three years following the grant of exclusivity to a pioneer drug if the ANDA "relies on . . . information supporting a change approved in the supplemental new drug application." 21 C.F.R. § 314.108(b)(5)(ii). In this case, for example, the FDA has granted AstraZeneca exclusivity over two pediatric indications for Seroquel until December 2, 2012. Therefore, any generic version of Seroquel approved before that date may not be marketed as a drug for the pediatric indications for which AstraZeneca retains exclusivity.*fn4

Under section 355(j)(5)(F)(iv), approval for a new use of a drug must be predicated on new clinical investigations. The FDA defines "new clinical investigation" in its implementing regulation, 21 C.F.R. § 314.108(a), as "an investigation in humans the results of which have not been relied on by [the] FDA to demonstrate substantial evidence of effectiveness of a previously approved drug product for any indication or of safety for a new patient population and do not duplicate the results of another investigation that was relied on by the agency to demonstrate the effectiveness or safety in a new patient population of a previously approved drug product." 21 C.F.R. § 314.108(a). The FDA elaborates that "data from a clinical investigation previously submitted for use in the comprehensive evaluation of the safety of a drug product but not to support the effectiveness of the drug product would be considered new." Id. In other words, data from a previously submitted clinical investigation may nonetheless be considered "new" if the previous submission was to support the safety of indications already approved in the NDA and the data is later presented in a supplemental NDA to show the effectiveness of the drug for new populations or new indications. Moreover, under section 355(j)(5)(F)(iv), the new clinical investigations must be "essential to the approval of the supplement." In its regulations, the FDA explains that "[e]ssential to approval means, with regard to an investigation, that there are no other data available that could support approval of the application." 21 C.F.R. § 314.108(a).

According to the FDA, the new indication exclusivity regulation, 21 C.F.R. § 314.108, when read in context with the definition of "new clinical investigation," "requires a relationship between the information from the new clinical investigation, the change to the product or to the use of the product approved in the supplement, and the scope of any resulting three-year exclusivity." Defs.' Mem. at 7. Thus, "[i]n accordance with the statute and regulation, the scope of three-year exclusivity depends on the nexus between the subject of the new clinical investigations and the changes to the product that the investigations support." Id.; see also ViroPharma, 2012 U.S. Dist. LEXIS 56128, at *9 ("The FDA has interpreted [§ 355(j)(5)(F)(iv)] as establishing a relationship between the information obtained from the clinical investigation, the change approved through the pioneer drug company's [sNDA], and the scope of the information relied upon by a generic competitor in a specific ANDA.") (quoting AstraZeneca, 2012 U.S. Dist. LEXIS 39611, at *3).

The FDA has issued additional regulations on the implementation of 21 U.S.C. § 355(j)(5)(F)(iv). While not defining all types of changes approved in a supplement warranting 3- year exclusivity, the FDA discussed limits on the scope of this statutory provision. For example, during consideration of proposed implementing regulations, the FDA received comments requesting clarification "whether a clinical investigation establishing new risks could be eligible for exclusivity." Abbreviated New Drug Application Regulations; Patent and Exclusivity Provisions, 59 Fed. Reg. 50,338, 50,356 (Oct. 3, 1994). The FDA responded that "such studies would not qualify for exclusivity because 'protection of the public health demands that all products' labeling contain all relevant warnings.'" Id. (quoting preamble to proposed rule published in 54 Fed. Reg. 28,872, 28,899). The FDA explained that:

Changes that would not warrant exclusivity are, as discussed in the preamble to the proposed rule, changes in labeling that involve warnings or other similar risk information that must be included in the labeling of generic competitors. Applicants obtaining approval for such changes in labeling would, in any event, have no valid interest in precluding such information from the labeling of other products.

59 Fed. Reg. 50,338, 50,357.

The FDA further noted that it "does not consider a study to be 'essential to approval'

simply because the applicant conducted it and submitted the study for agency review . . . ." Id. Rather, citing the legislative history, the FDA stated that 3-year exclusivity is reserved for investigations "that are necessary for approval of important innovations," and require "a considerable investment of time and money." Id. at 50,358. According to the FDA, "an applicant is not entitled to 3-year exclusivity merely because it supplements an approved application based in part on a clinical investigation or because it certifies to FDA that the clinical investigation is essential to approval of the application or supplement." Id.*fn5 In short, the FDA regulations make clear that 3-year exclusivity is not triggered merely by labeling changes related to the safety or risks posed by the drug for indications already approved; such changes, if known, would have been incorporated into the original labeling at the time of the approval of the original NDA. Nor is a 3-year period of exclusivity triggered by the simple submission of new clinical investigations or on the applicant's "say-so."


AstraZeneca developed and now manufactures the drug Seroquel, which was first approved by the FDA as an NDA (NDA 20639) on September 26, 1997. See AR 70-81 (FDA Approval, dated Sept. 26, 1997, of Seroquel, NDA 20639); see also Defs.' Mem. at 8 (citing Orange Book). Seroquel is an atypical antipsychotic medication that is used to treat a variety of psychological disorders, including schizophrenia and bipolar disorder.*fn6 Although more than 50 generic atypical antipsychotics have FDA approval, Compl. ¶ 39, Seroquel has been marketed without generic competition for the past fourteen years. See AR 66-67 (Orange Book); see also Defs.' Mem. at 8.

Since Seroquel's approval in 1997, AstraZeneca has filed multiple supplemental applications ("sNDAs"). Based on the approval of those sNDAs, Seroquel has been approved for multiple new medical indications and new patient populations. Although originally used solely for the treatment of schizophrenia, through several sNDAs, Seroquel is now approved for use with the following medical indications and populations: "(1) in adults and adolescents (ages 13 to 17) to treat schizophrenia; (2) in adults, adolescents and children (ages 10 to 17) for the acute treatment of manic episodes associated with bipolar I disorder, both as a monotherapy and as an adjunct to lithium or divalproex; (3) in adults as a monotherapy for the acute treatment of depressive episodes associated with bipolar disorder; and (4) in adults for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex." Defs.' Mem. at 9; see AR 66-69 (Orange Book); see also Compl. ¶¶ 21, 42.

AstraZeneca's labeling has also changed multiple times since Seroquel's original approval. The labeling changes fall into two main categories. First, as the FDA has approved supplements to Seroquel's NDA, the newly-approved medical indications and patient populations ("with accompanying three-year exclusivity periods") have been added to Seroquel's labeling. Defs.' Mem. at 8-9 (citing AR 66-69 (Orange Book)). Second, changes involving new safety information have been made to the labeling. These additional labeling changes, according to the FDA, "have not resulted in exclusivity." Id.

Atypical antipsychotics, such as Seroquel, may have numerous side effects, including hyperglycemia. To minimize the risk of hyperglycemia in users of atypical antipsychotics, the FDA has investigated the metabolic changes caused by that class of medications. See Compl.¶ 51. To this end, the FDA has required manufacturers of atypical antipsychotic drugs to provide data and has mandated labeling changes. See id. ¶¶ 50-54. In 2000, the FDA performed a "comprehensive review" of pre-clinical, clinical, and post-marketing data to see whether atypical antipsychotics disturb glucose regulation. Id. ¶ 51. After reviewing the entire class of atypical antipsychotics, in 2001, the FDA announced that "further study will be needed to elucidate the potential causality of [diabetes mellitus] by" atypical antipsychotics. Id. In September 2003, after years researching the issue, the FDA "mandated a class-wide diabetes/hyperglycemia label change for all atypical antipsychotics," including Seroquel. Id.

The FDA's concern about the effects of atypical antipsychotics on diabetes and hyperglycemia has prompted the agency to require AstraZeneca and other manufacturers continually to update the labels for their atypical antipsychotics with warning information and data that informs prescribers about possible metabolic effects, including glucose shift data.*fn7 Id.

¶ 52.The FDA intended to use the glucose shift data to "'create a universal format for presentation of metabolic information in the atypical package insert labels,'" thereby standardizing the hyperglycemia warning across the entire class of atypical antipsychotic medications. Id. ¶ 53 (quoting the FDA); see also AR 325-39 (FDA Letter, dated Jan. 8, 2008, to AstraZeneca, referencing original NDAs for Seroquel and Seroquel XR and requesting metabolic data analyses for the FDA to evaluate the "effects of atypical antipsychotic drugs on metabolic parameters (e.g., weight, lipids, glucose)"); AR 21 (FDA Email, dated July 22, 2011, to AstraZeneca, stating that "[t]he Division has been working with sponsors class-wide to create a universal format for presentation of metabolic information in the atypical package insert labels.").

As the FDA considered the metabolic data issue for the entire class of antipsychotic drugs, AstraZeneca continued to market Seroquel and invest in research and development to find new indications, patient populations, and forms of Seroquel. In 2007, the FDA approved a new drug application for Seroquel XR, an extended-release tablet version of Seroquel that only had to be taken once a ...

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