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Graceway Pharmaceuticals, LLC v. Kathleen Sebelius

May 10, 2011


The opinion of the court was delivered by: Reggie B. Walton United States District Judge


The plaintiff filed its Complaint in this case on July 8, 2010, alleging that certain actions taken by the United States Food and Drug Administration (the "FDA") violated both the Administrative Procedure Act ("APA"), 5 U.S.C. § 702 (2006), and the Food, Drug, and Cosmetic Act ("FDCA"), 21 U.S.C. § 355(a) (2006). This case is now before the Court on the parties' cross-motions for summary judgment. See Plaintiff's Motion for Summary Judgment ("Pl.'s Mot."); Federal Defendants' Motion for Summary Judgment ("Defs.' Mot.").*fn1 Defendant- Intervenor Nycomed US, Inc. ("Nycomed") opposes the plaintiff's motion for summary judgment and supports the federal defendants' motion for summary judgment.*fn2 See Def.-Int.'s Mem. at 1. For the reasons explained below, the plaintiff's motion for summary judgment is denied and the defendants' motion for summary judgment is granted.


A. Statutory and Regulatory Framework

The FDCA provides that "[n]o person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application filed pursuant to . . . this section is effective with respect to such drug." 21 U.S.C. § 355(a). In other words, the FDCA "requires all new prescription drugs to obtain FDA approval under a new drug application ('NDA') before they can enter the marketplace." Pl.'s Mem. at 4. An NDA submitted by a drug manufacturer seeking FDA approval of a brand name drug, also known as a pioneer drug,*fn3 must include, among other information, "full reports of investigations which have been made to show whether . . . [the] drug is safe for use and whether [the] drug is effective in use." 21 U.S.C. § 355(b)(1)(A). A drug manufacturer seeking FDA approval of a generic drug may, however, obtain such approval with an abbreviated new drug application ("ANDA"). Id. § 355(j)(1). An ANDA "must show that the generic drug contains the same active ingredient as the pioneer, in the same strength, dosage form, and route of administration; is labeled for the same uses and . . . is shown to be 'bioequivalent' to the pioneer." Pl.'s Mem. at 5 (citing 21 U.S.C. § 355(j)(2)(A)). Thus, rather than requiring a new showing of the generic's safety and effectiveness, the FDCA "requires a showing that the proposed generic operates in the same manner as the pioneer drug on which it is based." Astellas Pharmas, 642 F. Supp. 2d at 14. The FDA must approve the generic manufacturer's ANDA unless the ANDA fails to provide the statutorily required information. See id. (citing 21 U.S.C. § 355(j)(4)).

"A drug shall be considered to be bioequivalent to a listed drug if the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug." 21 U.S.C. § 355(j)(8)(B)(i). Additionally, for locally acting, topical drugs, "the Secretary may establish alternative, scientifically valid methods to show bioequivalence if the alternative methods are expected to detect a significant difference between the [proposed generic] drug and the listed drug in safety and therapeutic effect." Id. § 355(j)(8)(C).

A demonstration of bioequivalence can depend on the type of drugs involved. For example, for drugs that work systemically by circulating in the bloodstream after ingestion in the form of a pill or capsule, bioequivalence is typically measured "by comparing the rate and extent of absorption of the active ingredients in the blood." Compl. ¶ 21. More relevant to this case, for products that are administered topically and act locally, bioequivalence must be measured differently, using a more subjective approach. Id. ¶ 22. For such products, the FDA must often rely on comparative clinical studies to conclude that a proposed generic drug and a pioneer drug are bioequivalent. Id. (citing 21 C.F.R. § 210.24(b)(4)). In a comparative clinical trial, patients are given either the proposed generic drug, the listed drug, or a placebo, with the goal being the determination "whether there is a clinically significant difference in the performance of the two drugs in treating a specific" condition.*fn4 Id. ¶ 23. A comparative clinical trial, therefore, does not directly measure "the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of action." Id.¶ 24 (quoting 21 C.F.R. § 320.1(e), the federal regulation defining bioequivalence); see Compl. ¶ 24 (citing 21 C.F.R. § 324(b) and observing that FDA regulations list methodologies for determining bioequivalence). Nonetheless, because a comparative clinical trial measures the effect of the pioneer drug and the proposed generic in treating a specific condition and compares the results, there can be a finding of bioequivalence even though there is no direct measurement of the rate and extent of drug absorption. Compl. ¶ 24. The bioequivalence analysis can be more complicated when a single, locally acting drug is approved for treating two or more conditions. Id. ¶ 25. Nevertheless, the FDA has allowed a comparative study of a locally acting drug approved to treat one condition to suffice as proof of bioequivalence in the treatment of another condition when the conditions are "related" and involve the "same site of action." Id. ¶ 26. According to the plaintiff, the "rationale behind this practice is that if two conditions are related and occur at the same site of action, [the] FDA can properly extrapolate bioequivalence from one condition to the other." Id.

B. Factual and Procedural History

The plaintiff manufactures Aldara, a topical, locally acting cream that was first approved as a pioneer drug by the FDA on February 27, 1997. Pl.'s Stmnt. ¶ 1. Aldara's active ingredient is imiquimod. Id. Aldara is currently approved by the FDA for the treatment of three conditions (also known as "indications"). Id. ¶ 2; see Defs.' Stmnt. ¶ 1. First, in 1997, the FDA approved Aldara for the treatment of external genital and perianal warts ("genital warts" or "EGW"), a form of sexually transmitted disease caused by infection with certain strains of the human papillomavirus. Pl.'s Stmnt. ¶ 2. Then in 2004, the FDA approved Aldara for the treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses ("actinic keratoses") on the face or scalp. Id. ¶ 3. Actinic keratoses are flat, scaly growths on the skin that usually form on parts of the body that are exposed to direct sunlight. Id. In order to obtain this approval for the use of Aldara in treating actinic keratoses, the FDA required the plaintiff to conduct clinical studies involving patients with actinic keratoses and did not allow the plaintiff to extrapolate the drug's effectiveness in treating actinic keratoses from studies conducted in connection with Aldara's approval in treating genital warts. Id. "Also in 2004, [the] FDA approved Aldara for the topical treatment of biopsy-confirmed, primary superficial basal cell carcinoma" ("sBCC"), which "is among the most common forms of cancers in" Caucasians. Id. ¶ 4.

On June 23, 2004, defendant-intervenor Nycomed submitted to the FDA a draft protocol for conducting a clinical bioequivalence study involving patients with EGW as part of its effort to obtain FDA approval for a generic version of Aldara. Id. ¶ 8. On March 11, 2005, the FDA's Office of Generic Drugs, the division of the FDA charged with reviewing Nycomed's ANDA, provided written comments on Nycomed's proposed protocol in which it instructed the applicant to perform a single clinical bioequivalence study involving patients with actinic keratoses, rather than EGW. Id. ¶ 9; Pl.'s Mem. at 8. On that same date, the Office of Generic Drugs provided the same instructions regarding clinical bioequivalence studies involving patients with actinic keratoses to a number of other applicants seeking approval for generic versions of Aldara. Pl.'s Stmnt. ¶ 10. Four years later, in March of 2009, the Office of Generic Drugs prepared a draft guidance for imiquimod and sent it to the FDA Dermatology Division for review. Id. ¶¶ 12-13.

In its June 15, 2009 response, the Dermatology Division rejected the Office of Generic Drugs' view that a single study concerning actinic keratoses was appropriate. Id. ¶ 14. Rather, the Dermatology Division recommended that if the FDA were going to allow generic applicants for Aldara to conduct a single clinical trial for purposes of demonstrating bioequivalence, that the study should involve patients with sBCC, not actinic keratoses. Id. The Dermatology Division later went a step further and recommended that applicants for generic versions of Aldara conduct clinical studies involving patients with EGW as well. Id. ¶ 15.

On July 30, 2009, the plaintiff filed a Citizen Petition in which it asked the "FDA to require any ANDA for a generic imiquimod cream product relying on Aldara as the [pioneer drug, or] referenced product[,] to include [among other things,] comparative clinical data showing bioequivalence in patients with genital warts."*fn5 Id. ¶ 19. The Petition set forth the plaintiff's view that genital warts are completely unrelated to actinic keratoses and sBCC, both in terms of the cause and the nature of the conditions. Id. ¶ 21. The Petition further explained the plaintiff's position that genital warts have a different site of action than actinic keratoses and sBCC because they occur in "very different skin at very different locations on the body." Id. In other words, the plaintiff's Citizen Petition made both "relatedness" and "site of action" arguments. July 30, 2009 Citizen Petition of Graceway Pharmaceuticals ("Citizen Petition") at 7 (FDA 000007).*fn6

As part of the FDA's review and analysis of the plaintiff's Citizen Petition, the FDA's Center for Drug Evaluation and Research ("CDER"), Office of Regulatory Policy, prepared a set of questions and formally presented them to both the FDA's Office of Generic Drugs and the Dermatology Division. Defs.' Stmnt. ¶ 33. The Office of Generic Drugs responded to the Office of Regulatory Policy's questions with a 42-page memorandum, in which it set forth its reasons for concluding that a "well-designed imiquimod bioequivalence study that did not include an EGW study would be sufficiently sensitive to detect formulation differences." Id. ¶ 34. By contrast, the Dermatology Division responded to the questions with a five-page memorandum, in which it noted its agreement with the plaintiff that EGW is unrelated to and occurs at different anatomical locations than actinic keratoses and sBCC. Id. ¶ 35. The Dermatology Division also recommended that trials involving patients with EGW should be required to establish bioequivalence between Aldara and generic imiquimod creams. Id. Due to the conflicting recommendations from the Office of Generic Drugs and the Division of Dermatology, "the matter was elevated" within the FDA and Dr. Julie Beitz, the Director of the Office of Drug Evaluation III, of which the Division of Dermatology is a component, was asked to review and resolve the disputed issues. Id. ¶ 36. Dr. Beitz, an oncologist, an internist, and the supervisor of the FDA dermatologists, id., conducted an independent review of the issues and the relevant scientific literature before ultimately concluding that a clinical trial using patients with actinic keratoses would be "sufficient to establish bioequivalence for generic imiquimod." Id. ¶ 37. Dr. Beitz's decision thus overruled the Division of Dermatology, supported the Office of Generic Drug's conclusion, and resolved the conflict that had arisen between the two divisions of the FDA. Id.

On January 26, 2010, the FDA issued a Citizen Petition Response (the "Response") in which it concluded that a single comparative clinical study involving patients with actinic keratoses is sufficient to demonstrate bioequivalence in all three conditions for which Aldara has FDA approval-genital warts, actinic keratoses, and sBCC.*fn7 Pl.'s Stmnt. ¶ 22; see January 26, 2010 letter from Dr. Janet Woodcock at 1 (FDA000366). The Response drew largely from Dr. Beitz's research and conclusions. Defs.' Stmnt. ¶ 41. In its Response, the FDA rejected the plaintiff's argument that indications must be related for a clinical trial in one indication to establish bioequivalence for a multi-indication drug. Id. ¶ 9. Despite its rejection of the plaintiff's argument that indications must be related in order for the extrapolation of data from a study of one indication to be appropriate, the FDA Response nevertheless concluded that genital warts, actinic keratoses, and sBCC "were in fact related because each [condition] responds to topical treatments that enhance local and cell-mediated immunity in immunocompetent individuals." Id. ¶ 15. The FDA's Response also gave two reasons why the FDA rejected the plaintiff's site of action argument. Id. ¶ 16. First, the FDA concluded that it would be appropriate to use an actinic keratoses trial to establish bioequivalence between Aldara and a generic imiquimod cream even if the sites of action for genital warts and imiquimod were different. See id. ¶ 17 ("The [FDA] explained that 'even for drugs with multiple sites of action, one study would be sufficient to show bioequivalence if the [FDA] reasonably concluded that a showing of equivalent drug delivery . . . in an indication with a certain site of action was sufficiently predictive of equivalent drug delivery at the other site or sites of action."). Second, the FDA concluded that even if separate clinical trials were required where the site of action is different, the outcome with regard to Aldara and generic imiquimod creams would be unchanged because the sites of action for genital warts and sBCC are the same. Id. ¶ 18. The FDA explained that because "the therapeutic action of topical ...

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