IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA

Transcription

1 IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA VIROPHARMA INCORPORATED, 730 Stockton Drive, Exton, PA 19341, Plaintiff, Civil Action No. v. MARGARET A. HAMBURG, M.D., in her official capacity as COMMISSIONER, FOOD AND DRUG ADMINISTRATION, and FOOD AND DRUG ADMINISTRATION, New Hampshire Ave., Silver Spring, MD 20903; KATHLEEN SEBELIUS, in her official capacity as SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES, and DEPARTMENT OF HEALTH AND HUMAN SERVICES, 200 Independence Avenue, S.W., Washington, D.C , Defendants. COMPLAINT FOR DECLARATORY & INJUNCTIVE RELIEF Plaintiff ViroPharma Incorporated ( ViroPharma ) brings this action for declaratory and injunctive relief against the Food and Drug Administration ( FDA ), Margaret A. Hamburg, M.D, in her official capacity as Commissioner of the FDA, the United States Department of Health and Human Services ( HHS ), and Kathleen Sebelius in her official capacity as Secretary of HHS.

2 NATURE OF THE ACTION 1. This action seeks review under the Administrative Procedure Act of the FDA s April 9, 2012 response to ViroPharma s Petition for Stay of Action (the Petition Response (attached hereto as Exhibit A)) and its approval of three Abbreviated New Drug Applications ( ANDAs ) for generic versions of ViroPharma s drug Vancocin (vancomycin hydrochloride) capsules. 2. The FDA approved the three ANDAs (1) in violation of ViroPharma s statutory right under the Federal Food, Drug and Cosmetic Act ( FDCA ), 21 U.S.C. 301 et seq., to a three-year period of exclusivity for Vancocin (extending through December 15, 2014); and (2) based solely on in vitro bioequivalence testing in violation of the FDA s own regulations requiring in vivo bioequivalence test results unless a valid waiver of such testing has been found to be applicable in accordance with FDA regulations. 3. The FDA decisions challenged here are arbitrary, capricious, an abuse of discretion, and otherwise not in accordance with law; were made without observance of procedure required by law; and are in excess of the FDA s statutory jurisdiction, authority, and limitations under the FDCA and the Administrative Procedure Act, 5 U.S.C. 701 et seq. JURISDICTION AND VENUE 4. This Court has jurisdiction over this action pursuant to 5 U.S.C. 555, 702, and 706 (Administrative Procedure Act); 28 U.S.C (federal question); and 28 U.S.C (mandamus). 5. Venue is proper in this district under 28 U.S.C. 1391(e)

3 PARTIES 6. ViroPharma Incorporated is a small pharmaceutical company incorporated in Delaware in ViroPharma is headquartered in Exton, Pennsylvania and has approximately 300 employees. ViroPharma is committed to the development and commercialization of products that address serious diseases, with a focus on products used by physician specialists or in hospital settings. 7. Defendant Department of Health and Human Services is an executive department administered by Secretary Kathleen Sebelius, with responsibility under the Federal Food, Drug and Cosmetic Act for regulating drugs marketed in the United States. 21 U.S.C. 201 et seq. HHS headquarters is located at 200 Independence Ave., S.W., Washington, DC Defendant Kathleen Sebelius is the Secretary of HHS and is responsible for carrying out the powers delegated to the HHS by the FDCA. Secretary Sebelius executes the FDCA through a delegation of authority to the Food and Drug Administration. 21 U.S.C. 393(d)(2). Ms. Sebelius is sued in her official capacity. 9. Defendant Food and Drug Administration ( FDA ) is an administration of the Department of Health and Human Services responsible for regulating drugs marketed in the United States. 21 U.S.C The FDA has its principal office at 5600 Fishers Lane, Rockville, Maryland Defendant Margaret Hamburg, M.D. is the Commissioner of Food and Drugs, with responsibility for executing the FDCA. 21 U.S.C. 903(d). Ms. Hamburg is sued in her official capacity

4 STATEMENT OF FACTS Vancocin: Drug of Last Resort 11. In late 2004, ViroPharma exclusively licensed the right to market the prescription drug Vancocin in the United States from Eli Lilly and Company. 12. Vancocin is the trade name for the FDA-approved drug vancomycin hydrochloride capsules. 13. Ingested orally, Vancocin is used primarily to treat life-threatening gastrointestinal ( GI ) infections cause by the bacterium Clostridium Difficile ( C. difficile ). Vancocin is one of only two drugs approved by FDA to treat C. difficile-associated diarrhea, or CDAD. 14. CDAD is serious, can be life threatening, and is currently an epidemic in the United States. 15. Orally administered Vancocin is effective against GI infections because the active ingredient, after its release into the GI tract, generally is not absorbed into the bloodstream (unless, as indicated in Vancocin s labeling, drug leaks from a diseased gut rather than being absorbed through the intestinal wall) and thus acts locally in the affected area. 16. When CDAD is severe enough to persist even after treatment with other drugs, Vancocin is viewed as a drug of last resort against this potentially fatal infection. 17. In recent years, the occurrence of CDAD has increased dramatically, and an epidemic, toxin-producing new strain has appeared, which can trigger fulminant that is, sudden, severe, and rapidly deteriorating disease within a few days. 18. Vancocin is one of only four drugs that ViroPharma markets, and represents roughly half ViroPharma s revenue

5 19. Prior to acquiring the license to market Vancocin in 2004, ViroPharma had no sales revenue and sustained annual operating losses. 20. ViroPharma relies on revenue from Vancocin sales to fund its research and development efforts. 21. Roughly half of ViroPharma s revenue from product sales derives from sales of Vancocin. 22. Vancocin is no longer subject to patent protection. 23. Upon information and belief, the absence of patent protection, and the recent increase in infections related to C. difficile, have led to increased interest in developing a generic version of Vancocin. 24. On April 9, 2012, the FDA approved for sale in the United States three generic versions of Vancocin. Testing for Generic Bioequivalence: Traditional Approach 25. Under relevant FDCA provisions, parties may file an Abbreviated New Drug Application ( ANDA ) with FDA, seeking approval to market a generic copy of an FDAapproved innovator drug. 21 U.S.C. 355(j). 26. An ANDA can be approved based on the findings of safety and effectiveness of the innovator drug, without the generic manufacturer having to conduct the same costly tests. 27. To rely on an innovator drug product s proven record of safety and effectiveness, the applicant must demonstrate that its drug product is pharmaceutically equivalent and bioequivalent to the innovator drug in essence it must demonstrate that the drug is the same as the innovator product. A finding of pharmaceutical equivalence and bioequivalence means - 5 -

6 that the two products are expected to have the same safety profile and therapeutic effect. 21 U.S.C , 355(j)(2)(A). 28. Once a generic drug is approved, pharmacies, hospitals and other institutions may automatically substitute a marketed generic drug when a doctor prescribes the innovator drug product. In some states such substitution is required by law. 29. In order for bioequivalence to be demonstrated, an ANDA filer must show that its drug, when compared to the brand drug it references in its ANDA (known as the Reference Listed Drug or RLD ), has no significant difference in the rate and extent to which it becomes available at the site(s) of action. 21 U.S.C. 355(j)(2)(A)(iv). 30. For drugs intended to be absorbed into the bloodstream to reach the site of action, bioequivalence is generally demonstrated by showing comparable profiles of an active ingredient s absorption into the bloodstream. 21 U.S.C. 355(j)(8)(B). This is generally demonstrated through blood tests, known as pharmacokinetic or PK studies, that measure the concentration of the active ingredient in the blood at various time intervals after administration. 31. For drugs that are not intended to be absorbed into the bloodstream, such as Vancocin, the FDCA gives the FDA the authority to establish alternative, scientifically valid methods to show bioequivalence if the alternative methods are expected to detect a significant difference between the drug and the listed drug in safety and therapeutic effect. Id. 355(j)(8)(C). 32. Except in certain very limited circumstances, regulations adopted by FDA to implement the statute require bioequivalence to be demonstrated through in vivo testing, i.e., clinical testing on humans. 21 C.F.R In vivo testing methods can include analyses of blood levels through PK studies, analyses of a pharmacodynamic effect produced by the drug s - 6 -

7 activity at the local site of action, and clinical endpoint bioequivalence studies that assess the equivalence of treatment with the generic product to treatment with the brand product in terms of safety and therapeutic effect. 33. FDA regulations permit the FDA to waive the in vivo testing requirement and approve ANDAs based solely on in vitro data only in specific circumstances. 21 U.S.C (f), The FDA s Guidance on bioequivalence recommendations for orally administered drug products, published in March 2003, states that for any drug that produces its effects by local action in the GI tract which includes Vancocin bioequivalence can be established through studies with clinical efficacy and safety endpoints and/or suitably designed and validated in vitro studies, if the latter are either reflective of important clinical effects or are more sensitive to changes in product performance compared to a clinical study. See Letter from Janet Woodcock, M.D. (FDA) to Thomas F. Doyle (ViroPharma) dated April 9, 2012 ( Petition Response ) at 10 (citing FDA Center for Drug Evaluation and Research, Guidance for Industry, Bioavailability and Bioequivalence Studies for Orally Administered Drug Products General Considerations, at 20 (Mar. 2003)) (attached hereto as Exhibit A). 35. Another FDA Guidance published in August 2000 known as the BCS Guidance states the conditions under which in vivo testing can be waived for certain types of orally administered drugs. See Petition Response at 9-10 (citing FDA Center for Drug Evaluation and Research, Guidance for Industry, Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (Aug. 2000) ( BCS Guidance )). The BCS Guidance categorizes drugs based on their solubility, permeability, and rate of dissolution, and provides for - 7 -

8 a waiver of the in vivo bioequivalence testing requirement for orally administered drugs that are intended to be absorbed if they are highly soluble, highly permeable, and rapidly dissolving (i.e., not less than 85% of the labeled amount of the active ingredient dissolves within thirty minutes), known as Class I Drugs. Petition Response at FDA also has acknowledged that since 1996 it has formally recommended in vivo bioequivalence studies for generic copies of Vancocin. See Petition Response at 9 ( FDA s initial recommendation for sponsors to establish bioequivalence to vancomycin capsules was to conduct in vivo studies with clinical endpoints. ). And, until early 2006, FDA consistently affirmed that clinical trials were required to demonstrate bioequivalence to Vancocin. See Petition Response at 9 ( Until 2006, FDA recommended that generic applicants for vancomycin capsules submit an in vivo bioequivalence clinical endpoint study in lieu of in vivo PK measurements to demonstrate bioequivalence of generic vancomycin. ). 37. Upon information and belief, prior to 2006 there was no public statement by the FDA in any forum indicating that the FDA would approve a generic form of Vancocin on the basis of in vitro testing, or that the FDA would even consider doing so. FDA Abandons In Vivo Approach for New, Less Stringent Testing Requirement 38. In or about March 2006, the FDA reversed its established recommendation that in vivo studies were required under FDA regulations to demonstrate bioequivalence for Vancocin by announcing to select individuals and groups that ANDAs for generic forms of Vancocin could be accepted and approved without any in vivo testing, and could instead rely on a mere in vitro dissolution test, which simply compares the rates at which drugs dissolve in laboratory flasks. See Petition Response at

9 39. The FDA sent letters to at least sixteen parties (but not ViroPharma) conveying its revised recommendation that vancomycin bioequivalence can be established using in vitro methods. Petition Response at The letters explained that [v]ancomycin is a highly soluble drug and the reference listed drug (RLD) product [i.e., Vancocin] is rapidly dissolving. Petition Response at 12. Thus, the FDA stated, [w]aivers of in-vivo bioequivalence testing can be requested in [vancomycin] abbreviated new drug applications (ANDAs), provided that the test product is rapidly dissolving at the conditions specified in the [BCS guidance]. Petition Response at Infinium Capital Corp., a Canadian stock analyst that received one of these letters from the FDA, Petition Response at 12 n.69, published a report on March 16, 2006, announcing that the FDA had adopted the unprecedented and more easily satisfied in vitro test for establishing bioequivalence to market generic versions of Vancocin. As a result of this report, ViroPharma stock lost nearly 40% of its value. 42. Although vancomycin is not highly permeable, the FDA nonetheless based its March 2006 bioequivalence recommendation on the BCS Guidance. Petition Response at Relying on faulty dissolution data submitted by third parties purporting to show that vancomycin is rapidly dissolving (and without independently verifying those data), the FDA declared vancomycin to be a BCS Class I drug, and thus eligible for a waiver of in vivo bioequivalence testing. Petition Response at

10 ViroPharma s Petition for Stay of Action 43. On March 17, 2006, immediately after learning of the FDA s action in changing the long-standing in vivo bioequivalence recommendation for vancomycin, ViroPharma submitted a Petition for Stay of Action (the Citizen Petition ) to the FDA pursuant to 21 C.F.R See FDA Docket No. 2006P-0124 (re-designated as 2006-P-0007). 44. The Citizen Petition requested that the FDA stay any agency action that would result in the approval of an ANDA that referenced Vancocin and did not rely on in vivo testing. Petition Response at ViroPharma supplemented its Citizen Petition with additional submissions providing legal and scientific materials setting forth the problems with the FDA s new bioequivalence method and the scientific reasons why in vitro dissolution testing is an inadequate means of determining bioequivalence for vancomycin. In addition, numerous independent consumers, health care providers, and researchers filed comments to the Citizen Petition docket opposing the FDA s recommendation that bioequivalence to Vancocin could be established using in vitro testing only. 46. ViroPharma explained in the Citizen Petition and in the supplemental submissions both its concerns that the BCS Guidance was inapplicable to Vancocin and that waiver of in vivo testing for Vancocin was inappropriate. For example, ViroPharma explained that Vancocin is not highly permeable, may not be highly soluble under physiologically relevant conditions, and is not rapidly dissolving. 47. In response to ViroPharma s submission of data showing that Vancocin is not rapidly dissolving as that term is used in the BCS Guidance, the FDA performed its own dissolution study to determine the dissolution characteristics of Vancocin capsules. Petition

11 Response at 13. The FDA s dissolution study confirmed that Vancocin was not rapidly dissolving. Petition Response at As a result of the dissolution testing results and in response to ViroPharma s Citizen Petition filings, the FDA in December 2008 switched course again and published in the Federal Register a notice of the availability of a document entitled Draft Guidance on Vancomycin Hydrochloride (the Draft Guidance ). 73 Fed. Reg. 76,362, 76,363 (Dec. 16, 2008); Petition Response at 14. The full text of the Draft Guidance is set forth in the Petition Response at pages The Draft Guidance departed from both the FDA s pre-2006 recommendation of in vivo studies, as well as the FDA s March 2006 recommendation to use the BCS dissolution test. Petition Response at Because the FDA s original theory that Vancocin is rapidly dissolving had been disproved, the FDA was forced to abandon the rapid dissolution test that it had advocated in The FDA now suggested that bioequivalence could be demonstrated by a comparable dissolution test if the generic drug product is qualitatively (Q1) and quantitatively (Q2) the same as Vancocin (i.e., contains all the same inactive ingredients in the same amounts). Petition Response at For drugs that are not Q1/Q2 the same as Vancocin, the FDA would require in vivo testing to establish bioequivalence. Petition Response at The Draft Guidance fails to cite any regulatory authority for the approval of vancomycin ANDAs based solely on in vitro bioequivalence testing. 51. In August, 2009, the FDA convened a meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology to advise the FDA regarding the Draft Guidance. The Committee endorsed the idea of an in vitro bioequivalence method provided the generic products are Q1/Q2 the same as Vancocin. The committee was not asked to consider

12 and did not advise the FDA regarding the regulatory basis for the proposed in vitro bioequivalence method for vancomycin. ViroPharma s Request for Three Years of Exclusivity 52. Sections 505(c)(3)(E)(iv) and 505(j)(5)(F)(iv) of the FDCA provides for three years of exclusivity for a supplement to an NDA (an snda ) that 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. 21 U.S.C. 355(c)(3)(E)(iv) & (j)(5)(f)(iv). 53. On December 14, 2011, the FDA approved ViroPharma s snda for Vancocin on the basis of two clinical studies acquired by ViroPharma subject to a substantial financial commitment. These two new studies, the first modern, robust clinical studies ever submitted in support of Vancocin, were essential to modernize Vancocin s label with information guiding the safe and effective use of Vancocin by physicians. As a result of these studies, Vancocin s labeling was extensively changed. 54. Based on the approval of the snda, ViroPharma on December 22, 2011, filed a supplement to its Citizen Petition explaining that it is statutorily entitled to three years of exclusivity under sections 505(c)(3)(E)(iv) and 505(j)(5)(F)(iv) of the FDCA. 21 U.S.C. 355(c)(3)(E)(iv) & (j)(5)(f)(iv)

13 FDA s Response to ViroPharma s Petition, Approval of ANDAs, and Denial of Exclusivity 55. On April 9, 2012, the FDA simultaneously responded to ViroPharma s Citizen Petition and approved three ANDAs for vancomycin. See Petition Response at 2 & n.6 (Ex. A). In the Petition Response, the FDA also denied ViroPharma s claim to three years of exclusivity. Id. at 2. The Petition Response states that a final version of the guidance regarding bioequivalence for vancomycin is forthcoming. Id. at 2 n Based on information and belief, the three companies whose ANDAs were approved are Akorn, Inc., Watson Pharmaceuticals (via its subsidiary Watson Labs), and Alvogen, Inc. in collaboration with Strides Arcolab Ltd. (collectively the generic manufacturers ). 57. Based on information and belief, the FDA did not require these ANDA applicants to submit any data from in vivo or other clinical trials to demonstrate bioequivalence. Rather, the FDA based its approval of the ANDAs on in vitro dissolution testing to establish bioequivalence to Vancocin. 58. The FDA explained at length in the Petition Response the purported scientific rationale for the recommendation of in vitro bioequivalence methods for vancomycin. 59. In the Petition Response, FDA also explained its purported legal authority for approving vancomycin ANDAs based solely on in vitro bioequivalence testing. 60. The FDA claims that it has unfettered authority under its bioequivalence regulations to approve generic drugs based on in vitro bioequivalence methods whenever it chooses. See Petition Response at Specifically, the FDA claims that there is no default requirement for in vivo data to demonstrate bioequivalence, but, instead, the bioequivalence regulations namely 21 C.F.R

14 320.24(a) allow the FDA to determine as an initial matter whether to require in vivo or in vitro bioequivalence testing. The FDA claims that the waiver provisions of 21 C.F.R and come into play only if the FDA decides to require in vivo bioequivalence testing as an initial matter under ; if, by contrast, the FDA, in its unfettered discretion, decides not to require in vivo bioequivalence testing, then the waiver criteria in these regulations are rendered irrelevant. Petition Response at 54 ( In other words, the waiver procedure set forth in section applies only after FDA determines that in vivo data should be submitted. ). 62. The FDA claims that the waiver criteria discussed in the regulations at 21 C.F.R and do not apply to the agency, but rather only apply to ANDA applicants and only if FDA decides to require in vivo bioequivalence testing. Petition Response at 54 ( Subparagraph (2) [of (b)] requires conformance with section when an applicant seeks waiver of an Agency-imposed in vivo data requirement. (emphasis added)). 63. The FDA argues in the alternative that if a waiver were required, a waiver is appropriate for vancomycin ANDAs under 21 C.F.R (e). Petition Response at In fact, the FDA lacked the authority under its regulations to permit in vitro bioequivalence testing for vancomycin. 65. The FDA denied ViroPharma the three years of exclusivity to which it is statutorily entitled based on an erroneous and unreasonable construction and application of a narrow exception to exclusivity contained in section 505(v) of the FDCA, 21 U.S.C. 355(v). In fact, the snda-approved changes to Vancocin s labeling falls outside of this exception and qualifies for exclusivity under the FDCA

15 Irreparable Harm to ViroPharma 66. Upon information and belief, the three generic manufacturers whose vancomycin ANDAs were approved this week are prepared to immediately begin marketing and distributing their generic vancomycin capsules. In fact, on April 10, 2012, Akorn Inc. issued a press release stating that it has already begun shipping its generic vancomycin products. 67. The entry of these three generic products into the market is expected to cause ViroPharma irreparable harm in the form of significant and swift lost sales of Vancocin. 68. FDA s denial of ViroPharma s Citizen Petition, its approval of the generic vancomycin ANDAs, and its denial of ViroPharma s request for three years of exclusivity each constitute final agency action that is subject to judicial review. 5 U.S.C. 701(a), 702, 704. CLAIMS Count I: APA Agency Action Not in Accordance With Regulations 69. ViroPharma repeats, and incorporates by reference, the allegations contained in all of the preceding paragraphs as if fully set forth herein. 70. The FDA violated the Administrative Procedure Act ( APA ), 5 U.S.C. 706(2)(A) & (D), by adopting and applying in vitro dissolution testing as the bioequivalence testing method for vancomycin, in direct conflict with the FDA s own regulations, and by basing its approval of the three generic vancomycin ANDAs on this improper in vitro testing. 71. A plain reading of the bioequivalence regulations requires in vivo bioequivalence testing to support an ANDA unless one of the waiver criteria of 21 C.F.R is met. 72. The FDA failed to establish that the in vitro bioequivalence method for vancomycin recommended in its Petition Response, and relied upon to approve vancomycin

16 ANDAs, satisfies any of the criteria for waiving the in vivo bioequivalence requirement found in 21 C.F.R To the extent FDA purports to have amended its bioequivalence regulations, it has unlawfully done so without the required notice and comment rulemaking. 5 U.S.C Accordingly, the Petition Response and the ANDA approvals fail to comply with FDA s own regulations, and are therefore arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law and without observance of procedure required by law. 5 U.S.C. 706(2)(A) & (D). Count II: APA and FDCA Agency Action Not in Accordance With Statute 75. ViroPharma repeats, and incorporates by reference, the allegations contained in all of the preceding paragraphs as if fully set forth herein. 76. The FDA violated the Administrative Procedure Act ( APA ), 5 U.S.C. 706, and the FDCA, 21 U.S.C. 355(c)(3)(E)(iv) & (j)(5)(f)(iv), by denying ViroPharma s claim to three years of exclusivity to which ViroPharma is entitled under the FDCA by virtue of FDA s approval of ViroPharma s snda, and by approving the three generic vancomycin ANDAs in the face of that exclusivity. 77. Therefore, the FDA s denial of the request for three-year exclusivity contained in ViroPharma s Citizen Petition constitutes agency action unlawfully withheld, 5 U.S.C. 706(1), and is arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law; in excess of statutory jurisdiction, authority, or limitations; and without observance of procedure required by law, 5 U.S.C. 706(2)(A), (C) & (D) 78. Additionally, because the FDA did not account for the three years of exclusivity to which ViroPharma is entitled when the FDA approved the three ANDAs for generic

17 vancomycin, those ANDA approvals violate the FDCA and are arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law and without observance of procedure required by law. 5 U.S.C. 706(2)(A) & (D). Prayer for Relief WHEREFORE, ViroPharma requests that the Court issue judgment in its favor and against defendants and issue the following relief: A. An order and judgment holding unlawful and setting aside the FDA s in vitro bioequivalence method for vancomycin. B. An order and judgment holding unlawful and setting aside the FDA s denial of ViroPharma s Citizen Petition. C. An order and judgment holding unlawful and setting aside the FDA s approval of the ANDAs for generic vancomycin. D. An order and judgment compelling the FDA to grant Vancocin three-year exclusivity (through December 15, 2014). E. An order and judgment enjoining the FDA from issuing any further approvals of generic versions of Vancocin until December 15, 2014, or in the absence of a showing of bioequivalence through in vivo testing. F. To preserve the status quo and to prevent ViroPharma from suffering irreparable harm until ViroPharma can be heard on its preliminary injunction motion, a temporary restraining order setting aside and enjoining the FDA s approval of any vancomycin ANDA and enjoining the FDA from issuing any further approvals of generic versions of Vancocin

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