United States District Court, District of Columbia
[Copyrighted Material Omitted]
Christian G. Vergonis, Jacob M. Roth, Rosanna K. McCalips, Thomas F. Cullen, Jr., Jones Day, Matthew David Peterson, Peterson Wilmarth and Robertson, LLP, Washington, DC, for Plaintiff.
Andrew E. Clark, U.S. Department of Justice, Washington, DC, for Defendants.
John Robert Fleder, Jennifer McVey Thomas, Hyman, Phelps & McNamara, PC, Chad A. Landmon, Axinn, Veltrop & Harkrider LLP, Edward Anthony Figg, Glenn E. Karta, Sharon Lynch Davis, Rothwell, Figg, Ernst & Manbeck, PC, Washington, DC, Elizabeth P. Retersdorf, Axinn, Veltrop & Harkrider LLP, Hartford, CT, Evan S. Storm,
Nicholas E.O. Gaglio, Suchira Ghosh, Axinn, Veltrop & Harkrider LLP, New York, NY, for Defendants-intervenors.
ELLEN SEGAL HUVELLE, District Judge.
ViroPharma, Inc., manufactures the antibiotic Vancocin® . On April 13, 2012, ViroPharma sued Margaret Hamburg, in her official capacity as the Commissioner of the Food and Drug Administration; Kathleen Sebelius, in her official capacity as the Secretary of the Department of Health and Human Services; and the agencies themselves (collectively, the " FDA" ) to challenge the FDA's approval, on April 9, 2012, of three Abbreviated New Drug Applications (" ANDAs" ) permitting the marketing of generic versions of Vancocin (vancomycin hydrochloride capsules or " vancomycin" ). ( See Complaint, April 13, 2012 [Dkt. No. 1] (" Compl." ).) ViroPharma alleges that the FDA approved the three ANDAs (1) in violation of ViroPharma's statutory right under the Federal Food, Drug, and Cosmetic Act (" FFDCA" ), 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 (laboratory) bioequivalence testing in violation of the FDA's own regulations requiring in vivo (human) bioequivalence testing. ( Id. ¶ 2.) The Court will refer to these as ViroPharma's " statutory exclusivity claim" ( see id. ¶¶ 75-78 (Count II)) and its " bioequivalence claim." ( See id. ¶¶ 69-74 (Count I).)
Before the Court is ViroPharma's motion for a preliminary injunction to require the FDA to withdraw its approval of the three vancomycin ANDAs and to refuse to approve any additional vancomycin ANDAs until ViroPharma's claims are adjudicated on the merits. ( See Motion for a Temporary Restraining Order and/or Preliminary Injunction, April 13, 2012 [Dkt. No. 4] (" Pl.'s Mot." ). ) The FDA has opposed ViroPharma's motion ( see Federal Defendants' Memorandum in Opposition to Plaintiff's Motion for Temporary Restraining Order and/or Preliminary Injunction, April 17, 2012 [Dkt. No. 22] (" FDA Opp'n" )), as have defendants-intervenors, the three generic manufacturers whose vancomycin ANDAs have been approved. ( See Intervenor-Defendant Akorn's Memorandum in Opposition to ViroPharma Incorporated's Motion for a Temporary Restraining Order, April 17, 2012 [Dkt. No. 23] (" Akorn Opp'n" ); Alvogen, Inc.'s Memorandum in Opposition to Plaintiff ViroPharma Inc.'s Motion for Temporary Restraining Order and/or Preliminary Injunction, April 17, 2012 [Dkt. No. 24] (" Alvogen Opp'n" ); Opposition of Defendant-Intervenor Watson Laboratories, Inc. to Plaintiff's Motion for Temporary Restraining Order and/or Preliminary Injunction and Expedited Hearing, April 17, 2012 [Dkt. No. 25] (" Watson Opp'n" ).)
Following a hearing held on April 19, 2012, and having considered all of the parties' arguments and pleadings, including the reply filed by plaintiff after the hearing ( see Reply, April 20, 2012 [Dkt. No. 32] (" Pl.'s Reply" )), the Court concludes that ViroPharma has not demonstrated that it is entitled to a preliminary injunction. Therefore, its motion will be denied.
Prior opinions of this Court and others describe the background relevant to ViroPharma's
statutory exclusivity and bioequivalence claims.
I. STATUTORY AND REGULATORY FRAMEWORK
A. ViroPharma's Statutory Exclusivity Claim
Prior to 1997 and the passage of the [Food and Drug Modernization Act of 1997 (" FDAMA" ), Pub. L. No. 105-115, 111 Stat. 2296], " antibiotic" drugs were approved under Section 507 of the FFDCA, 21 U.S.C. § 357 (" Section 507" ), and non-antibiotic drugs were approved under Section 505, 21 U.S.C. § 355 (" Section 505" ). This difference had a long history, dating back to the development of penicillin, the first drug to have the capacity to kill microbes, i.e., be " anti-biotic." Because penicillin was manufactured in batches through fermentation, its strength and efficacy could vary depending on the rigor of that process. Congress required that FDA test all batches of penicillin to ensure that appropriate doses were administered to the military during World War II. Initially, Section 507 applied only to penicillin or any derivative of penicillin; other named antibiotic drugs were added to the statute as they were developed. When the FFDCA was amended in 1962, a more generalized definition was added so that the law would not need amending with each new discovery of an antibiotic drug. [ See Drug Amendments of 1962, Pub. L. No. 87-781, 76 Stat. 780.]
Two key consequences arose from these different treatments. Applicants for generic versions of antibiotic drugs were only requested to show conformance with statutorily-mandated, published standards of identity, strength, quality, and purity for the antibiotic substance, as reflected in antibiotic " monographs" published by FDA. Pharmaceutical companies did not have to submit the safety and efficacy data that was required for pioneer and generic non-antibiotic drugs. Therefore, generic antibiotics were developed and marketed fairly readily. See Glaxo, Inc. v. Heckler, 623 F.Supp. 69, 72 (E.D.N.C.1985); Abbreviated New Drug Applications, Proposed Rule, 54 Fed.Reg. 28,872, 28,878 (July 10, 1989). However, antibiotic drugs did not receive the patent listing, patent certification, and marketing exclusivity benefits available to pioneer and non-antibiotic drugs after enactment of the Drug Price Competition and Patent Term Restoration Act (" Hatch-Waxman" ), Pub. L. No. 98-417, 98 Stat. 1585 (1984)....
The significance of the Hatch-Waxman Amendments to FFDCA cannot be understated. 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, 623 F.Supp. at 72. 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(jj). 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).
Because 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) which bars FDA approval of a generic ANDA for the NDA product. See 21 U.S.C. § 355(c)(3)(D)(ii)-(iv), (j)(5)(D)(ii)-(iv).
Allergan, Inc. v. Crawford,
398 F.Supp.2d 13
Thus, pursuant to Hatch-Waxman's provisions, " pioneer drug companies are entitled to certain periods of marketing exclusivity during which they are protected from generic competition." AstraZeneca Pharm. LP v. FDA, 850 F.Supp.2d 230, 234 (D.D.C.2012). " Included among these various exclusivity periods is what is sometimes referred to as a ‘ new patient population’ or ‘ new indication’ exclusivity because it frequently arises when a pioneer drug company conducts post-approval clinical studies, submits a supplemental application to the FDA [ (an " sNDA" ) ], and secures the FDA's approval to market an approved drug to a new population or for a new indication." Id. Specifically, if an sNDA is approved and it
contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the [sNDA] and conducted or sponsored by the person submitting the [sNDA], the [FDA] may not make the approval of an [ANDA] submitted ... for a change approved in the supplement effective before the expiration of three years from the date of the approval of the [sNDA].
21 U.S.C. § 355(j)(5)(F)(iv).
Although referred to " new indication exclusivity," this provision applies beyond situations where an existing drug is approved for the treatment of a disease for which it had not been approved before. " 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." AstraZeneca, 850 F.Supp.2d at 235. Therefore, labeling changes approved in an sNDA can qualify for exclusivity under § 355(j)(5)(F)(iv) as well. As relevant here, if an sNDA that prescribes labeling changes is approved on the basis of " new clinical investigations (other than bioavailability studies) ... conducted or sponsored by the person submitting the [sNDA]," then an ANDA that includes the labeling changes may only be approved three years thereafter. 21 U.S.C. § 355(j)(5)(F)(iv). And because a generic drug product may not be approved unless its label is (with certain exceptions not relevant here) the " same as" the brand-name drug's label, id. § 355(j)(2)(A)(v); 21 C.F.R. § 314.94(a)(8)(iv), if an approved sNDA prescribing labeling changes qualifies under 21 U.S.C. § 355(j)(5)(F)(iv), then the three years of labeling exclusivity the statute provides can in practice amount to an exclusive right to market the drug for that time period.
As described above, however, when Hatch-Waxman was enacted, its exclusivity provisions did not apply to antibiotics such as Vancocin. In 1997, with the enactment of the FDAMA, Congress extended Hatch-Waxman to antibiotics by repealing
Section 507 of the FFDCA and requir[ing] that all applications for antibiotic drugs be submitted under Section
505. FDAMA § 125(d)(1) (Transition). In subsection (d)(1), the Transition provided that applications for antibiotic drugs approved under Section 507 before FDAMA would be considered approved under Section 505. Id. However, subsection (d)(2) added the provision that when " the drug that is the subject of the application contains an antibiotic drug and the antibiotic drug was the subject of any application" received by FDA before the enactment of FDAMA, it is exempt from Hatch-Waxman benefits. FDAMA § 125(d)(2); Proposed Rule: Marketing Exclusivity and Patent Provisions for Certain Antibiotic Drugs, 65 Fed.Reg. 3,623, 3,624-25 (Jan. 24, 2000); Section 507 Repeal Guidance at 2. Specifically, § 125(d)(2) exempts from Hatch-Waxman:
any application for marketing in which the drug that is the subject of the application contains an antibiotic drug and the antibiotic drug was the subject of any application for marketing received by the Secretary of Health and Human Services under section 507 of such Act (21 U.S.C. § 357 [Section 507] ) before the date of enactment of this Act.
Pub. L. No. 105-115, 111 Stat. 2327 (1997), § 125(d)(2) ( reprinted in 21 U.S.C.A. § 355 Historical and Statutory Notes, " Transition" ). Antibiotic drugs that were the subject of pre-FDAMA applications are known as " [O]ld [A]ntibiotics" and will be so referenced here.
Allergan, 398 F.Supp.2d at 17-18. Thus, with the enactment of the FDAMA in 1997, Congress eliminated the separate approval pathway for antibiotics and made antibiotics approved after the statute's effective date, but not Old Antibiotics, eligible for exclusivity provided the other statutory criteria were met. As discussed below, ViroPharma's Vancocin is an Old Antibiotic.
Congress closed this gap when it enacted the QI Program Supplemental Funding Act of 2008, Pub. L. No. 110-379, 122 Stat. 4075 (the " QI Act" ). Section 4 of the QI Act, entitled " Incentives for the Development of, and Access to, Certain Antibiotics," amended the FFDCA to make Old Antibiotics eligible for exclusivity. Id. § 4. Thus, the FFDCA now provides:
Notwithstanding any provision of the [FDAMA] or any other provision of law, a sponsor of [an Old Antibiotic] shall be eligible for, with respect to the drug, the 3-year exclusivity period referred to under clauses (iii) and (iv) of subsection (c)(3)(E) and under clauses (iii) and (iv) of subsection (j)(5)(F), subject to the requirements of such clauses, as applicable.
21 U.S.C. § 355(v)(1)(A). However, Section 4 of the QI Act also provides that the 3-year exclusivity period provided in 21 U.S.C. § 355(j)(5)(F)(iv) is not available for " any condition of use for which the [Old Antibiotic] ... was approved before the date of the enactment [of the QI Act]." Id. § 355(v)(3)(B). The FDA's interpretation of this exemption is the focus of ViroPharma's statutory exclusivity claim.
B. ViroPharma's Bioequivalence Claim
Under the FFDCA, in order for a generic applicant to rely on the record of safety and effectiveness demonstrated by a pioneer drug, known as the " reference listed drug" (" RLD" ) for purposes of the process by which a generic copy gains approval,
an ANDA must include information demonstrating that the generic drug is the same as the RLD in a number of specified ways. 21 U.S.C. § 355(j)(2)(A). Of particular relevance
here, the ANDA must demonstrate that the generic is the " bioequivalent" of the RLD, and is therefore absorbed into the body at the same rate and to the same extent as the innovator drug. [ Id. ] § 355(j)(2)(A)(iv). Where ... " a drug ... is not intended to be absorbed into the bloodstream, the Secretary may establish alternative, scientifically valid methods to show bioequivalence if the alternative methods are expected to detect a significant difference between the drug and the [RLD] in safety and therapeutic effect." [ Id. ] § 355(j)(8)(C).
Depending on the circumstances and the particular drug in question, the FDA may require an applicant [to] use one or more of a variety of different methodologies in order to demonstrate bioequivalence. In general, however, methodologies for demonstrating bioequivalence may be classified as either in vivo ( i.e., through human testing) or in vitro ( i.e., laboratory testing).
ViroPharma, Inc. v. ...