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Sanofi-Aventis U.S. LLC v. Food and Drug Administration

August 25, 2010


The opinion of the court was delivered by: Emmet G. Sullivan United States District Court Judge


Pending before the Court is the motion for preliminary injunction of Plaintiff Sanofi-Aventis U.S. LLC ("Sanofi"). Plaintiff, manufacturer of the leading and widely prescribed anticoagulant Lovenox, seeks an Order directing the Food and Drug Administration ("FDA") to withdraw its approval of an abbreviated new drug application ("ANDA") submitted by Sandoz Inc. ("Sandoz") for a generic version of Lovenox - enoxaparin sodium injection. Upon consideration of the motion, the response, the reply and surreply thereto, the amicus brief of AARP, the arguments made during the hearing on August 17, 2010, the applicable law, the administrative record, and for the following reasons, the Court hereby DENIES plaintiff's motion for a preliminary injunction.


A. Statutory Background

The Food, Drug, and Cosmetic Act (the "FDCA" or the "Act") provides that "[n]o person shall introduce or deliver for introduction into interstate commerce any new drug" without first obtaining FDA approval. 21 U.S.C. § 355(a). To obtain approval of a "new drug" a pharmaceutical company must file either a new drug application ("NDA") or an abbreviated new drug application ("ANDA"). See id.

Under the FDCA, a company seeking to market a "pioneer" or "innovator" drug must obtain FDA approval by filing an NDA containing, among other things, "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 . . . a full list of the articles used as components of such drug . . . [and] a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug . . . ." Id. § 355(b)(1). After an NDA is approved, this pioneer drug is referred to as the listed drug. 21 C.F.R. § 314.3(b).

Recognizing that the NDA process is costly and time-consuming, and seeking "to make available more low cost generic drugs," Congress amended the FDCA in 1984 to permit a manufacturer of a generic alternative to an RLD to seek FDA approval by submitting an ANDA. Serono Labs., Inc. v. Shalala, 158 F.3d 1313, 1316 (D.C. Cir. 1998) (citing H.R. Rep. No. 98-857, pt. 1 at 14 (1984)). The ANDA process shortens the time and effort needed for new drug approval by, among other things, allowing an ANDA applicant to rely on the FDA's previous findings of safety and effectiveness for the reference listed drug ("RLD").*fn1 See generally 21 U.S.C. § 355(j). Therefore, instead of submitting independent clinical studies in support of the safety and effectiveness of its proposed generic drug, an ANDA applicant must submit sufficient information to establish that its proposed drug is "the same as" the RLD with respect to active ingredient, dosage form, strength, route of administration, and labeling, and that its product is bioequivalent to the listed drug. See id. § 355(j)(2)(A); see also Astellas Pharma US, Inc. v. FDA, 642 F. Supp. 2d 10, 13-14 (D.D.C. 2009) ("Rather than requiring the applicant to make an independent showing that the proposed generic is itself safe and effective, the amended statute requires a showing that the proposed generic operates in the same manner as the pioneer drug on which it is based -- its reference listed drug. Thus, the FDA's approval of a new generic drug relies on its prior determination that the RLD is safe and effective."). "The underlying premise of the ANDA approval requirements is that the generic drug product and the RLD can be substituted for each other with the full expectation that they will have the same clinical effect and safety profile." AR 2879.

The FDA must approve an ANDA unless, among other things, the ANDA sponsor has failed to make the statutorily-required showings of sameness and bioequivalence, or if the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug are inadequate to assure and preserve its identity, strength, quality, and purity. See 21 U.S.C. § 355(j)(4).

B. Factual & Procedural Background

On March 29, 1993, the FDA approved plaintiff's NDA for Lovenox. AR 2881. Lovenox is a widely prescribed anticoagulant used to prevent or treat thromboembolic disease and deep vein thrombosis, as well as to prevent complications associated with angina and certain forms of heart attack. Pl.'s Mem. at 4; AR 2881-82. With its active ingredient enoxaparin sodium ("enoxaparin"), Lovenox is part of a relatively new class of anticoagulants known as low molecular weight heparins ("LMWHs"). AR 2882. LMWHs such as enoxaparin are manufactured by depolymerizing heparin sodium polysaccharide chains into correspondingly shorter oligosaccharide chains. AR 2882.

On February 19, 2003, plaintiff submitted a citizen petition to the FDA requesting that the FDA withhold approval of any ANDA for a generic version of Lovenox "[u]ntil such time as enoxaparin has been fully characterized . . . unless the manufacturing process used to create the generic product is determined to be equivalent to [Sanofi's] manufacturing process for enoxaparin, or the application is supported by proof of equivalent safety and effectiveness demonstrated through clinical trials." AR 1.*fn2 Plaintiff also requested that the FDA refrain from approving any ANDA citing Lovenox as the RLD unless the generic product contained a "1,6 anhydro ring structure" at certain terminal ends of the oligosaccharide chains. AR 1. In its petition, plaintiff argued that "[b]ecause enoxaparin is not fully characterized, utilizing [Sanofi's] process (or an acceptable equivalent) is the only way to ensure that the generic product will contain all of the pharmacologically active components (both known and yet to be discovered) for enoxaparin. Absent that, FDA cannot consider the generic to have the 'same' active ingredient as enoxaparin and must therefore require a demonstration of equivalent safety and effectiveness through clinical testing." AR 4.

On August 26, 2005, while Sanofi's citizen petition was pending, Sandoz filed an ANDA with the FDA seeking approval for a generic version of Lovenox. AR 4167. On November 5, 2007, the FDA sent a letter to Sandoz informing the company that the agency had determined that "the ANDA is not approvable because the application does not adequately address the potential for immunogenicity of the drug product." AR 4167.*fn3 The agency offered, however, to meet with Sandoz "to address what additional information should be provided to adequately address this concern." AR 4167.

In a follow-up letter dated December 4, 2007, the FDA informed Sandoz that:

FDA is particularly concerned with product and process derived impurities that may modify the biological activity or enhance the immunogenicity of your product. Understanding the potential for your product to elicit an immune response is critical, since [LMWHs] are associated with a serious immune-driven adverse event, heparin induced thrombocytopenia ("HIT"). Impurities can interact with either the product or with the host immune system in ways that alter outcome. Thus, for products that have the potential for immunologic adverse events and certainly for products with known immunologic adverse events, the contribution of impurities needs to be carefully considered.

AR 4170. The letter then provided a list of items that Sandoz needed to address as part of its ANDA, as well as a list of suggested approaches to address the agency's concerns. AR 4171-73. Following Sandoz's submission of this additional information, the FDA approved Sandoz's ANDA for generic enoxaparin on July 23, 2010. See AR 4440-41 ("We have completed the review of this ANDA and have concluded that adequate information has been presented to demonstrate that the drug is safe and effective for use as recommended in the submitted labeling. Accordingly, the ANDA is approved, effective on the date of this letter. The Office of Generic Drugs has determined that your Enoxaparin Sodium Injection . . . ...

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