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

February 7, 2012


The opinion of the court was delivered by: Amy Berman Jackson United States District Judge


Plaintiff sanofi-aventis U.S. LLC ("Sanofi") brought this action against the Food and Drug Administration ("FDA"), its Commissioner of Food and Drugs, Margaret A. Hamburg, and the Secretary of Health and Human Services, Kathleen Sebelius, alleging that FDA exceeded its statutory authority under the Federal Food, Drug, and Cosmetic Act ("FDCA") and unlawfully departed from agency precedent when it approved a generic version of the Sanofi drug Lovenox. Sandoz, Inc. ("Sandoz"), the manufacturer of the generic drug, intervened as a defendant, and now the parties have cross-moved for summary judgment. The Court concludes that 1) the FDA acted within its statutory authority when it called for Sandoz to file immunogenicity data as part of its abbreviated new drug application; 2) it did not unlawfully depart from agency precedent by approving a generic before the listed drug had been fully characterized; and 3) it reasonably found that the active ingredient in the generic drug was the same as the active ingredient in Lovenox. Therefore, plaintiff's motion for summary judgment will be denied, and defendants' cross-motions will be granted.


I. Statutory Background

The FDCA requires all new drugs to be approved by the FDA before they are introduced into interstate commerce. 21 U.S.C. § 355(a). It provides two primary pathways for obtaining approval: (1) the new drug application ("NDA"), described in section 355(b); and (2) the abbreviated new drug application ("ANDA") for generic products set forth in section 355(j).

A drug that follows the NDA pathway is referred to as a "pioneer" drug because it is the first drug of its kind to go through an approval process with the FDA. The NDA procedure requires the applicant to conduct a spectrum of safety and effectiveness tests and to inform the FDA of the results. The information that must be provided with an NDA includes in relevant part: "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," § 355(b)(1)(A); "a full list of the articles used as components . . . " and "a statement of the composition." of the drug, § 355(b)(1)(B)-- (C); and, "a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug," § 355(b)(1)(D). Once the drug is approved, it is referred to as a "listed drug." See 21 C.F.R. § 314.3(b).

In some cases, a new drug applicant may seek to rely on research conducted by a third party in order to meet the approval requirements.*fn1 In that instance, the statute sets out a procedure under section 355(b)(2), which requires the applicant to file additional information showing that the drug's approval will not infringe a valid patent. 21 U.S.C.§ 355(b)(2).

Congress added the truncated ANDA approval process to the FDCA as part of the 1984 Hatch-Waxman amendments, which sought "to make available more low cost generic drugs" by providing a pathway that was less costly and time consuming than the NDA process. 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). ANDA applicants must file information showing that the conditions of use, active ingredient, dosage form, strength, route of administration, and labeling of the generic drug are "the same as" those of the reference listed drug ("RLD")*fn2 that was previously approved.*fn3 21 U.S.C.. § 355(j)(2)(A)(i)--(iii), (v). They are thereby relieved of the obligation to supply the extensive testing demonstrating safety and effectiveness that is the hallmark of the NDA process, see § 355(b)(1)(A), but ANDA applicants are still required to supply the other information required of a new drug applicant. See § 355(j)(2)(A)(vi)("An abbreviated application for a new drug shall contain -- . . . (vi) the items specified in clauses (B) through (F) of subsection (b)(1) of this section[.]"). This means the ANDA applicant must list the components and composition of the generic drug, and must provide "a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug . . . ." § 355(b)(1)(a)(D), incorporated into requirements for ANDA applications by § 355(j)(2)(A)(vi).

But, in accordance with Congress's goal to keep the ANDA pathway less costly and time consuming than the NDA pathway, the statute expressly prohibits the FDA from requiring ANDA applicants to submit any other categories of information. § 355(j)(2)(A), (j)(4). Section 355(j)(2)(A) provides: "The Secretary may not require that an abbreviated application contain information in addition to that required by clauses (i) through (viii)." In addition, the statute limits the FDA's discretion to reject an ANDA. § 355(j)(4). Section 355(j)(4) mandates that "the Secretary shall approve" an ANDA "unless" he or she makes certain specified findings, including that the generic drug's active ingredient is not the same as the listed drug's active ingredient, or that "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[.]" § 355(j)(4).

II. Factual Background*fn4

A. Sanofi and Lovenox

Sanofi owns the NDA for the injectable anti-coagulation drug Lovenox, which was approved by FDA in 1993. AR 2881--82. The active ingredient in Lovenox is a compound called enoxaparin sodium ("enoxaparin"). AR 2882. Enoxaparin is made up of a core protein from which an assortment of different sugar chains, known as oligosaccharide chains, extend. AR 5, 12, 2882. To date, no one has fully determined enoxaparin's complete chemical makeup, or fully "characterized" it, because the sugar chains are too difficult to identify, and the relative abundance of the different chains varies from batch to batch of enoxaparin. AR 10--12, 2904.

Apparently, this variation is common among compounds in the class of anticoagulants that enoxaparin belongs to, called low molecular weight heparins. AR 2884.

On February 19, 2003, Sanofi submitted a Citizen Petition*fn5 urging FDA to withhold approval of any ANDA for generic enoxaparin "[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."*fn6 AR 1. FDA ultimately rejected this request to forestall the marketing of a generic.*fn7 AR 2878--2922.

Instead, FDA found that "enoxaparin has been adequately characterized for the purposes of approving . . . generic enoxaparin," and it articulated a five-pronged test to be used to determine whether the active ingredient in any proposed generic version of Lovenox would be the same as the enoxaparin in Lovenox.*fn8 AR 2879--80. According to FDA, "each of [the five prongs] captures different aspects of the active ingredient's 'sameness.'" AR 2879--80.

The record indicates that when the five-pronged approach was under consideration, there was a difference of opinion among two internal FDA units. AR 3836. While the Office of Generic Drugs ("OGD") supported the test, the Office of New Drug Quality Assessment ("ONDQA") argued that the test was insufficient, and that the only way to show active ingredient sameness would be to fully characterize enoxaparin. AR 3836. The determination to adopt the test was made by the Deputy Director of the Office of Pharmaceutical Science, Center for Drug Evaluation and Research, who, in a memorandum that thoroughly considered both sides' arguments, found the five-pronged test to be sufficient. AR 3836--61.

B. Sandoz

On August 26, 2005, while Sanofi's Citizen Petition was pending, Sandoz filed an ANDA for generic enoxaparin. See AR 4440. FDA approved the ANDA on July 23, 2010, and it rejected Sanofi's Citizen Petition the same day. AR 4440--44. The approval process took just under five years, and it included lengthy exchanges between Sandoz and FDA as well as multiple amendments to the ANDA. See AR 4440-44.

At issue here is FDA's request, two years into the approval process, for information regarding the potential of Sandoz's proposed drug to elicit an adverse immune response (its immunogenicity). AR 4167--73. In making its request, FDA relied on studies showing that enoxaparin has been known to cause a dangerous immune response in certain patients, called thrombocytopenia, which can be life-threatening. AR 3848--49, 3853. Importantly, the cause of thrombocytopenia is complex. AR 3854. Although enoxaparin itself can stimulate thrombocytopenia, it may also be stimulated by impurities in the drug. AR 2918, 3848--49, 3853--54. Furthermore, impurities may affect the strength of the reaction when it occurs. AR 2918, 3854.

In a November 5, 2007 letter to Sandoz, FDA concluded that its ANDA was "not approvable because the application does not adequately address the potential for immunogenicity of the drug product." AR 4167. FDA required Sandoz to either amend the ANDA so that it addressed that deficiency or to withdraw the application. AR 4167 In a December 4, 2007 follow-up letter, FDA explained its decision, informing Sandoz that its amended ANDA should address the impurity profile of its generic enoxaparin and suggesting several approaches. AR 4170--74. The letter stated:

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 low molecular weight heparins are associated with a serious immune-driven adverse event, heparin induced thrombocytopenia (HIT). Impurities can interact either with 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. FDA asked Sandoz to address three concerns: x The ability of its generic drug to bind to and form complexes with the compound

PF4, relative to Lovenox. FDA asserted that one known cause of thrombocytopenia is the presence of certain dangerous complexes that are formed when enoxaparin binds to PF4. Furthermore, impurities are known to facilitate the creation of these harmful complexes. Since Sandoz had sufficiently shown that the enoxaparin in its generic drug was the same as in Lovenox, comparative information about the ability of its generic drug to bind to and form these enoxaparin-PF4 complexes relative to Lovenox would shed light on whether the generic drug contains any harmful impurities.

x The amount and nature of potential product contaminants (innate immune agonists) in its generic drug, relative to those in Lovenox.

x The functional immunogenic properties of the generic drug, relative to Lovenox (i.e., its actual effect on immune response). FDA explained that this could be tested by in vitro assays or animal models that would show the immune response elicited by the generic drug as compared to Lovenox.

AR 4170--73.

In response, Sandoz provided FDA with data from laboratory tests that compared the immunity profile and immunogenicity of its generic enoxaparin to Lovenox. AR 4181--90. The results submitted compared Sandoz's generic to Lovenox with regard to: "(a) the ability of enoxaparin to form complexes with PF4, (b) the presence of impurities that could stimulate the immune system directly, (c) activation of human PBMC, and (d) the induction of antibodies to the product in mice." AR 4433; see also AR 4181--90.

Based on all the information that Sandoz submitted, including the immunogenicity data, and its application of the five-pronged test described above, FDA found that "Sandoz's ANDA for enoxaparin sodium injection [met] the requirements for ANDA approval, including those regarding active ingredient sameness and purity of the proposed drug." AR 4437--38.

III. Procedural background

On July 26, 2010, Sanofi filed this action against FDA. Compl. [Dkt. # 1]. Count I alleges that FDA exceeded its authority under the FDCA, in violation of the APA, by requiring Sandoz to submit the immunogenicity data as part of its ANDA. Compl. ¶¶ 37--42. Count II alleges that FDA departed from agency precedent in violation of the APA by approving Sandoz's ANDA before enoxaparin had been fully characterized. Compl. ¶¶ 43--46. Count III alleges that FDA exceeded its authority under the FDA and acted contrary to established agency precedent in violation of the APA by approving Sandoz's ANDA without sufficient evidence that the active ingredient in Sandoz's generic enoxaparin was "the same as" the active ingredient in Lovenox. Compl. ¶¶ 47--51.

On the same day it filed its complaint, Sanofi filed a motion seeking a temporary restraining order ("TRO") and preliminary injunction ("PI") to compel FDA to withdraw approval of Sandoz's ANDA pending a trial on the merits. Pl.'s Mot. for TRO and PI [Dkt. # 3]. After consolidating the TRO and PI, the Court denied them both, relying in part on its finding that Sanofi was unlikely to ...

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