SANOFI-AVENTIS U.S. LLC, Plaintiff, v. FOOD AND DRUG ADMINISTRATION, et al., Defendants.
Civil Action No. 10-01255 (ABJ)
United States District Court, District of Columbia.
Feb. 7, 2012.
842 F. Supp. 2d 195
AMY BERMAN JACKSON, District Judge.
12. Invoicing. The Ombudsman shall submit a statement to the Court approximately monthly for approval of fees and expenses with copies to counsel for both parties. Objections to the statement shall be filed with the Court, with copies to the Ombudsman and to the opposing party, within ten (10) days of the submission of the statement. Any party that does not object to a fee statement within ten (10) days of its submission shall be deemed to have waived any objection permanently. At the conclusion of the ten-day period, the Court will enter an order directing payment from the Court Registry of any sums approved. Any sum approved by the Court shall be paid within fifteen (15) days unless otherwise ordered or agreed upon.
13. Records. The Ombudsman shall keep a complete record of all fees and expenses, which shall be made available at the Court‘s or the parties’ request for their inspection.
14. Payment into Court Registry. Within fifteen (15) days after a payment of the amount of an approved Ombudsman budget to the Designated Account pursuant to Section 10 of this Order of Reference, Class Counsel shall deposit with the Clerk of Court, United States District Court for the District of Columbia, the full amount of the approved budget. Deposits made by Class Counsel shall be placed by the Clerk of Court in an interest-bearing account. Any monies on deposit with the Clerk of Court that are unspent in a given budget period shall be carried over and applied to payment of future fees and expenses of the Ombudsman. The funds deposited by Class Counsel with the Clerk of Court come from “2008 Funds,” as that term is defined in the Settlement Agreement.
15. Refund of Surplus. At such point as the Court concludes that the Ombudsman‘s duties are completed, any surplus funds on deposit with the Clerk‘s Office will be transmitted to Class Counsel for deposit in the “Designated Account,” as that term is defined in the Settlement Agreement.
SO ORDERED.
Emily Johnson Henn, Covington & Burling LLP, Redwood Shores, CA, Peter Oliver Safir, Scott L. Cunningham, U.S. Commodity Futures Trading Commission, Washington, DC, for Plaintiff.
Andrew E. Clark, U.S. Department of Justice, Washington, DC, for Defendants.
AMY BERMAN JACKSON, 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
BACKGROUND
I. Statutory Background
The FDCA requires all new drugs to be approved by the FDA before they are introduced into interstate commerce.
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,”
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.1 In that instance, the statute sets out a procedure under
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), 1984 U.S.C.C.A.N. 2647, 2647. 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“)2 that was previously approved.3
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.
II. Factual Background4
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 Petition5 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 pro-
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. AR 2879-80. According to FDA, “each of [the five prongs] captures different aspects of the active ingredient‘s ‘sameness.‘”8 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-
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:
- 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.
- The amount and nature of potential product contaminants (innate immune agonists) in its generic drug, relative to those in Lovenox.
- 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
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 succeed on the merits of any of the three claims. Sanofi-Aventis U.S. LLC v. FDA, 733 F.Supp.2d 162 (D.D.C. 2010).
On July 28, 2010, the Court granted Sandoz‘s motion for leave to intervene as a defendant. Sandoz‘s Mot. to Intervene [Dkt. # 6]. The parties have now cross-moved for summary judgment on all counts.
STANDARD OF REVIEW
Summary judgment is appropriate “if the movant shows that there is no genuine dispute as to any material fact and the movant is entitled to judgment as a matter of law.”
“The rule governing cross-motions for summary judgment ... is that neither party waives the right to a full trial on the merits by filing its own motion; each side concedes that no material facts are at issue
ANALYSIS
I. FDA did not exceed its authority under the FDCA by requiring Sandoz to submit immunogenicity data as part of its ANDA.
The first question at issue here—whether FDA had the authority to require Sandoz to submit immunogenicity data for generic enoxaparin as part of its ANDA—can be decided on summary judgment because it is a pure question of statutory interpretation. Plaintiff cites
A. The Chevron framework for the review of FDA action
The APA establishes the scope of judicial review of agency action, and the standard of review under the APA is quite narrow. See Vermont Yankee Nuclear Power Corp. v. Natural Res. Def. Council, Inc., 435 U.S. 519, 545-49, 98 S.Ct. 1197, 55 L.Ed.2d 460 (1978).
The Court is required to analyze an agency‘s interpretation of a statute by following the two-step procedure set forth in Chevron U.S.A. Inc. v. Natural Res. Def. Council, Inc., 467 U.S. 837, 104 S.Ct. 2778, 81 L.Ed.2d 694 (1984). First, the Court must determine “whether Congress has directly spoken to the precise question at issue.” Id. at 842. “If the intent of Congress is clear, that is the end of the matter, for the court, as well as the agency, must give effect to the unambiguously expressed intent of Congress.” Id. at 842-43. Courts “use ‘traditional tools of statutory construction’ to determine whether Congress has unambiguously expressed its intent,” Serono Labs., Inc. v. Shalala, 158 F.3d 1313, 1319 (D.C.Cir.1998), including an examination of the statute‘s text, structure, purpose, and legislative history. Bell Atl. Tel. Co. v. FCC, 131 F.3d 1044, 1047 (D.C.Cir.1997).
If the Court concludes that the statute is either silent or ambiguous, the second step of the review process is to determine whether the interpretation proffered by the agency is “based on a permissible construction of the statute.” Chevron, 467 U.S. at 843. Once a reviewing court reaches the second step, it must accord “considerable weight” to an executive agency‘s construction of a statutory scheme it has been “entrusted to administer.” Id. at 844. Indeed, “under Chevron, courts are bound to uphold an agency interpretation as long as it is reasonable—regardless whether there may be other reasonable, or even more reasonable, views.” Serono, 158 F.3d at 1321. And the court must defer to an agency‘s reading of its own regulations unless it is “plainly erroneous or inconsistent with the regulation.” Id. at 1320 (internal quotation marks omitted).
Using this framework, the Court reaffirms the determinations that were made
B. Chevron Step I
Sanofi argues that the FDCA expressly provides that the FDA may not require ANDA applicants to provide any information beyond the eight categories of information listed by Congress in
FDA and Sandoz respond by pointing out that one of the categories listed in
Sanofi submits, fairly, that those words do not literally appear to encompass test results comparing the potential adverse effects of a generic drug to the pioneer. Pl.‘s Mem. at 19. Therefore, the Court cannot enter judgment for the defendants without going beyond the Chevron step I stage.
Defendants note that the statute requires FDA to approve an ANDA unless it determines that “the methods used in, or the facilities and controls used for, the manufacturing, processing and packing of
For the reasons to be set forth in more detail below, the Court agrees. Through the ANDA pathway‘s specific embrace of the NDA requirements, and the imposition of the clear demands in
1. Circuit precedent suggests that the statute is ambiguous, and that the agency has been entrusted with its interpretation.
The Court‘s conclusion is supported by guidance provided in Serono Laboratories, Inc. v. Shalala, 158 F.3d at 1324-25, where the Court of Appeals indicated that the clauses enumerating what the FDA may review in an ANDA should be construed broadly. In Serono, a pharmaceutical company filed an ANDA for a generic version of Serono‘s drug Pergonal, and Serono opposed it with a Citizen Petition. Id. at 1316. The FDA questioned whether the concentration of a certain inactive ingredient in the generic drug raised safety concerns, and in making the ultimate decision that it did not, the agency reviewed three animal studies that the ANDA applicant had submitted as part of its application. Id. at 1323-4. As in this case, the manufacturer of the pioneer drug objected to the consideration of the test results. Id. at 1324. Among other questions in the case, then, the court was asked to address whether the FDA had the statutory authority to consider animal studies submitted as part of an abbreviated application.
The Court of Appeals observed:
The only provision of the Act to which Serono points for support of its no-animal-studies proposition is one that states the FDA “may not require that an abbreviated application contain information in addition to that required by clauses (i) through (viii)” of
21 U.S.C. § 355(j)(2)(A) . Because nothing in those clauses mentions animal studies, Serono contends they are barred. This provision, however, does not bear the weight Serono applies.
Id. at 1324 (internal citations omitted). The same principle applies here.
Serono argued that
[T]he indicated clauses do not suggest that animal studies are in any way disfavored. The clauses simply describe what the “information” in an application must “show.” They do not specify the kinds of studies that can or cannot be used to satisfy the requirement.
Id. The Court then cited one of the categories in
While these observations may not have been necessary to the ruling in Serono, they express a clear view that
Sanofi attempts to distinguish Serono on the grounds that the tests FDA required here were justified under
The Serono court indicated that it was considering the larger question of whether the
On that point, it is important to remember that the first step of the Chevron analysis requires the Court to look not only at the words in question, but at the entire statute. And the text at issue here—the statutory requirement that an ANDA applicant must supply a “full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of [the] drug“—comes straight from the new drug requirements.
Furthermore, an analysis of the provisions in question in the context of the entire statute requires that
Moreover, the fact that
Sanofi does not disagree with that much of the analysis.14 See Tr. at 7, 16. But it insists that
But reading the provision in light of the statutory scheme as a whole militates against this approach. First of all, the words “full description” themselves do not support plaintiff‘s rigid position, and the fact that the ANDA requirement is lifted from the NDA requirements compels a broad reading. Finally, the fact that Congress described the agency‘s task in
Sanofi argues that FDA‘s request for the immunogenicity information was improper because it went beyond a request to compare the impurity content of Sandoz‘s generic drug with that of Lovenox, but asked Sandoz to assess whether any difference in impurities would increase the likelihood of adverse consequences and thus be harmful to consumers. Pl.‘s Mem. at 53-54. It is true that FDA required some of the studies in order to show whether the difference in the impurity profiles of Sandoz‘s generic drug and Lovenox made the generic more likely to cause immune responses than Lovenox.15 See AR 4170-73, 4433. But FDA did not call for the sort of safety and effectiveness tests that are part of an NDA and excluded from the ANDA process; the tests were expressly requested to answer questions about the purity of the product. See AR 4170. And, as counsel for Sandoz pointed out at the motions hearing, if one reads
Counsel for Sandoz: ... I guess what I would say is, first of all if you look at
(j)(4)(A) and it says that FDA has to make findings with respect to manufacturing, processing, packaging, methods and controls adequate, among other things, to assure purity. Now,(j)(4)(A) doesn‘t say the words “in comparison to the brand,” but I think given the whole context of the Hatch-Waxman provisions, it has to be implicit. And that‘s the whole nature of this.Q: Otherwise, what difference would purity make?
A: That‘s right. It‘s only in comparison to the brand. If the brand has a certain level of impurity and you are at or below that level, you‘re okay. If you come in with a product that‘s otherwise the same but your impurity levels are ten times higher than the brand, well that‘s an inquiry that the FDA has to make, and you‘re not going to get approved under that scenario as a true generic under (j).
Tr. at 77-78.
A close reading of the statute suggests that the argument can be put more strongly, and that the comparative nature of the inquiry is not merely implicit, but expressed, in the ANDA provisions. Congress directed FDA to determine whether the generic manufacturer‘s processes and controls were adequate not only to “assure,” but to “preserve” the drug‘s “identity, strength, quality, and purity.”
3. An analysis of the text in light of the statute‘s purpose suggests that the statute is ambiguous.
The Chevron step I exercise also involves a consideration of the provisions at issue in light of the statute‘s purpose. See Mova Pharm. Corp. v. Shalala, 140 F.3d 1060, 1067-68 (D.C.Cir.1998), quoting Pilot Life Ins. Co. v. Dedeaux, 481 U.S. 41, 51, 107 S.Ct. 1549, 95 L.Ed.2d 39 (1987) (“[I]n expounding a statute, we must not be guided by a single sentence or member of a sentence, but look to the provisions of the whole law, and to its object and policy.“). Sanofi cited Mova Pharmaceutical, id., and Schering Corp. v. FDA, 51 F.3d 390 (3d Cir.1995), and maintained that “these statutes are entry-restricting statutes.” Tr. at 28. But the legislative history and the text of the statute point to the opposite conclusion, and the precedents Sanofi cites do not address the situation here.
While certain terms of the Hatch-Waxman amendments may have been the result of a legislative compromise as plaintiff suggested, see Tr. at 51, and they may reflect the balancing of the interests of manufacturers of listed drugs, would-be marketers of generics, and consumers, the clear purpose of the amendments is set out in the very first sentence of the House Report: “The purpose of Title I of the bill is to make available more low cost generic drugs by establishing a generic drug approval procedure....” H. REP. NO. 98-857(I), pt. 1, at 1 (1984), 1984 U.S.C.C.A.N. 2647, 2647. The instruction in
Neither Schering Corp. nor Mova Pharmaceutical compels a different conclusion. Both cases raise the market entry concept only in the context of a ruling on the pioneer manufacturer‘s standing, and both found particular provisions—not the statute as a whole or the provisions at issue here—to be barriers to market entry. In Schering Corp., the court found that the bioequivalence requirement contained in
In sum, considering
C. Chevron Step II
At Chevron step II, the Court must ask whether the FDA‘s interpretation of
Here, FDA sought tests that compared the immunogenicity of the generic to the parent, and it specified that the tests were sought to alleviate its concerns about purity. AR 4170. In Serono, the D.C. Circuit underscored that deference is particularly appropriate when FDA approval of drugs is involved. 158 F.3d at 1324. It cited the holding in Schering Corp. that “judgments as to what is required to ascertain the safety and efficacy of drugs fall squarely within the ambit of the FDA‘s expertise and merit deference from us.” Id., quoting Schering Corp., 51 F.3d at 399. Since
According FDA the deference required under Serono to make its own determination about the information it might need, the Court finds that FDA‘s interpretation of the ANDA approval regime was reasonable, and that it was reasonable for the agency to conclude that immunogenicity studies are encompassed by the “full description” described in
FDA maintains that its call for test results was also fully consistent with its regulations. The Court must defer to the agency‘s reading of its own regulations unless it is “plainly erroneous or inconsistent with the regulation,” Serono, 158 F.3d at 1320 (internal quotation marks omitted), and in this case, the Court cannot make such a finding. The FDA regulations implementing the ANDA approval provisions in the statute describe the information applicants must provide to the agency to fulfill each of the requirements listed in
D. The statute did not require FDA to abandon the ANDA pathway and invoke section 355(b)(2).
Finally, contrary to Sanofi‘s contentions, the ambiguity in the ANDA provisions is not clarified by the availability of
Furthermore, as the Court noted in its opinion denying the motion for preliminary injunction, FDA‘s reading of the statute accords with its own regulations on when
FDA‘s determination of what constitutes a modification versus a replication of a listed drug is a scientific determination within the agency‘s area of expertise, and therefore is entitled to heightened deference from this Court. A.L. Pharma, Inc. v. Shalala, 62 F.3d 1484, 1490 (D.C.Cir.1995) (“[C]ourts give a high level of deference to an agency‘s evaluations of scientific data within its area of expertise.“). While “there may well be more than one reasonable way to read” the word modification, it is not unreasonable for FDA to determine that a mere variance in the impurity profile of the drug is not a modification, and therefore, this Court is bound to uphold that interpretation. See Serono, 158 F.3d at 1321.
Sanofi further claims that allowing FDA to require immunogenicity data as part of an AND would render the
Since the statute is ambiguous as to whether FDA may require immunogenicity data and FDA‘s interpretation of the statute is reasonable, the Court finds that FDA did not exceed its authority by requiring Sandoz to submit comparative immunogenicity data as part of its ANDA.
II. FDA did not depart from agency precedent by approving a generic drug that is not fully characterized.
The next question at issue here—whether FDA departed from agency precedent by approving a generic version of enoxaparin without it being fully charac-
Since Sanofi spends the majority of its summary judgment briefing arguing its first and third claims and does not assert any new arguments in support of this second claim, the Court finds no reason to diverge from the reasoning in the memorandum opinion denying the motion for a preliminary injunction on this Count, and it specifically incorporates that analysis here. Sanofi-Aventis, 733 F.Supp.2d at 171-73.
The Court looks to whether the challenged agency decision was “arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with the law.” Sanofi-Aventis, 733 F.Supp.2d at 171, quoting
III. FDA sufficiently proved that Sandoz‘s generic enoxaparin has the same active ingredient as Lovenox.
The final issue here—whether FDA sufficiently proved that Sandoz‘s generic enoxaparin has the same active ingredient as Lovenox—can also be decided on summary judgment because it is a pure question law. Sanofi asks the Court to reverse FDA‘s approval of Sandoz‘s generic enoxaparin based on the way FDA determined active ingredient sameness.
As with Count II, the Court looks to whether FDA‘s determination was “arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with the law.”
Sanofi picks at the third and fifth prongs of FDA‘s five-pronged sameness test, but, as FDA argues, this attempt to invalidate an individual criterion for failing to show active ingredient sameness alone ignores FDA‘s overarching five-pronged approach. FDA‘s Mem. at 35. “Instead of relying solely on ... any ... single criterion, ... FDA relied upon additional overlapping evidence derived from all five criteria” to show sameness. Id.
In criterion three, FDA required Sandoz to utilize direct sequencing techniques to compare the chemical makeup of the enoxaparin in Lovenox with the enoxaparin in Sandoz‘s drug. AR 2897. However, rather than requiring Sandoz to sequence and compare all of the sugar chains (oligosaccharide chains) that make up enoxaparin—which would require completely characterizing enoxaparin—FDA required it to sequence only a comparable subset of oligosaccharide chains. Id. The subset FDA chose included short chains, but excluded the longer chains. Id. FDA explained that these short sugar chains are “the result of the most cleavage reactions of the heparin oligosaccharide chains” and are therefore the most sensitive to variation in the process conditions used to make the drug.19 Id. Therefore, a showing that this subset of sugar chains from both the generic drug and Lovenox possess the same sequence “provides further corroborative evidence that the generic drug product‘s enoxaparin possesses the same distribution of oligosaccharide sequences as Lovenox‘s enoxaparin” and is therefore the same. Id.
Clearly this factor alone is insufficient to show active ingredient sameness because it does not show complete equivalence of the two active ingredients. But, FDA did not rely on sequencing alone to determine active ingredient sameness; rather, it was one of five factors that FDA considered together. FDA concluded that “[t]hese five criteria together comprise a robust test that provides overlapping evidence by which an ANDA applicant for enoxaparin can demonstrate active ingredient sameness for enoxaparin within the meaning of [
However, nowhere in the administrative record does FDA claim that prong five requires a generic enoxaparin manufacturer to show full equivalence of in vivo pharmacodynamics profiles between its drug and Lovenox. Although in FDA‘s response letter to Sanofi‘s citizen petition, criterion five is titled, “Equivalence of In Vivo Pharmacodynamics Profile,” the body of the letter explains that “[t]he comparison of in vivo pharmacodynamics profiles is based upon measurements of in vivo anti-Xa and anti-IIa profiles.” AR 2899.
Furthermore, given the high level of deference this Court must accord FDA‘s determination, Sanofi does not persuade the Court that it was unreasonable for FDA to focus only on anti-Xa and anti-IIa. Although it may be true that “enoxaparin‘s effect on TFPI is a part of its overall pharmacodynamics profile[,]” Pl.‘s Mem. at 42, FDA chose anti-Xa and anti-IIa as the most important factors, AR 2899. FDA therefore, could reasonably have decided that if Sandoz could show that the effect of its drug on the two most important factors was equivalent to Lovenox, then it did not need to further show that the effect on a less important factor was equivalent. This is particularly true given the “overlapping” nature of the five prongs in the sameness test.
Thus, the Court‘s analysis turns on whether the five-pronged approach itself was a reasonable way for FDA to determine active ingredient sameness. Not only did FDA support its approach in a thorough, well-reasoned response to Sanofi‘s citizen petition, but it also carefully considered both sides of the argument internally to settle the internal dispute over the validity of the five-pronged test—before doing so. AR 3836-48, 3853-61. “Of course, differing views among an agency‘s staff may indicate that there is more than one reasonable way to read a statute.... But under Chevron, courts are bound to uphold an agency interpretation as long as it is reasonable—regardless whether there may be other reasonable, or even more reasonable, views.” Serono, 158 F.3d at 1321. While fully characterizing enoxaparin would have been another reasonable, or perhaps even more reasonable, way to determine active ingredient sameness, the Court is satisfied that the five-pronged approach FDA used was reasonable.
The Court is further convinced that the reason FDA required immunogenicity testing was to determine whether the drug contained harmful impurities, not to settle a last minute worry that the five criteria were insufficient to establish sameness. FDA has represented all along that it sought the immunogenicity data in order to determine whether the generic drug contained potentially harmful impurities. See AR 3849-50, 4193-94, 4433-34. And that is exactly what the immunogenicity data Sandoz submitted actually told FDA. AR 4433-35. Perhaps it would have also been rational for FDA to require immunogenicity data to show whether its generic drug contained the same active ingredient as Lovenox. However, that is not why FDA required the data here.
Because FDA‘s request for immunogenicity data in Sandoz‘s ANDA was both lawful and reasonable, its approval of the drug did not constitute an arbitrary departure from agency precedent, and its determination of active ingredient sameness was not arbitrary and capricious, an abuse of discretion, or otherwise not in accordance with the law, the Court will grant defendants’ motions for summary judgment and deny plaintiff‘s cross-motion.
AMY BERMAN JACKSON
UNITED STATES DISTRICT JUDGE