In the Supreme Court of the United States

Transcription

1 Nos , -1039, In the Supreme Court of the United States PLIVA, INC. ET AL., Petitioners, v. GLADYS MENSING, Respondent. ACTIVIS ELIZABETH, LLC, Petitioner, v. GLADYS MENSING, Respondent. ACTIVIS, INC., Petitioner, v. JULIE DEMAHY, Respondent. On Writs of Certiorari to the United States Courts of Appeals for the Fifth and Eighth Circuits BRIEF OF APOTEX, INC. AS AMICUS CURIAE IN SUPPORT OF PETITIONERS CHARLES A. FITZPATRICK III ARTHUR B. KEPPEL Rawle & Henderson LLP The Widener Building One South Penn Square Philadelphia, PA (215) SHASHANK UPADHYE Apotex, Inc. 150 Signet Drive Toronto, ON Canada M9L 1T9 (416) ROY T. ENGLERT, JR.* ALAN UNTEREINER LISA K. HELVIN Robbins, Russell, Englert, Orseck, Untereiner & Sauber LLP 1801 K Street, NW Suite 411 Washington, D.C (202) renglert@robbinsrussell.com * Counsel of Record

2 TABLE OF CONTENTS Page TABLE OF AUTHORITIES... iii INTEREST OF THE AMICUS CURIAE...1 STATEMENT...1 A. The Hatch-Waxman Act and the Federal Regulatory Regime Governing the Labeling of Generic Drugs...1 B. The Proceedings in the Lower Courts...4 C. The Acting Solicitor General s Invitation Brief...8 INTRODUCTION AND SUMMARY OF ARGUMENT...10 ARGUMENT...14 I. THE FIFTH AND EIGHTH CIRCUITS MISUNDERSTOOD AND MISAPPLIED FUNDAMENTAL, LONGSTANDING PRINCIPLES GOVERNING THE DOCTRINE OF IMPLIED PREEMPTION...14 A. The Doctrine Of Conflict Preemption Is An Indispensable Part Of The Constitutional Scheme...15

3 ii TABLE OF CONTENTS Continued Page B. Congress s Failure To Include An Express Preemption Clause In The Hatch-Waxman Act Has No Bearing On Whether Conflict Preemption Bars Respondents Claims...20 C. The Fifth And Eighth Circuits Misapplied This Court s Decision In Wyeth v. Levine...23 II. RESPONDENTS CLAIMS ARE BARRED BY OBSTACLE PREEMPTION...26 III. THE EIGHTH CIRCUIT S APPROACH IS UNWORKABLE AND INCONSISTENT WITH BUCKMAN...30 CONCLUSION...36

4 iii TABLE OF AUTHORITIES Page(s) Cases American Nat l Red Cross v. S.G., 505 U.S. 247 (1992)...19 Brown v. Hotel & Restaurant Employees & Bartenders Int l Union Local 54, 468 U.S. 491 (1984)...16 Buckman Co. v. Plaintiffs Legal Committee, 531 U.S. 341 (2001)... passim Cipollone v. Liggett Group, Inc., 505 U.S. 504 (1992)...17 Crosby v. National Foreign Trade Council, 530 U.S. 363 (2000)...15 Demahy v. Actavis, Inc., 593 F.3d 428 (5th Cir. 2010)... passim Demahy v. Wyeth, 586 F. Supp. 2d 642 (E.D. La. 2008), aff d, 593 F.3d 428 (5th Cir. 2010)...4, 7 Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661 (1990)...2, 27 Fidelity Federal Savings & Loan Ass n v. de la Cuesta, 458 U.S. 141 (1982)...18

5 iv TABLE OF AUTHORITIES Continued Page(s) Freightliner Corp. v. Myrick, 514 U.S. 280 (1995)...19 Gaeta v. Perrigo Pharmaceuticals Co., No (9th Cir. Jan. 24, 2011)...18 Geier v. American Honda Motor Co., 529 U.S. 861 (2000)...17, 19, 22 Gibbons v. Ogden, 22 U.S. (9 Wheat.) 1 (1824)...17, 19 Hines v. Davidowitz, 312 U.S. 52 (1941)...18 Houston v. Moore, 18 U.S. (5 Wheat.) 1 (1820)...17, 19 Hughes v. Oklahoma, 441 U.S. 322 (1979)...16 M Culloch v. Maryland, 17 U.S. (4 Wheat.) 316 (1819)...17, 19 Medtronic, Inc. v. Lohr, 518 U.S. 470 (1996)...32 Mensing v. Wyeth, 588 F.3d 603 (8th Cir. 2009)... passim Mensing v. Wyeth, 562 F. Supp. 2d 1056 (D. Minn. 2008), rev d, 588 F.3d 603 (8th Cir. 2009)...5, 6

6 v TABLE OF AUTHORITIES Continued Page(s) Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005)...2 New York v. United States, 505 U.S. 144 (1992)...16 Perez v. Campbell, 402 U.S. 637 (1971)...18 Rice v. Santa Fe Elevator Corp., 331 U.S. 218 (1947)...31 Savage v. Jones, 225 U.S. 501 (1912)...19 Wyeth v. Levine, 129 S. Ct (2009)... passim Constitutional Provisions, Statutes, and Regulations U.S. CONST. art. I, U.S. CONST. art. VI, cl U.S. CONST. amend. X...15 Drug Amendments of 1962, Pub. L. No , 76 Stat. 780 (1962)...23

7 vi TABLE OF AUTHORITIES Continued Page(s) Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No , 98 Stat (1984) U.S.C. 355(a) U.S.C. 355(b) U.S.C. 355(b)(1) U.S.C. 355(j) U.S.C. 355(j)(2)(A) U.S.C. 355(j)(2)(A)(ii) U.S.C. 355(j)(2)(A)(iv)...2, U.S.C. 355(j)(2)(A)(v)... passim 21 U.S.C. 355(j)(2)(C) U.S.C. 355(j)(4)(G)...3, 10, 12, U.S.C. 355(j)(8)(B) U.S.C. 355(k) U.S.C. 360k(a) U.S.C. 360k(b) C.F.R (d)...27

8 vii TABLE OF AUTHORITIES Continued Page(s) 21 C.F.R , 5 21 C.F.R (2001) C.F.R (2008) C.F.R (c) C.F.R (a) C.F.R (b) C.F.R (c) C.F.R (j) C.F.R (d) C.F.R (a)(8)(iii) C.F.R (a)(8)(iv) C.F.R C.F.R (a) C.F.R (a)(7) C.F.R (b)(1) C.F.R (b)(10)...4

9 TABLE OF AUTHORITIES Continued Other Authorities viii Page(s) 130 CONG. REC. H24421 (Sept. 6, 1984) Fed. Reg. 17,950 (Apr. 28, 1992)... 3, 4, 27, Fed. Reg. 18,764 (Apr. 8, 2004)...4 H.R. REP. NO (I) (1984), reprinted in 1984 U.S.C.C.A.N , 27 H.R. REP. NO (II) (1984), reprinted in 1984 U.S.C.C.A.N Brief for the United States as Amicus Curiae Supporting Petitioners, Warner-Lambert Co. v. Kent, No (filed Nov. 28, 2007)...35 Brief of the Chamber of Commerce of the United States of America as Amicus Curiae in Support of Respondents, Williamson v. Mazda Motors, No (filed Sept. 28, 2010)...16, 17 Brief for the United States as Amicus Curiae Supporting Petitioner, Buckman Co. v. Plaintiffs Legal Committee, No (filed Sept. 13, 2000)...35

10 BRIEF OF APOTEX, INC. AS AMICUS CURIAE IN SUPPORT OF PETITIONERS INTEREST OF THE AMICUS CURIAE 1 Apotex, Inc. is the largest pharmaceutical company in Canada and a leading worldwide manufacturer and distributor of generic pharmaceuticals. Founded in 1974, Apotex manufactures approximately 300 generic drugs and sells those products worldwide. Apotex s customers include physicians, hospitals, and patients in the United States. Apotex has substantial experience dealing with the United States Food and Drug Administration ( FDA ) and the federal statutes and regulations governing the approval and labeling of generic drugs. Accordingly, Apotex has a valuable perspective to contribute to this case as well as a substantial interest in the proper resolution of the important issue presented. STATEMENT A. The Hatch-Waxman Act and the Federal Regulatory Regime Governing the Labeling of Generic Drugs 1. The Drug Price Competition and Patent Term Restoration Act of 1984, known as the Hatch- Waxman Act, modified the FDA approval process for 1 The parties letters of consent to the filing of amicus briefs have been filed with the Clerk. Under S. Ct. Rule 37.6, amicus curiae states that no counsel for a party wrote this brief in whole or in part, and no counsel or party made a monetary contribution intended to fund the preparation or submission of this brief. No person or entity, other than the amicus curiae or its counsel, has made a monetary contribution to this brief s preparation or submission.

11 2 generic drugs. A primary objective of the Act was to make available more low cost generic drugs. H.R. REP. NO (I), at 14 (1984), reprinted in 1984 U.S.C.C.A.N. 2647, Thus, the Act established a framework designed to promote generic competition and speed the FDA approval process for generic drugs. See Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661, 676 (1990). Before the enactment of Hatch-Waxman, manufacturers seeking approval for generic versions of drugs that had been approved after 1962 were required to duplicate the expensive and timeconsuming scientific and clinical studies already performed by the brand-name manufacturers. See H.R. REP. NO (I), at 16; H.R. REP. NO (II), at 2, reprinted in 1984 U.S.C.C.A.N. 2686, 2688; Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193, 196 (2005); see also 21 U.S.C. 355(a), (b) (setting forth new drug application ( NDA ) process for brand-name drugs). The Hatch-Waxman Act eliminated that requirement. It authorized generic drug makers instead to file abbreviated new drug applications ( ANDAs ) that relied on the same clinical safety and efficacy data that had been used to support the NDA. ANDA applicants need only demonstrate that the generic drug is bioequivalent to an approved brand-name drug. Merck, 545 U.S. at 196 n.1; Eli Lilly, 496 U.S. at 676; 21 U.S.C. 355(j)(2)(A)(ii), (iv). This new, streamlined review process speeds the FDA s approval of generic drugs and promotes generic competition. It also eliminates duplication of clinical studies. See Eli Lilly, 496 U.S. at 676; Merck, 545 U.S. at 196 n.1 (citing 21 U.S.C.

12 3 355(j)(2)(A)(ii), (iv), 355(j)(8)(B)). That, in turn, keeps generic drug manufacturers costs down and allows them to offer generic drugs at a lower price, with significant benefits for consumers and for public health. 2. The abbreviated review process rests on the premise that generic drugs are pharmaceutically and therapeutically equivalent to their brand-name counterparts. To ensure that consumers and healthcare professionals appreciate that equivalency, and are not dissuaded from using lower-cost generics based on a misimpression about differences in safety or efficacy, the Hatch-Waxman Act requires the labeling on every generic drug to be the same as the FDA-approved labeling for the drug s brand-name version. 21 U.S.C. 355(j)(2)(A)(v); 21 C.F.R (a)(8)(iii); see also 21 U.S.C. 355(j)(4)(G) (ANDA may be refused if the proposed labeling is not the same as that for the brand-name product); 21 C.F.R (a)(7) (same). Each ANDA must include a side-by-side comparison of the labeling for the generic drug and its brand-name equivalent (21 C.F.R (a)(8)(iv)) in order to enable FDA reviewers to readily identify differences between the two (57 Fed. Reg. 17,950, 17,961 (Apr. 28, 1992)). 2 Even after receiving FDA approval, generic drug manufacturers have a continuing obligation to ensure that their labeling does not deviate from that employed by the brand-name manufacturer. Indeed, the FDA may withdraw approval of an ANDA if it 2 The statute and regulations do permit certain labeling variations not relevant here. 21 U.S.C. 355(j)(2)(A), (C); 21 C.F.R (a)(8)(iv). Notably, additional warnings are not authorized. See also PLIVA Pet. Br

13 4 finds that the generic drug s labeling is no longer consistent with that for the [brand-name] drug. 21 C.F.R (b)(10). Should a generic drug maker determine that labeling changes to its product are warranted, it must seek FDA approval before implementing those changes. Generic drug manufacturers may not modify their products labeling without prior agency approval. See 21 U.S.C. 355(j); 21 C.F.R Instead, the manufacturer must provide adequate supporting information to FDA, and FDA will then determine whether the labeling for the generic and [brand-name] drugs should be revised. 57 Fed. Reg. at 17,961 (emphasis added). 4 B. The Proceedings in the Lower Courts These consolidated cases involve tort actions brought under state law against manufacturers of the generic drug metoclopramide ( MCP ), which is bioequivalent to the brand-name drug Reglan. Plaintiffs in both cases alleged, among other things, that MCP s labeling was inadequate because it failed to provide adequate warnings concerning the risk of developing tardive dyskinesia ( TD ), a neurological movement disorder, from the long-term use of MCP. 3 Section was revised in 2004, 69 Fed. Reg. 18,764 (Apr. 8, 2004), after the relevant events in Mensing v. Wyeth, 588 F.3d 603, 605 (8th Cir. 2009), but before the relevant events in Demahy v. Wyeth, 586 F. Supp. 2d 642, (E.D. La. 2008). Neither the pre-2004, nor the post-2004, version of the regulation authorizes generic drug manufacturers to make labeling changes without FDA approval. Compare 21 C.F.R (2001) with 21 C.F.R (2008). 4 For additional discussion of the federal generic-drug labeling scheme, see PLIVA Pet. Br

14 5 1. Mensing v. Wyeth. Between 2001 and 2005, respondent Gladys Mensing took MCP as prescribed by her physician to treat certain gastrointestinal disorders. After she developed TD, she brought suit against Wyeth, Inc., the manufacturer of Reglan, and four manufacturers of MCP: petitioners Actavis Elizabeth LLC ( Actavis ), PLIVA, Inc., Teva Pharmaceuticals USA, and UDL Laboratories, Inc. Although Mensing advanced a variety of tort claims under Minnesota law, all of her claims targeted the defendants alleged failure to provide adequate warnings. The district court dismissed the failure-to-warn claims against the generic drug manufacturers on the ground that they were impliedly preempted by federal law. 562 F. Supp. 2d 1056 (D. Minn. 2008). The district court conclude[d] that a generic drug manufacturer may not unilaterally strengthen a label without prior approval of the FDA. Id. at In particular, the court rejected Mensing s contentions that a generic manufacturer is free either (1) to alter its labeling without prior approval of the FDA through the Changes Being Effected ( CBE ) regulation, 21 C.F.R (c), or (2) to send Dear Doctor or Dear Health Care Provider ( DHCP ) letters to physicians and other providers. 562 F. Supp. 2d at The court also rejected Mensing s alternative argument that the generic manufacturers should have invoked the prior approval supplemental [PAS] process under 21 C.F.R by asking FDA to approve a global change to the labeling not only of MCP but also of Reglan, explaining that the outcome of such a request was uncertain and would require speculation as to what the FDA might have done. 562 F. Supp. 2d at 1065.

15 6 Relying on this analysis of the governing statute and regulations, the district court concluded that there was a direct conflict between Mensing s claim and the requirements of federal law: [U]nder the federal statutory scheme, the labeling for generic drugs must always remain the same as that of the name brand drug and... a generic drug manufacturer cannot unilaterally change its label without prior FDA approval.... Plaintiff s failure to warn claims... rely on state law imposing a duty on the generic drug manufacturers to provide adequate warnings that Actavis and Pliva allegedly did not provide. Any such duty to unilaterally heighten their warning labels, however, would directly conflict with the federal law requiring that their labels be the same as those of the listed drug, Reglan. 562 F. Supp. 2d at Indeed, the court further explained, under these circumstances, it would be impossible for Actavis and Pliva to abide by both state and federal laws : the generic manufacturers would be forced to choose between complying with the federal law while being exposed to state tort liability, or unilaterally adding a heightened warning to their labels at the risk of exposing themselves to federal liability. Id. at This conflict, the court noted, would also stand as an obstacle to the accomplishment and full purposes and objectives of the Hatch-Waxman Act, a key purpose of which is to increase the availability of low-cost generic drugs and to relax the generic approval and labeling process. Ibid. The Eighth Circuit reversed the dismissal of the failure-to-warn claims against the generic manufac-

16 7 turers. 588 F.3d 603 (2009). That ruling was based, in large part, on the court of appeals view that the generic manufacturers could have either proposed a labeling change through the PAS process or suggested that the FDA send out a warning letter to health care professionals. Id. at The Eighth Circuit also emphasized that Congress could have crafted a preemption provision for generic drugs as part of the Hatch-Waxman Act, but had failed to do so. Id. at 607. Finally, the court reasoned that Wyeth v. Levine, 129 S. Ct (2009), required rejection of the preemption defense even though that case did not involve a generic drug or implicate the policies underlying the Hatch-Waxman Act. 588 F.3d at Demahy v. Wyeth. Between 2002 and 2006, respondent Julie Demahy took MCP manufactured by Actavis for the treatment of acid reflux. After she developed TD in 2007, Demahy brought suit in Louisiana state court against Wyeth and Actavis. After the lawsuit was removed to federal court and Wyeth was dismissed, Actavis moved to dismiss Demahy s state-law claims alleging that Actavis had failed to provide adequate warnings and had withheld information from the FDA concerning the hazards of MCP. The trial court granted the motion with respect to Demahy s fraud-on-the-fda claim, which it held was preempted under Buckman Co. v. Plaintiffs Legal Committee, 531 U.S. 341 (2001), but denied the motion with respect to the failure-to-warn claim. 586 F. Supp. 2d 642, (E.D. La. 2008). The Fifth Circuit affirmed. 593 F.3d 428 (2010). In concluding that Demahy s failure-to-warn claim was not preempted, the court opined that neither the

17 8 Hatch-Waxman Act nor FDA s labeling regulations prevented Actavis from altering its generic drug labeling either unilaterally through the CBE process, or (following approval by FDA) either through the PAS process or by sending Dear Doctor letters. Id. at Relying on that understanding of the federal regulatory scheme, the Fifth Circuit rejected Actavis s conflict preemption argument. Id. at Like the Eighth Circuit, the Fifth Circuit relied heavily on and declined to distinguish Wyeth v. Levine. 593 F.3d at , C. The Acting Solicitor General s Invitation Brief After petitions for certiorari were filed seeking review of the Eighth Circuit s decision in Mensing v. Wyeth (Nos and -1039), this Court invited the Solicitor General to file a brief expressing the views of the federal government (including the FDA). 130 S. Ct (2010) (order). Although urging this Court to deny the petitions, the Acting Solicitor General s brief acknowledged that the Eighth Circuit in several respects had seriously misunderstood the federal regulatory regime governing the labeling of generic drugs. Nos & U.S. Br. 10, 11, 13, 17. First, the Eighth Circuit had incorrectly concluded that the PAS process was intended for the use of generic manufacturers, when in fact that process was not expressly available to any manufacturer to change approved labeling to add or strengthen a warning. Id. at 11, 13; see also id. at (labeling changes relating to added or strengthened warnings were not intended to be made through the PAS process ). Second, the Eighth Circuit had misunderstood the

18 9 status of DHCP letters. Id. at 17. Generic drug manufacturers, the government explained, do not customarily send Dear Doctor or DHCP letters without coordinating with FDA. Id. at Moreover, if such a letter warned about risks seemingly unique to its product (as respondent Mensing seems to envision should have been sent in this case), the letter would likely be misleading because it could mislead consumers and providers into believing that the generic drug and branded drug were not therapeutic equivalents. Ibid.; see also id. at 13 (explaining that sending the Dear Doctor letters sought by Mensing could have resulted in misbranding the drug in violation of federal law). Finally, with respect to the third potential route for labeling changes claimed by Mensing the CBE regulation the government confirmed that the district court was correct in concluding that the CBE process was also unavailable to petitioners. Id. at 11; see also id. at 13. Although the Eighth Circuit did not disturb that holding, id. at 13, the Fifth Circuit in Demahy v. Actavis built its analysis in part on the flawed contrary assumption that a generic manufacturer could use the CBE process to make unilateral changes to the MCP labeling, id. at 22 n.10. The government s description of how the federal statutory and regulatory regime operates based on FDA interpretations that the Acting Solicitor General contends are entitled to receive Chevron deference, id. at 13 confirmed the fundamental premise of petitioners preemption argument: that federal law required them to maintain labeling for their generic drugs that was the same as the labeling of the branded equivalent, and a generic manufacturer is

19 10 not free to change its approved labeling at will. Id. at 11-13; see also id. at 13 (a generic manufacturer may not unilaterally change its approved labeling ). Nevertheless, the government suggested that Mensing s failure-to-warn claims may not be categorically preempted (id. at 11 (emphasis added)) because (1) their maintenance would not frustrate the purposes underlying the Hatch- Waxman Act; and (2) as the Eighth Circuit had suggested, a claim that the generic manufacturer should have communicated risk information to the FDA and urged the FDA to approve a global labeling change or a Dear Doctor letter would not be preempted. Id. at Lastly, the government agreed with the Eighth Circuit that, in litigation over such a failure-to-inform-the-fda-and-request-alabeling-change claim, it would be reasonable to place the burden on the defendant to prove that the FDA would not have approved the labeling change if one had been sought. Id. at 19. INTRODUCTION AND SUMMARY OF ARGUMENT These cases present the question whether federal law in particular, the Hatch-Waxman Act s command that a generic drug s labeling be the same as the labeling approved for the brand-name drug equivalent (21 U.S.C. 355(j)(2)(A)(v), (4)(G)) impliedly preempts a state-law requirement that the generic drug s manufacturer use labeling that is not the same as the brand-name drug s. In rejecting the preemption defense, the Fifth and Eighth Circuits misread Wyeth v. Levine, profoundly misunderstood the relevant federal drug-labeling regulations, and misapplied longstanding principles of federal

20 11 preemption law. They also overlooked critical distinctions between the regulatory regimes governing generic and brand-name drugs. As a result of these errors, the courts below failed to recognize that the state-law requirements underlying respondents tort claims are preempted for at least three reasons: it is impossible for manufacturers to comply with them while at the same time obeying the federal labeling requirements set forth in the Hatch- Waxman Act and in the FDA s related regulations; they squarely conflict with those federal requirements; and finally, if left unpreempted, they would frustrate Congress s central purpose in enacting Hatch-Waxman, which was to ensure the broad availability of affordable generic medications. I. The lower courts decisions reflect several fundamental misunderstandings about the doctrine of conflict preemption. As this Court has repeatedly recognized, that doctrine is of vital importance to the constitutional scheme, and all three of the variants of conflict preemption implicated in this case impossibility, obstacle, and ordinary conflict preemption have deep roots in the Supremacy Clause and in this Court s preemption decisions. Nevertheless, the Fifth and Eighth Circuits apparently are of the view that, in cases concerning generic drug labeling, federal law cannot impliedly preempt state-law tort requirements because Congress failed to include an express preemption clause in the Hatch-Waxman Act. That reasoning is unsound. Whenever it legislates, Congress acts against the backdrop of the well-established principles of conflict preemption, which are assumed, in every instance, to protect federal laws from

21 12 conflicting state requirements. Contrary to the lower courts opinions, Wyeth v. Levine does not direct otherwise. In Levine, this Court observed, with respect to brand-name drugs, that federal oversight is not the exclusive means of ensuring drug safety and effectiveness. 129 S. Ct. at But it certainly did not direct that, whenever Congress has not expressly preempted state law in this field, state-law requirements must prevail, even when they are directly contrary to and interfere with the fundamental objectives of federal legislation. In addition to misunderstanding this Court s discussion of preemption in Levine, each court of appeals below overlooked crucial differences between the case before it and Levine. These consolidated cases involve a federal statute (and its implementing regulations) that mandate national uniformity in labeling between branded drugs and their generic equivalents. In this case, unlike Levine, federal law mandates that generic drug manufacturers maintain labeling that is the same as the FDA-approved labeling of the bioequivalent brand-name drug. 21 U.S.C. 355(j)(2)(A)(v), (4)(G). And, unlike the brand-name drug manufacturer in Levine (which was governed by a different set of federal regulations), petitioners here have fewer mechanisms available to them for bringing about changes to their products labeling. (Indeed, they may take no action without explicit FDA approval.) Finally, because Levine involved only brand-name pharmaceutical products, that case did not implicate the congressional purposes underlying the Hatch-Waxman Act, which include promoting competition for generic drugs and ensuring that consumers understand that such drugs

22 13 are in fact bioequivalent to their brand-name counterparts. II. The Fifth and Eighth Circuits also failed to appreciate that state-law requirements such as those respondents seek to enforce mandating that generic drug manufacturers unilaterally modify their labeling (or suggest new labeling) incorporating new safety information would fundamentally frustrate Congress s effort to promote competition for generic drugs. Because generic drug manufacturers do not conduct clinical trials or studies on drug safety and efficacy, they never acquire the knowledge base enjoyed by the brand-name drug manufacturer and the FDA. As a result, unlike their branded counterparts, they cannot make meaningful judgments to support new labeling proposals at least not without replicating the costly and timeconsuming research efforts previously undertaken by the brand-name manufacturers. And if, contrary to Congress s intent, generic drug manufacturers were required to duplicate brand-name manufacturers efforts in order to satisfy their state tort-law obligations, they would be unable to bring their products to market as quickly or at as low a cost as the Hatch-Waxman Act envisioned. III. In its decision below, the Eighth Circuit proposed a preemption regime in which generic drug manufacturers may still be held liable for failing to (1) inform the FDA of new safety information, and (2) take steps to obtain a labeling change incorporating that information. 588 F.3d at 608, 611. Such a claim would be preempted, the Eighth Circuit held, only if the manufacturer could prove that FDA officials would have decided not to direct a requested

23 14 change to the drug s labeling. Id. at That proposal is completely unworkable in practice as well as fundamentally inconsistent with Buckman Co. v. Plaintiffs Legal Committee, 531 U.S. 341 (2001). Much like the fraud-on-the-fda claims this Court found impliedly preempted in Buckman, the unorthodox state-law claims envisioned by the Eighth Circuit would inappropriately interfere with the relationship between a federal regulatory agency and the entities it regulates. Moreover, as in Buckman, the proposed liability framework has the potential to create significant operational difficulties for the FDA. Just as the Solicitor General (speaking for the FDA), argued in Buckman, here too the maintenance of these state-law claims would threaten to delay agency action and harm both competition and the delivery of medical care. ARGUMENT Respondents state-law claims are preempted by the federal generic-drug labeling requirements in the Hatch-Waxman Act and FDA regulations. Because the Fifth and Eighth Circuits committed numerous critical legal errors when reaching contrary conclusions, the decisions below should be reversed. I. THE FIFTH AND EIGHTH CIRCUITS MISUNDERSTOOD AND MISAPPLIED FUNDAMENTAL, LONGSTANDING PRINCI- PLES GOVERNING THE DOCTRINE OF IMPLIED PREEMPTION As the government s invitation brief at the petition stage demonstrates, the Fifth and Eighth Circuits, in rejecting the preemption defense, relied on a misunderstanding of the federal statutes and

24 15 regulations governing generic-drug labeling. Both courts of appeals also profoundly misunderstood how the FDA has long interpreted and administered those statutory and regulatory provisions. As fundamental as those errors were, however, they were not the only reasons why both courts of appeals went astray. As we next explain, the flawed decisions below were also predicated on fundamental misunderstandings concerning the doctrine of implied preemption, including the meaning of Wyeth v. Levine, 129 S. Ct A. The Doctrine Of Conflict Preemption Is An Indispensable Part Of The Constitutional Scheme Contrary to the apparent assumption of the Fifth and Eighth Circuits, federal preemption of state and local law is an ordinary, intended, and indispensable feature of the constitutional scheme. Congress s authority to legislate preemptively (rather than concurrently with sub-national governments) is [a] fundamental principle of the Constitution. Crosby v. National Foreign Trade Council, 530 U.S. 363, 372 (2000). Congress so legislates using its powers enumerated in Article I of the Constitution, including the Necessary and Proper Clause, U.S. CONST. art. I, ' This constitutional basis is important because it explains why the exercise of preemptive authority by Congress raises no concern under the Tenth Amendment, which provides that [t]he powers not delegated to the United States by the Constitution, nor prohibited by it to the States, are reserved to the States respectively, or to the people. U.S. CONST. amend. X (emphasis added). As this Court has explained, [i]f a power is delegated to Congress in the Constitution, the Tenth Amendment expressly disclaims any reservation of that power to the States; if a power is an attribute of state sovereignty reserved by the Tenth

25 16 In many statutes covering a wide array of subjects, Congress has elected to include provisions that expressly preempt state and local law. More importantly for present purposes, Congress s handiwork and other federal laws, including duly promulgated agency regulations have a preemptive effect on inconsistent state and local laws even in the absence of such express preemption provisions. This result flows directly from the Supremacy Clause of the Constitution, which provides: This Constitution, and the laws of the United States... and all Treaties... shall be the supreme Law of the Land; and the Judges in every State shall be bound thereby, any Thing in the Constitution or Laws of any State to the Contrary notwithstanding. U.S. CONST. art. VI, cl. 2. State and local laws that conflict with federal law are preempted by direct operation of the Supremacy Clause. Brown v. Hotel & Restaurant Employees & Bartenders Int l Union Local 54, 468 U.S. 491, 501 (1984). The Framers included the Supremacy Clause to remedy glaring shortcomings in the Articles of Confederation. See Hughes v. Oklahoma, 441 U.S. 322, 325 (1979) (the Framers believed that, to succeed, the new Union would have to avoid the tendencies toward economic Balkanization that had plagued relations... among the States under the Articles of Confederation ). Moreover, the Framers chose to include the Supremacy Clause only after considering various other structural alternatives for ensuring federal supremacy. See No Amicus Br. of the U.S. Amendment, it is necessarily a power the Constitution has not conferred on Congress. New York v. United States, 505 U.S. 144, 156 (1992) (emphasis added).

26 17 Chamber of Commerce, Williamson v. Mazda Motors, at (filed Sept. 28, 2010) (discussing this history). The Supremacy Clause reflected a decision by the Framers to entrust the Judiciary (rather than other institutions of government) with the responsibility, in the first instance, for ensuring that state and local laws that conflict with federal law shall be accorded no effect. Id. at This Court s decisions interpreting the Supremacy Clause and articulating what has come to be known as the doctrine of implied conflict preemption stretch back to the earliest days of the Republic. See, e.g., Gibbons v. Ogden, 22 U.S. (9 Wheat.) 1 (1824); Houston v. Moore, 18 U.S. (5 Wheat.) 1 (1820); M Culloch v. Maryland, 17 U.S. (4 Wheat.) 316 (1819). [S]ince our decision in M Culloch, the Court has explained, it has been settled that state law that conflicts with federal law is without effect. Cipollone v. Liggett Group, Inc., 505 U.S. 504, 516 (1992). There are at least three variations or types of conflict preemption. This Court s precedents have separately discussed conflicts that prevent or frustrate the accomplishment of a federal objective (so-called obstacle preemption) and conflicts that make it impossible for private parties to comply with both state and federal law ( impossibility preemption). Geier v. American Honda Motor Co., 529 U.S. 861, (2000); see also Wyeth v. Levine, 129 S. Ct. at , In Geier, the Court refused to drive[] a legal wedge between the doctrines of obstacle and impossibility preemption, reaffirming its understanding that both forms of conflicting state law are nullified by the Supremacy

27 18 Clause. 529 U.S. at In addition to impossibility and obstacle preemption, the Court has long recognized and applied what might be called ordinary conflict preemption, under which the Supremacy Clause nullifies state and local laws that stand in conflict with requirements imposed by federal law. 6 These doctrines of conflict preemption have been established for many years. For example, the Court s test for obstacle preemption has been the same for 70 years, and is derived from Hines v. Davidowitz, 312 U.S. 52, 67 (1941): The Supremacy Clause nullifies state or local law that stands as an obstacle to the accomplishment and execution of the full purposes and objectives of Congress. See also Perez v. Campbell, 402 U.S. 637, (1971) ( Since Hines the Court has frequently adhered to this articulation of the meaning of the Supremacy Clause. ) (citing multiple cases). Moreover, the doctrine of obstacle preemption is much older than Hines, with deep roots extending back almost two centuries to this Court=s earliest preemption decisions. See Perez, 402 U.S. at 649 (obstacle preemption has roots extending at least 6 See, e.g., Buckman Co. v. Plaintiffs Legal Committee, 531 U.S. at 348 (state-law fraud-on-the-agency claims preempted because they conflict with the delicate balance of statutory objectives that the FDA was charged with achieving in regulating medical devices); Fidelity Federal Savings & Loan Ass n v. de la Cuesta, 458 U.S. 141, , (1982) (statelaw doctrine preempted because it conflicts with federal regulation). In contrast, the Eighth Circuit incorrectly treated conflict preemption as consisting of only obstacle and impossibility preemption. See Mensing, 588 F.3d at 608; accord Gaeta v. Perrigo Pharmaceuticals Co., No , slip op. 1371, 1382 (9th Cir. Jan. 24, 2011) (making same mistake).

28 19 back to Gibbons v. Ogden, which recognized that state laws that interfere with, or are contrary to the laws of Congress..., are invalid under the Supremacy Clause ) (quoting 22 U.S. (9 Wheat.) at 211) (emphasis added). 7 Congress is presumptively aware of the settled backdrop of existing law including the ordinary rules of conflict preemption that are applied to all statutes whenever it legislates. American Nat l Red Cross v. S.G., 505 U.S. 247, 252, 260 (1992). For that reason, this Court on several occasions has cautioned that it is inappropriate to draw inferences from Congress s inclusion of an express preemption provision or savings clause in a federal statute about the effects such decisions might have on background principles of implied preemption. Thus, in Freightliner Corp. v. Myrick, 514 U.S. 280 (1995), the Court rejected the notion that Congress s inclusion of an express preemption clause entirely forecloses any possibility of implied pre-emption. Id. at And, more recently in Geier, this Court squarely rejected the argument that the proponent of a defense of conflict preemption must carry a special burden because of Congress s inclusion in the relevant statute of either an express preemption clause or a 7 See also Houston, 18 U.S. (5 Wheat.) at (Supremacy Clause overrides state laws whenever their enforcement would thwart[] or oppose[] the will of Congress, even if they do not contradict federal law); M Culloch, 17 U.S. (4 Wheat.) at 427 (Marshall, C.J.) ( It is of the very essence of [federal] supremacy, to remove all obstacles to its action within its own sphere.... ) (emphasis added); Savage v. Jones, 225 U.S. 501, 533 (1912) (a state law must yield if it prevents the purpose of a federal law from being accomplished or frustrate[s] the federal law s operation ).

29 20 savings clause. 529 U.S. at Nothing in the statute, the Court there explained, suggests Congress wanted to complicate ordinary experienceproved principles of conflict pre-emption with an added special burden. Id. at 870, 872, 874 (emphasis added). Instead, ordinary conflict preemption principles apply. Id. at 871; see also id. at 874 (same). So, too, here. B. Congress s Failure To Include An Express Preemption Clause In The Hatch-Waxman Act Has No Bearing On Whether Conflict Preemption Bars Respondents Claims In rejecting the generic manufacturers preemption defense, the Eighth Circuit attached significance to Congress s failure to include in the Hatch-Waxman Act an express preemption clause. Congress could have crafted a preemption provision for generic drugs in its 1984 amendments, the court of appeals reasoned, having done so for medical devices less than 10 years earlier yet Congress chose not to do so. Mensing, 588 F.3d at 607. The Fifth Circuit similarly relied on the absence of an express preemption provision in the Hatch-Waxman Act as a reason for rejecting the conflict-preemption defense. Demahy, 593 F.3d at 435. This rationale does not withstand scrutiny. As noted above, the legal principles governing conflict preemption are well settled and of ancient lineage. At bottom, they represent this Court s longstanding interpretation of the Supremacy Clause. Whenever Congress enacts any statute, it does so against the backdrop of those long-settled principles, which are assumed automatically to apply to every federal law

30 21 to protect it against being nullified or subverted by state and local requirements. Once this basic truth is grasped, it should be obvious that the Congress need not ever include an express preemption provision in a statute unless it wishes to preempt a domain of state law that is different from what would be nullified through the ordinary operation of the doctrine of implied preemption. That is manifestly what Congress did in enacting the express preemption clause of the Medical Device Amendments ( MDA ), 21 U.S.C. 360k(a), which preempts state tort requirements that are different from, or in addition to, federal requirements even if they do not conflict (and further creates a method by which exemptions from preemption may be obtained from the FDA, see 21 U.S.C. 360k(b)). Nor were the Fifth and Eighth Circuits correct in suggesting that Wyeth v. Levine lends support to this rationale. See Mensing, 588 F.3d at 607; Demahy, 593 F.3d at 435. In Levine, this Court cited the example of the MDA s express preemption clause only in the limited context of evaluating the brand-name manufacturer s broad argument that permitting any state-law tort actions based on inadequate branddrug labeling would thwart Congress s purpose underlying the FDCA that FDA oversight... be the exclusive means of ensuring drug safety and effectiveness. 129 S. Ct. at The Court rejected that interpretation of congressional intent as untenable, reasoning that Congress s principal goal was to bolster consumer protection against harmful products. Id. at If Congress had truly intended FDA oversight to be the exclusive means of ensuring drug safety and effectiveness, the Court explained, it would have taken action to limit

31 22 the alternative means of product liability actions. The Court in Levine manifestly did not say that Congress s failure to enact an express preemption clause reflects a desire to tolerate state and local laws that conflict with federal law. If credited, the lower courts broad reading of this language in Levine would place that case on a collision course with Geier, where the Court observed that it was difficult to believe that Congress, in enacting a federal statute, would not have wanted ordinary pre-emption principles to apply where an actual conflict with a federal objective is at stake. 529 U.S. at 871 (emphasis added). To hold otherwise, the Court explained in Geier, would have the effect of tak[ing] from those who would enforce a federal law the very ability to achieve the law s congressionally mandated objectives that the Constitution, through the operation of ordinary pre-emption principles, seeks to protect an outcome that permits [the federal] law to defeat its own objectives, or... destroy itself. Id. at 872 (internal quotation marks omitted). Here too, there is no good reason why Congress would have wanted to permit enforcement of state laws that would directly conflict with the requirements imposed by Hatch-Waxman or the congressional purposes underlying that statute. The Fifth and Eighth Circuit s reliance on the absence of an express preemption provision in the Hatch-Waxman Act is especially perverse given that Congress recognized the principles of conflict preemption in the FDCA, the statute that Hatch- Waxman amended. Levine, 129 S. Ct. at 1221 n.4 (Alito, J., joined by Roberts, C.J., and Scalia, J., dissenting) (citing Drug Amendments of 1962, Pub. L.

32 23 No , ' 202, 76 Stat. 780, 793 (1962) ( Nothing in the amendments made by this Act to the [FDCA] shall be construed as invalidating any provision of State law... unless there is a direct and positive conflict between such amendments and such provision of State law. )). By enacting that provision, Congress made clear that it did not intend to occupy the entire field of drug regulation; and Congress s reference to direct and positive conflicts a shorthand for implied conflict preemption clearly demonstrated both an awareness of, and an intent to preserve, the operation of conflict preemption. The Fifth and Eighth Circuits made no effort to reconcile their conclusions with this provision. C. The Fifth And Eighth Circuits Misapplied This Court s Decision In Wyeth v. Levine Although the Fifth Circuit acknowledged that Levine is not the case before us, it nevertheless went on to rely heavily on that decision, which in its view carr[ies] important implications for the implied preemption defense of generic manufacturers. 593 F.3d at 433; see also id. at , 446, 449. The Eighth Circuit likewise was of the view that Levine carries important implications for this case. Mensing, 588 F.3d at 607. The courts of appeals, however, simply failed to appreciate crucial distinctions between Levine and this case and between the federal statutory and regulatory regime governing brand-name and generic drugs. In Levine, there was no federal statute mandating that the pharmaceutical manufacturer use labeling that was the same as the labeling approved for the bioequivalent drug by FDA (21

33 24 U.S.C. 355(j)(2)(A)(v), (4)(G)). It is that federal-law command missing in Levine that is at the heart of petitioners arguments based on ordinary conflict (as well as impossibility) preemption. Nor, as the government s invitation brief confirms, are the regulatory requirements imposed on generic manufacturers the same as those at issue in Levine. On the contrary, as the government explains, a generic manufacturer may not use the CBE regulation to make a change to its product labeling. In contrast, the brand-name manufacturer may use the CBE process to make such a change. It was precisely this capability which generic manufacturers lack that was the basis for rejecting the brand-name manufacturer s argument for impossibility preemption in Levine. This makes all the difference in the world. The Fifth and Eighth Circuits also overlooked crucial differences between this case and Levine with respect to the manufacturers obstacle preemption arguments. Levine did not involve the Hatch- Waxman Act and therefore did not in any way implicate the congressional purposes underlying that statute. Those purposes, of course, lie at the very heart of petitioners obstacle preemption arguments, yet they had no bearing on the issue resolved in Levine. In other words, the maintenance of the failure-to-warn claim in Levine did not undermine Congress s objective of ensuring the uniformity of approved brand-name labeling and generic labeling (so that consumers would not be confused about the bioequivalence of generics and deterred from using them); did not undermine Congress s objective of reducing the cost of generic drugs for consumers (by freeing generic manufacturers from expensive

34 25 research and risk-analysis obligations); and did not implicate the FDA s regulatory commands designed to carry out these congressional objectives. The reason is simple: all of the congressional objectives were expressed in the Hatch-Waxman Act, which was in no way implicated in Levine. Rather than credit these basic and dispositive differences between this case and Levine, the Fifth and Eighth Circuits seized on tertiary rationales and supporting reasons mentioned by this Court in passing or for quite limited purposes, and sought to elevate those points to broader legal principles that this Court s opinion does not fairly support (and that are inconsistent with other preemption decisions of this Court). As explained above, the Fifth and Eighth Circuits did that with respect to Levine s mention of the absence of any express preemption clause dealing with brand-name drug labeling similar to the express preemption clause included in the MDA. That is not the only example. The Eighth Circuit, for example, read Levine as establishing the general principle that uncertainty about the FDA s response to a manufacturer s request either to make alterations to its product labeling or to send out Dear Doctor letters makes federal preemption less likely. Mensing, 588 F.3d at 610. But this Court in Levine hardly endorsed such a general principle. Instead, the Court treated skeptically the brandname manufacturer s contention in Levine that, while it could unilaterally change its labeling under the CBE regulation, there was no guarantee that the FDA would not later reject it. It was in the context of rejecting that particular argument for impossibility preemption that this Court said what it said. Nor

35 26 could the Court have endorsed the broad principle attributed to it by the Eighth Circuit without creating a glaring inconsistency with other preemption decisions. For example, in Buckman v. Plaintiffs Legal Committee, 531 U.S. 341, this Court held that fraud-on-the-fda claims were impliedly preempted even though there was uncertainty as to whether the FDA would have approved the medical device in question in the absence of the alleged fraud. Yet that uncertainty about the FDA s response (588 F.3d at 610) in Buckman did not prevent this Court from ruling, unanimously, that the fraud-on-the-fda claim was preempted. 531 U.S. at 343. II. RESPONDENTS CLAIMS ARE BARRED BY OBSTACLE PREEMPTION Petitioners have persuasively demonstrated that respondents failure-to-warn claims are preempted by both impossibility and ordinary conflict preemption. See PLIVA Pet. Br ; Actavis Pet. Br It was impossible for petitioners to obey the requirements respondents sought to impose on them through these state tort-law actions while at the same time obeying federal law (which required them to maintain labeling that was the same as that of the branded products). And the state-law requirement to alter the labeling and provide additional warnings directly and unambiguously conflicts with the federal prohibition on doing so. Although this case could be resolved on the basis of either impossibility or ordinary conflict preemption, petitioners also should prevail because the maintenance of respondents claims would frustrate Congress s purposes in enacting the Hatch-Waxman Act.

36 27 With this legislation, Congress had two primary objectives. The first and most important was to enable new drugs to be marketed more cheaply and quickly. Eli Lilly, 496 U.S. at 676. As previously explained, the Act accomplished that goal by authorizing generic drug manufacturers to file ANDAs, which substantially shorten the time and effort needed to obtain marketing approval. Ibid. ANDA applicants may avoid the costly and time-consuming studies required for NDAs, by substitut[ing] bioequivalence data for the extensive animal and human studies of safety and effectiveness. Ibid.; 21 U.S.C. 355(j)(2)(A)(iv); compare 21 U.S.C. 355(b)(1) (datasubmission requirements for brand-name manufacturers) and 21 C.F.R (d) (same). The Act s other objective was to encourage the development of new brand-name drugs. To that end, Congress extended patent terms for pioneer drugs, restoring some of the time lost on patent life during the pre-market approval process. Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No , 201(a), 98 Stat (codified at 35 U.S.C. 156); H.R. REP. NO (I), at 15. The Hatch-Waxman Act thus reflects a careful balance between competition and innovation, easing barriers to entry for generic manufacturers, on the one hand, and extending brand exclusivity, on the other. See 57 Fed. Reg. at 17,951. Indeed, there is substantial evidence that the sponsors of the legislation regarded the provisions extending patent lives for brand manufacturers and relieving generic manufacturers from onerous research and testing requirements as a trade-off that benefited both industries as well as consumers and the overall