Latest Developments in Federal Preemption. Submitted for. ACI Drug and Medical Device Conference. New York, New York.

Latest Developments in Federal Preemption by Anand Agneshwar, 1 Michael Imbroscio, 2 and Lisa Martinez Wolmart 3 Submitted for ACI Drug and Medical Device Conference New York, New York December 2007 1 Partner, Arnold & Porter LLP. 2 Partner, Covington & Burling LLP. 3 Legal Director, Litigation, Schering-Plough Corp.

- 1 - INTRODUCTION The past few years have witnessed a remarkable development in the law of federal preemption for pharmaceuticals. Driven by the advent of mass tort litigation, pharmaceutical defendants have rediscovered preemption as a viable and important defense to claims that their products labeling information is inadequate. Aided by the Food and Drug Administration, which is eager to protect its prerogative as the final arbiter of safety labeling information for drugs, companies have succeeded in a number of courts. The strength of these arguments lies in their simplicity: companies should not be held liable -- sometimes at a massive scale -- for allegedly defective warnings that were explicitly reviewed, approved, and often written by the federal regulator. And companies especially should not be held liable for labeling that they cannot change because the federal regulator has ruled that the proposed labeling change is not scientifically supported and not permitted. Much has been written on preemption in recent years, and this brief review does not purport to provide a comprehensive review of the law of pharmaceutical and medical device preemption as it has developed over the last seven years. Instead, this review is designed to provide the moderately interested and engaged reader with a brief overview of the most recent pharmaceutical preemption cases. We next run through the likely key milestones for the upcoming year, including pending federal appellate court guidance and potential Supreme Court review of the central legal issues in pharmaceutical preemption cases. We also discuss the recent federal drug safety statute and its potential impact on the preemption debate. Finally, we briefly discuss the state of the preemption law for medical devices and the Supreme Court s recent decision to hear an appeal over the Second Circuit s decision to find preemption with a PMA-approved medical device. PHARMACEUTICAL CONFLICT PREEMPTION Where We ve Been: Overview of Key Recent Cases As the law of implied conflict preemption evolves, it is increasingly clear that the defense carries the greatest weight when the relevant regulatory history establishes the FDA s careful consideration of the particular issue or warning that provides the basis for a plaintiff s failure to warn claim. The greater FDA s scrutiny, the higher the likelihood of success of a preemption argument. However, as recent case law suggests, this is an area in which the law is far from settled. Consequently, the next battle ground will likely be the Circuit Courts of Appeal and the United States Supreme Court.

- 2 - This principle is underscored in Colacicco v. Apotex, Inc., 432 F. Supp. 2d 514 (E.D. Pa. 2006). In Colacicco, the plaintiff asserted claims against two manufacturers of selective serotonin reuptake inhibitor ( SSRI ) anti-depressants alleging that the defendants failed to provide adequate warnings of the risk of suicide, which resulted in his wife s death. The defendants moved to dismiss alleging that the claims were in direct conflict with, and preempted by, FDA s labeling determinations, as the FDA had reviewed and rejected six requests to add detailed warnings about the possible risk of suicide in the years that preceded the death of the plaintiff s wife. At the court s invitation, the FDA submitted a brief focused on the history of its regulation of SSRI antidepressants and its views on preemption. Colacicco, 432 F. Supp. 2d at 524-27. The court granted the defendants motions, deferring to the FDA s views on preemption, and the case is now pending before the Third Circuit. Similarly, in In re: Bextra & Celebrex Mktg. Sales Practices and Prod. Liab. Litig., 2006 WL 2374742 (N.D. Cal. August 16, 2006), the court rejected claims that advertising for arthritis medication did not include sufficient warnings of cardiovascular risks. Again deferring to the FDA, the court held that the claims were preempted due to the FDA s conclusion that state law cannot impose obligations that go beyond FDA-approved labeling. See also Pennsylvania Employees Benefit Trust Fund v. Zeneca Inc., 499 F.3d 239 (3d Cir. 2007) (affirming district court finding of implied preemption in Nexium false advertising case); Prohias v. Pfizer, Inc., 490 F. Supp. 2d 1228 (S.D. Fla. 2007) (finding implied conflict preemption of claims after July 2004, but not before, and relying upon FDA preemption preamble in Lipitor false advertising case); Brockert v. Wyeth Pharm., 2007 WL 2077554 (Tex. Dist. Ct. Jan. 31, 2007) (finding implied conflict preemption in Prempro heart attack case); Ledbetter v. Merck & Co., 2007 WL 1181991 (Tex. Dist. Ct. April 19, 2007) (finding implied conflict preemption of fraud on the FDA exception to state tort reform statute in Vioxx heart attack case); In re Baycol Prod. Litig., 495 F. Supp. 2d 977 (D. Minn. 2007) (applying implied preemption to exclude expert testimony offered to support allegations of fraud on the FDA in Baycol muscle and kidney damage MDL); Price v. Cook, 2007 WL 2154766 (W. Va. Cir. Ct. July 9, 2007) (finding implied conflict preemption and relying on prior FDA amicus briefs in Zoloft suicide attempt case); Conte v. Wyeth Inc., 2006 WL 2692469 (Cal. Super. Ct. Sept. 14, 2006) (finding implied preemption and relying on FDA preemption preamble in Metoclopramidine gastroesophageal reflux case); Abramowitz v. Cephalon, Inc., 2006 WL 560639 (N.J. Super. Ct. Law Div. March 3, 2006) (finding implied conflict preemption and relying of FDA preemption preamble in Actiq tooth decay case).

- 3 - In direct contrast to Colacicco, and consolidated on appeal with Colacicco in the Third Circuit, is McNellis v. Pfizer, Inc., 2006 WL 2819046 (D. N.J. Sept. 29, 2006). In McNellis, a New Jersey federal judge reviewing virtually identical arguments came to an opposite conclusion, rejecting the FDA s views, rejecting the implied preemption argument, and denying the defendant s motion for summary judgment. The court s decision focused on its perceptions of the FDA s inconsistent positions on the issue of preemption historically, and the court s understanding of a pharmaceutical company s ability to unilaterally (and without FDA approval) implement labeling changes. Recognizing the emerging split in authority on this issue, the court certified the issue under 28 U.S.C. 1292(b) for possible review by the Court of Appeals. The Third Circuit argument in the consolidated cases is schedules for December 10, 2007. Other recent cases have reached similar anti-preemption results. See Desiano v. Warner- Lambert & Co., 467 F.3d 85 (2d Cir. 2006) (as amended January 18, 2007), cert. granted, 75 U.S.L.W. 3623 (U.S. September 25, 2007) (No. 06-1498) (reversing district court and rejecting implied conflict preemption of fraud on the FDA exception to state tort reform statute and rejecting FDA preemption preamble in Rezulin diabetes case); In re Vioxx Prod. Liab. Litig., 501 F. Supp. 2d 776 (E.D. La. 2007) (rejecting implied conflict preemption and rejecting FDA preemption preamble in Vioxx heart attack MDL); In re Zyprexa Prod. Liab. Litig., 489 F. Supp. 2d 230 (E.D.N.Y. 2007) (rejecting implied conflict preemption and rejecting FDA preamble in Zyprexa side effects MDL); Giles v. Wyeth, 500 F. Supp. 2d 1063 (S.D. Ill. 2007) (rejecting implied conflict preemption in Effexor suicide case); Dunson v. McNeill-PPC, Inc., 2007 WL 3052315 (Pa. C.P. Ct. September 12, 2007) (finding no implied conflict preemption and distinguishing FDA preemption preamble in over the counter infant Tylenol liver failure/death case); Deutsch v. Wyeth, Inc., 2007 WL 2060072 (N.J. Super. Law June 22, 2007) (rejecting implied conflict preemption and rejecting FDA preemption preamble in Prempro breast cancer case); Weiss v. Fujisawa Pharm. Co., 464 F. Supp. 2d 666 (E.D. Ky. 2006) (rejecting implied conflict preemption, but relying on FDA preamble in Elidel lymphoma case); Perry v. Novartis Pharm. Corp., 456 F. Supp. 2d 678 (E.D. Pa. 2006) (rejecting implied conflict preemption and distinguishing FDA preemption preamble in Elidel lymphoma case); Coutu v. Tracy, 2006 WL 1314261 (R.I. Super. Ct. May 11, 2006) (rejecting implied conflict preemption and rejecting FDA preamble in Propofol liver and kidney failure case); Laisure- Radke v. Par Pharm., Inc., 2006 WL 901657 (W.D. Wash. March 29, 2006), reconsid. denied (May 3, 2006) (rejecting implied conflict preemption in generic Prozac suicide case); Jackson v. Pfizer, 432 F. Supp. 2d 964 (D. Neb. 2006) (rejecting implied conflict preemption and rejecting FDA preemption preamble in Zoloft-Effexor suicide case).

- 4 - Where We re Going: Circuit Court and Supreme Court Developments There are two key cases currently percolating in the Supreme Court that may impact preemption law. In the first, Warner-Lambert v. Kent (formerly Desiano), the Supreme Court has granted certiorari; in the second, Wyeth v. Levine, a petition for certiorari is pending. The Kent case arises out of the Rezulin product liability litigation. There, the plaintiff brought common-law failure to warn and design defect claims. The claims were predicated on the defendant s alleged fraud on the FDA because Michigan law provides that FDA approval is an absolute defense to a pharmaceutical product liability claim unless there has been, essentially, a fraud on the FDA. See Desiano v. Warner-Lambert & Co., 467 F.3d 85 (2d Cir. 2006) (as amended Jan. 18, 2007), cert granted, 75 U.S.L.W. 3623 (U.S. Sept. 25, 2007) (No. 06-1498). The defendant essentially argued that the very basis for the plaintiffs claim was an argument that the Supreme Court precluded in Buckman. See Desiano, 467 F.3d at 88-89. The Second Circuit had to decide the scope of Buckman and proceeded to limit it, largely because of the Buckman court s own statement that Medtronic, Inc. v. Lohr, 518 U.S. 470 (1996) remained good law. See Desiano, 467 F.3d at 93-94 (citing Buckman Co. v. Plaintiffs Legal Comm., 531 U.S. 341 (2001)). The Court found that Buckman resulted in implied preemption only where the cause of action was predicated solely on fraud on the FDA, in other words where the action was captioned fraud on the FDA. See Desiano, 467 F.3d at 97. In the Second Circuit s view, because the failure to warn and design defect claims were not premised solely on fraud on the FDA but instead on traditional state causes of action such as failure to warn, Buckman s prohibition on fraud on the FDA causes of action did not apply and the presumption against preemption did apply. Id. The court also reasoned that the regulation of health and safety issues is traditionally an area regulated by the state and there was no inherent conflict between FDA s regulatory scheme and state law common causes of action. Id. The court addressed the Preemption Preamble but found it irrelevant because it only applied to claims alleging inadequate labeling, and in any event was subject to conflicting interpretations. Id. at 97 n.9. Since Buckman, a significant question in pharmaceutical litigation has been whether the case is limited solely to fraud on the FDA causes of action, or whether it extends to traditional tort causes of action that rely on violations of FDA regulations or fraud on the FDA type of evidence to prove the claim. The Supreme Court s decision in Kent should offer guidance on this important question. Levine v. Wyeth, 2006 WL 3041078 (Vt. Oct. 27, 2006) pet. for cert. filed, 75 U.S.L.W. 3500 (U.S. March 12, 2007) (No. 06-1249), raises more far-reaching issues. The Supreme Court has delayed ruling on the pending petition for certiorari and has called for the views of the Solicitor General. The Solicitor General has not yet submitted its brief.

- 5 - In Levine the plaintiff lost her arm after an intravenous injection of defendant s product resulted in an inadvertent injection of the drug into an artery. She thereafter filed a claim alleging that the product label inadequately warned of the dangers of intravenous injections and that the label should have precluded at least some methods of intravenous injections. See 2006 WL 3041078 at 1-2. At the time of the plaintiff s injury, the label cautioned about the danger of inadvertent arterial injection. Id. at 3. Defendant argued that the claim was preempted under the doctrine of conflict preemption. There were two parts to the defendants argument -- first, it would have been impossible to comply with both state and federal law, as the FDA had told the defendant to retain [original] verbiage when the company had proposed different language for the label. Id. at 21. Second, the company argued that the state law interfered with the federal regulatory scheme. Id. The Supreme Court of Vermont analyzed numerous cases in the preemption context and found that there is no preemption unless it is impossible to comply with both state and federal law. Id. at 22. The Court reasoned that the state common law, together with federal regulations, share a common purpose of ensuring that consumers are adequately warned. Id. at 19, 25-28. An FDA-approved warning, in the Court s view, is only the first, minimum step in the process of warning consumers. Id. at 24. With this stringent an interpretation of preemption law, the Court put the burden squarely on the defendant -- if it is claiming impossibility, it must show that the FDA would have rejected a stronger warning. Id. at 22-23. The Court rejected the Preamble as inconsistent with the regulatory scheme. Id. at 32-34. The Chief Judge dissented, however, and would have found the claims preempted on several grounds, including that plaintiffs theory of the case would have eliminated an approved use, id. at 54; the FDA did reject a stronger warning, so there were inconsistent requirements, id. at 57; and finally, that the state law stood as obstacle to FDA s goals. Id. at 60. If the Supreme Court grants certiorari in Levine, it could either limit its analysis to situations in which companies claim a clear inconsistency between the FDA s direction and a requirement of state law or it could address the Preamble and the regulatory scheme in a more farreaching way. Either approach will provide invaluable guidance.

- 6 - Legislative Developments -- Enactment of FDAAA On September 27, 2007, with these preemption issues swirling in the background, President Bush signed into law the Food and Drug Administration Amendments Act of 2007. Pub. L. 110-085, 121 Stat. 823 (2007), amending the Federal Food, Drug, and Cosmetic Act ( FDCA ) and Public Health Service Act ( PHS Act ). The FDAAA significantly amended federal food and drug law, particularly with respect to FDA s post-approval authority over drugs (as well as biologics). The debates surrounding the preemption issue very much animated the bill s development in both the Senate and the House, and ultimately the legislation effectively resulted in a political stalemate that will have a still-uncertain effect on the larger preemption debate. The Act s Text and the Rule of Construction Perhaps the most significant aspect of the new FDAAA is its provisions greatly expanding the authority of the Agency to compel prescription drug labeling changes. Until enactment of the Act, FDA s only statutory power if it wanted a labeling change was to commence withdrawal proceedings or initiate a misbranding prosecution. Of course, as a practical matter, FDA has always had pervasive authority over the content of labeling, for no company would ever want to risk either of those drastic outcomes. In a new extensive regime, those practical powers have now been codified. When the agency becomes aware of new safety information that should be included in a drug s labeling, it must initiate a discussion process that can lead to a mandated labeling change. See FDAAA 901(a); 21 U.S.C. 355(o). With this new comprehensive scheme, including FDA s new statutory power to precisely dictate the content of safety labeling, one might legitimately suggest that field preemption now becomes a viable legal argument -- a topic beyond the scope of this review. Instead, this section will focus on the potential impact on the conflict preemption debate now raging. Within section 901(a) of the Act granting the FDA this increased safety surveillance authority is a Rule of Construction that provides: RULE OF CONSTRUCTION. This paragraph shall not be construed to affect the responsibility of the responsible person or the holder of the approved application under section 505(j) to maintain its label in accordance with existing requirements, including subpart B of part 201 and sections 314.70 and 601.12 of title 21, Code of Federal Regulations (or any successor regulations). FDAAA 901(a); 21 U.S.C. 355(o)(4)(I). On its face, this Rule appears directed at maintaining the legal status quo. Nonetheless, the plaintiffs bar has immediately seized on the provision, arguing that the Rule is a legislative rejection of preemption defenses. Looking beyond the language of the statute to the legislative history behind it, the Rule appears to represent a political compromise, which ultimately should not dramatically affect preemption arguments.

- 7 - Legislative History The bill (H.R. 3580) that became FDAAA was a compromise between companion bills in the Senate (S. 1082) and House of Representatives (H.R. 2900). The original bill as passed by the Senate would have effectively eliminated the ability of a drug manufacturer to unilaterally update a label with new safety information under the Changes Being Effected or CBE regulations. See 21 C.F.R. 314.70(c) and 601.12(f). These regulations allow a company to change product labeling without prior approval to add or strengthen a contraindication, warning, precaution, or adverse reaction. Under the provisions of a Senate Amendment originally proposed by Senator Burr and included as part of S. 1082, all safety-related changes would have to be approved by the FDA before a company could change the existing label, which would have effectively rescinded the CBE regulation for safety-related changes. See S. 1082, 110th Cong. 208(a) (2007). By contrast, the House Bill originally included strong anti-preemption language. H.R. 2273, the predecessor bill to H.R. 2900, contained express provisions requiring the FDA to adopt a policy against preemption and directing the agency to cease intervening in [product liability] actions to argue any interpretation [to the] contrary. H.R. 2273, 100th Cong. 6 (2007), as introduced by Rep. Hinchey on May 10, 2007 (requiring FDA to follow a previous interpretation that its labeling regulations only establish minimal standards and therefore are not intended to preclude the States from imposing additional requirements ). This approach was initially followed in H.R. 2900, which contained the following provision in a discussion draft: Nothing in this Act or the amendments made by this Act may be construed as having any legal effect on any cause of action for damages under the law of any State (including statutes, regulations, and common law). H.R. 2900 Committee Print, 110th Cong. (2007) (emphasis added). These anti-preemption provisions were political non-starters, however, and ultimately replaced with FDAAA s current Rule of Construction. Aside from the plain language of the final Rule, therefore, perhaps the strongest support for the conclusion that Congress did not intend to change the legal landscape surrounding preemption comes from the progression of the statute through Congress and the deletion of these early anti-preemption statutory provisions.

- 8 - The legislative history itself is not of much help. For one, there is no official conference report on the compromise bill, so no official congressional statement as to the intent of H.R. 2900 exists. Instead, the legislative history consists mainly of individual Member statements on all sides of the preemption debate. For example, during debates on H.R. 3580, Senator Kennedy, the bill s Senate sponsor, noted, Congress has stated very clearly in the legislation that we do not intend the new authority being given to FDA to preempt common law liability for a drug company s failure to warn its customers of health risks. 153 CONG. REC. S11833 (September 20, 2007); see also 153 CONG. REC. H10598 (September 19, 2007) (statement of Rep. Green). Likewise, Senator Durbin emphasized, [t]he drug labeling provisions in today s legislation include a rule of construction that makes clear that Congress does not intend to preempt state requirements regarding drug companies responsibilities. Rather, this legislation recognizes that State liability laws, including liability laws for improper drug labeling, play an essential role in ensuring that drug products remain safe and effective for all Americans. 153 CONG. REC. S11835. Even some critics of the Rule of Construction have asserted that it opens the floodgates for frivolous lawsuits and thus is a definite boon for trial lawyers because it removes any preexisting basis for finding preemption. Id. at S11837 (statement of Sen. Allard). Other legislators, however, expressed pro-preemption interpretations of the Act. For example, Senator Enzi stated, [t]o ensure that science is the guiding principle for all information with the drug label, FDA must be the sole arbiter of what is and is not in the label, adding that by providing through FDAAA a single, expedited pathway for safety labeling changes, it is clear that Congress intends there to be one standard for protecting all Americans. Id. at S11939 (September 21, 2007). Senator Coburn echoed this position, focusing on the comprehensiveness of FDA regulation of drug safety, effectiveness, and labeling to conclude that the newly expanded role of the FDA does and should preempt State law when it comes to drug safety and labeling. Id. at S11839-40 (September 20, 2007). Rejecting characterizations of the Rule as a gift to trial lawyers, Senator Gregg also emphasized that the Rule of Construction merely restates current law, explaining, [i]f we had intended through this legislation to give State courts and State juries the authority to second guess the scientific expertise of the FDA, we would have done so. In fact, based on the totality of the bill s 422 pages we have done the opposite. Id. at S11940 (September 21, 2007). Indeed, some anti-preemption advocates bemoaned the fact that the Rule does nothing to keep the FDA from its current misinformed policy of preempting State law on drug policy. 153 CONG. REC. H7603 (July 11, 2007) (statement of Rep. Hinchey). Even the House Report for H.R. 2900 contained an opinion from multiple anti-preemption Representatives that the bill could have the unintended consequence of triggering field preemption or providing additional support for preemption defenses, advocating for an amendment to the bill clarifying that state law failure to warn claims should not be preempted. H.R. Rep. No. 110-225, at 197 (2007). No such amendment was ever adopted, further undercutting the suggestion that the Rule of Construction has materially affected the preemption landscape.

- 9 - Indeed, several members recognized just this fact. For example, Senator Allard noted that the House and Senate took different stances as to how [the Rule of Construction] should play out in court. 153 CONG. REC. S11837 (September 20, 2007). Senator Enzi also expressed concern about the provisions related to labeling changes and liability, given that we do not fully understand the implications of that language. Id. at S11833. He further noted, [t]his new rule of construction was part of the House-passed language and not something the Senate fully debated. Id. These views reflect ambiguity about whether the Rule of Construction is intended to undermine or preserve preemption defenses. In the end, it is hard to see courts putting too much weight on these individual Member statements in evaluating the impact of the Rule of Construction. See, e.g., Chrysler Corp. v. Brown, 441 U.S. 281, 311 (1979) ( The remarks of a single legislator, even the sponsor, are not controlling in analyzing legislative history. ). Likely Arguments The implications of the Rule of Construction will likely generate some substantial activity in the preemption world. This brief review highlights a few arguments likely to be put forth by plaintiffs pressing for an expansive reading of the Rule of Construction, and industry responses. First, plaintiffs may argue that the text of the Rule -- stating that companies must maintain their labeling in accordance with existing requirements -- signals a congressional recognition of state-based independent labeling requirements that are not preempted by FDA s regulation of pharmaceutical products. Such a reading would embrace the minimum standards view of FDA regulation, a view adopted by many courts rejecting preemption defenses: [T]his minimum standards approach is fully consistent with Congress primary goal in enacting the FDCA, which is to protect consumers from dangerous products, as well as Congress stated intent that the FDCA must not weaken the existing laws, but on the contrary, it must strengthen and extend that law s protection of the consumer. McNellis v. Pfizer, Inc., 2005 WL 3752269, at *7 (emphasis added; citations and quotations omitted). Plaintiffs will likely add to this argument their standard reliance on the presumption against preemption, often cited by courts rejecting preemption. Rice v. Santa Fe Elevator Corp., 331 U.S. 218, 230 (1947); Wisconsin Pub. Intervenor v. Mortier, 501 U.S. 597, 605 (1991). In short, by not stating an intent to override state common law requirements, plaintiffs will argue, Congress chose to preserve this presumption.

- 10 - The plain text of the Rule of Construction, however, is best read as preserving the legal status quo. As such, the Rule simply provides that the new labeling requirements do not affect existing law under FDA s prescription drug labeling regulations. The Rule of Construction s reference to existing requirements encompasses pre-existing federal requirements arising from the federal drug labeling regulatory scheme that courts have held are in direct conflict with and thus preempt various state law claims in certain contexts. The Rule of Construction thus specifically preserves this carefully crafted federal scheme of existing case law. In addition to preserving existing case law on preemption, the Rule makes no effort (as did earlier versions of the Bill) to reject FDA s public position as to the proper role of preemption. See, e.g., Federal Housing Administration v. Darlington, Inc., 358 U.S. 84, 89-90 (1958) (allowing contemporaneous administrative construction to carry the day against doubts that might exist from a reading of the bare words of a statute ); Lorillard v. Pons, 434 U.S. 575, 580-81 (1978) ( where... Congress adopts a new law incorporating sections of a prior law, Congress normally can be presumed to have had knowledge of the interpretation given to the incorporated law, at least insofar as it affects the new statute. ). The FDA has interpreted the FDCA and its regulations to preempt state law failure-to-warn claims under various circumstances based, in part, upon the fact that safety labeling changes must be approved by the agency. This position is stated, among other places, in the 2006 Preamble that Congress specifically cited during FDAAA debates but chose not to change. The agency s interpretation must be given great weight, reinforced by Congress s determination not to alter that view of the law. Second, plaintiffs will undoubtedly argue that the Rule of Construction effectively codifies the CBE regulations. Because these regulations allow companies to act unilaterally in this manner, plaintiffs will argue, state tort lawsuits that seek to require greater warnings do not conflict with FDA labeling requirements. As noted in the cases cited above, several courts have explicitly rejected this view, recognizing FDA s ultimate authority over drug labeling. See, e.g., In re: Bextra & Celebrex, 2006 WL 2374742, at *8. Other courts, however, continue to rely on the CBE regulations to reject preemption arguments. See McNellis, 2005 WL 3752269, at *6-7. In a similar vein, plaintiffs present a related argument that, by endorsing each company s responsibility... to maintain its label independent of FDA s new powers to compel labeling changes, the Rule of Construction itself constitutes an additional legal requirement, separate and distinct from the CBE regulations. Stated differently, in the very place where Congress granted the FDA additional authority over labeling, Congress specifically affirmed the responsibility to maintain and update product labeling.

- 11 - Of course, neither the CBE regulations nor the anti-preemption arguments that plaintiffs have extrapolated from these regulations were codified by the Rule of Construction. By expressly recognizing the possibility of successor regulations to the CBE regulations, the Rule s language leaves open the possibility that the FDA may revise the CBE regulations as it deems appropriate. Likewise, the placement of the Rule in the overall context of the statute -- limited to paragraph (o)(4) of section 505 of the FDCA -- indicates that the new powers to mandate safety labeling changes conferred upon the FDA do not affect, in one way or the other, labeling requirements that already existed prior to passage of the FDAAA. 21 U.S.C. 355(o)(4). In other words, the Rule of Construction merely ensures that FDA s new authority does not displace or otherwise affect the agency s pre-existing authority, as implemented by FDA regulations, including the CBE regulations. Indeed, as mentioned above, the comprehensive scope of FDAAA may even strengthen preemption arguments advanced under FDA s pre-existing rules past criticisms that FDA could not explicitly compel labeling changes can no longer be used to argue that state laws may fill an alleged regulatory void. Finally, even assuming the Rule of Construction did in fact codify the CBE regulations, nothing would alter the very strong arguments for why the CBE provision itself is substantively meaningless in the preemption debate. At bottom, the CBE regulations speak only to timing, not FDA approval. No one disputes that FDA must approve all labeling supplements eventually and can reject CBEs submitted by a company. Thus, especially in those cases -- like the SSRI litigation -- where the FDA has already considered and rejected a labeling change, there is nothing in the CBE regulations that would permit a company to override that determination simply by submitting a CBE. Interestingly, none of the parties submitted Rule 28(j) letters to the Third Circuit panel hearing in Colacicco on December 10, 2007 raising the FDAAA or the Rule of Construction. In addition, it is important to keep in mind that the CBE regulations have no application to safety information relating to the Highlights section of the labeling. See 21 C.F.R. 314.70(c)(6)(iii); 601.12(f)(1) and (2)(i). The Highlights section is required to include the most important risk information, id. at 201.57(a)(4) and (9)-(11), and may not be revised without prior FDA approval. id. at 201.57(c)(6)(iii); 601.12(f)(2)(i). Thus, for the growing group of drugs with a Highlights section, a company is effectively prohibited from revising the full prescribing information to include new safety information until FDA has determined the appropriateness of this information in the Highlights section.

- 12 - LATEST DEVELOPMENTS IN DEVICE PREEMPTION Pursuant to the Food, Drug and Cosmetic Act ( FDCA ), 52 Stat. 1040, as amended by the Medical Device Amendments of 1976 ( MDA ), 90 Stat. 539, 21 U.S.C. 301 (1994 ed. & Supp. V), the FDA administers the premarket approval (PMA) process for medical devices to ensure that devices are safe and effective before being placed into the stream of commerce. Congress enacted the MDA to expand the authority of the FDA to regulate medical devices, while also protecting innovations in device technology from being stifled by unnecessary restrictions. H.R. Rep. No. 94-853, at 12 (1976). The MDA divides medical devices into three categories: Class I and II devices are those that are subject to regulatory controls and standards, but do not require premarket approval, i.e. tongue depressors and hearing aids; while Class III devices (e.g. pace makers) are those that sustain or support human life, have substantial importance in preventing the impairment of human life, or present a potential unreasonable risk of illness or injury, 21 U.S.C. 360c(a)(1)(C), and are subject to a rigorous PMA process. Not all Class III devices receive premarket approval, as many fall within one of two exceptions to the PMA requirement: (1) medical devices that were commercially available before the statute s effective date may remain on the market until the FDA issues regulations requiring such devices to undergo the PMA process, 21 U.S.C. 360e(b)(1)(A); and (2) newly developed devices that are substantially equivalent to the pre-mda devices need not be approved under the PMA process in the absence of FDA regulations requiring PMA review, 21 U.S.C. 360e(b)(1)(B)). The second exception has been the subject of much of the express preemption debate. For Class III medical devices subject to the rigorous PMA process, a manufacturer must submit detailed information relevant to the safety and efficacy of the device, including information derived from clinical investigations, information concerning the methods used, and controls for, the manufacture, processing, packaging and installation of the device, and information concerning the proposed labeling of the device. 21 U.S.C. 360e(c)(1); 21 C.F.R. 814.20(b)(13). The agency s review can entail in excess of one thousand hours, and may require consultations with scientific advisory committees comprised of outside experts. Lohr, 518 U.S. at 477.

- 13 - At the heart of the preemption debate is section 360k of the MDA which, by its express terms, preempts certain state law requirements governing medical devices. That section provides, in pertinent part: [N]o State or political subdivision of a State may establish or continue in effect with respect to a device intended for human use any requirement (1) which is different from, or in addition to, any requirement applicable under this chapter to the device, and (2) which relates to the safety or effectiveness of the device or to any other matter included in a requirement applicable to the device under this chapter. 21 U.S.C. 360k(a). The FDA s regulations implementing Section 360k explain that: State or local requirements are preempted only when [FDA] has established specific counterpart regulations or there are other specific requirements applicable to a particular device. 21 C.F.R. 808.1(d). Local requirements potentially subject to preemption include those having the force and effect of law (whether established by statute, ordinance, regulation, or court decision), 21 C.F.R. 808.1(b), including those that ha[ve] the effect of establishing a substantive requirement for a specific device, e.g., a specific labeling requirement... different from, or in addition to, a Federal requirement. 21 C.F.R. 808.1(d)(6)(ii). In Medtronic, Inc. v. Lohr, 518 U.S. 470 (1996), the United States Supreme Court addressed the issue of what is deemed a requirement for preemption purposes and held, in a 5-4 decision, that none of the plaintiffs claims were preempted by the MDA. The medical device at issue in Lohr was one that had received 510(k) clearance from the FDA namely, a finding that it was substantially equivalent to a device on the market. Lohr, 518 U.S. at 480. While the Court acknowledged that the pre-market approval process involves intense regulatory review concerning the safety and efficacy of medical devices, the Court was disinclined to preempt state tort claims pertaining to a device that had not, in the Court s view, undergone a rigorous PMA approval process. Rather, the Court held that FDA s determination under 21 U.S.C. 360k that a device is substantially equivalent to a legally marketed device does not impose any federal requirements that preempt state law. Lohr, 518 U.S. at 493. The manufacturer s contrary position in the case was viewed as having exaggerate[d] the importance of the [substantial-equivalence] process, as the Court believed that the FDA had determined only whether the device was substantially equivalent to a legally marketed device not whether the device was safe or effective. While Lohr rejected, without consensus, the doctrine of express preemption for substantially equivalent medical devices, express preemption is again squarely before the Court with the recent grant of certiorari in Riegel v. Medtronic, Inc, 451 F.3d 104 (2d. Cir. 2006). The Court must now decide whether the FDA s rigorous review and premarket approval of a Class III medical device preempts state law relating to the safety or efficacy of that device.

- 14 - At issue in Riegel is Medtronic s Evergreen Balloon Catheter, a Class III medical device, used during an angioplasty procedure to treat the plaintiff s diffusely diseased and heavily calcified right coronary artery. Medtronic alleged that Mr. Riegel s physician selected the Evergreen Balloon Catheter notwithstanding the labeling of the device, which stated that it should not be used in patients who have diffuse or calcified stenoses, and also used the device in a manner contrary to its labeling. Riegel filed an action in the U.S. District Court for the Northern District of New York asserting state law claims for negligent design, testing, inspection, manufacture, distribution, labeling, marketing, and sale of the Evergreen Balloon Catheter; strict liability; and breach of express and implied warranty. The district court granted Medtronic s summary judgment motion dismissing Riegel s claims for negligence, strict liability and implied warranty on the grounds that the claims were expressly preempted by 21 U.S.C. 360k(a). The Second Circuit affirmed, holding that Riegel s claims, if successful, would impose state law requirements that would be different from, or in addition to the device-specific requirements that the FDA established for the Evergreen Balloon Catheter through its PMA approval order. In so holding, the Second Circuit described the lengthy and rigorous PMA process, and explained that PMA approval explicitly signifies the FDA s substantive approval of the device s reasonable safety and effectiveness. Riegel, 451 F.3d at 119. The court concluded that a manufacturer cannot make any changes that might affect the safety and effectiveness of the device without further FDA approval, therefore, a PMA-approved device is clearly subject to the federal, device-specific requirement of adhering to the standards contained in its individual, federally approved PMA. Id. at 118. As Riegel s state law claims sought to impose state law requirements regarding the design, manufacture, and labeling of the catheter that differed from or added to the PMA-approved standards for the device, the Second Circuit concluded that the claims were preempted. The Second Circuit s position in Riegel is echoed in the amicus curiae brief submitted by the United States at the Court s invitation, and in accord with decisions of the Third, Fifth, Sixth, Seventh and Eighth Circuit Courts of Appeal. Indeed, all but one of the Circuit Courts of Appeal recognize the preemptive, device-specific requirements created by the PMA process. See Gomez v. St. Jude Med. Daig Div., Inc., 442 F.3d 919 (5th Cir. 2006); McMullen v. Medtronic, Inc., 421 F.3d 482 (7th Cir. 2005), cert. denied, 547 U.S. 1003 (2006); Cupek v. Medtronic, Inc., 405 F.3d 421 (6th Cir. 2005), cert. denied sub. nom. Knisley v. Medtronic, Inc., 546 U.S. 935 (2005); Horn v. Thoratec Corporation, 376 F.3d 163 (3d. Cir. 2004); Martin v. Medtronic, Inc., 254 F.3d 573, 584 (5th Cir. 2001), cert. denied, 534 U.S. 1078 (2002); Brooks v. Howmedica, Inc. 273 F.3d 785 (8th Cir. 2001), cert. denied, 535 U.S. 1056 (2002); Kemp v. Medtronic, Inc., 231 F.3d 216 (6th Cir. 2000), reh g denied, 2001 WL 91119 (6th Cir. January 26, 2001), cert. denied, 534 U.S. 818 (2001); Mitchell v. Collagen Corp., 126 F.3d 902, 911 (7th Cir. 1997), cert. denied, 523 U.S. 1020 (1998); but see Goodlin v. Medtronic, Inc., 167 F.3d 1367 (11th Cir. 1999). All that remains now is the Supreme Court s pronouncement.