1 Alex Berenson, Merck Victory in Vioxx Deal, N.Y. Times, Nov. 10, 2007 at A1 (reporting that Merck offered to settle the Vioxx litigation for $4.8 billion, which was less than the scope of liability originally projected). Pfizer recently began to settle liability suits over Celebrex and Bextra, which were other drugs in the class competing with Vioxx. Bloomberg News, Pfizer Begins Settling Painkiller Cases, N. Y. Times, May 4, 2008, at C8.

2 Preamble, Requirements on Content and Format of Labeling, 71 Fed. Reg. 3922, 3933-36 (Jan. 24, 2006) [hereafter Preamble].

3 Riegel v. Medtronic, 128 S. Ct. 999 (2008). See infra Part II.B.

4 Wyeth v. Levine, 128 S. Ct. 1118 (2008), (cert. granted, 944 A.2d 179 (Vt. 2006)). For an analysis in the context of the need for drug reform, see Gilhooley, Margaret, Addressing Potential Drug Risks: The Limits of Testing, Risk Signals, Preemption and the Drug Reform Legislation, 59 S.C. L. Rev. 347 (2008)Google Scholar [hereinafter Drug Risks].

5 Gardiner Harris & Alex Berenson, Drug Makers Near Old Goal: A Legal Shield, Court to Rule if F.D.A. Approval Bars Suits, N.Y. Times, Apr. 6, 2008 at A1; Editorial, No Recourse for the Injured, N. Y. Times, Feb. 22, 2008, at A22; Jeffrey Rosen, Supreme Court Inc., N.Y. Times Mag., Mar. 16, 2008, at 38. For a response on the basis of the Court's decision, see Scalia Says Media, Democrats Miss Legal Basis of Preemption Ruling, FDA Week (Inside Washington Publishers, Arlington, VA)Google Scholar Mar. 28, 2008 (reporting that in a speech the Justice criticized the New York Times editorial cited in this footnote for not recognizing the “textbased approach” of the preemption decision for medical devices and the Rosen article for making the case seem “like a policy decision by the courts.”).

6 See generally Epstein, Richard A., Why the FDA Must Preempt Tort Litigation: A Critique of Chevron Deference and a Response to Richard Nagareda, 1 J. Tort L. 4, 54 (2006)Google Scholar (finding preemption a “sound legal policy”); Schuck, Peter H., FDA Preemption of State Tort law in Drug Regulation: Finding the Sweet Spot, 13 Roger Williams U. L. Rev. 73 (2008)Google Scholar (finding that the comparative competence of the agency and the deficiency of the tort system in information-processing should lead to preemption absent disclosure deficits in submissions to the agency).

7 For criticisms and reservations about drug preemption, see Kessler, David A. & Vladeck, David C., A Critical Examination of the FDA's Efforts To Preempt Failure-to Warn Claims, 96 Geo. L. J. 461 (2008)Google Scholar [hereinafter Kessler & Vladeck] (finding deference to an agency's decision appropriate only for the initial approval of a drug – the only time when the FDA has adequate information to assess risks); Rabin, Robert L., Poking Holes in the Fabric of Tort: A Comment, 56 DePaul L. Rev. 293 (2007)Google Scholar (identifying the difficulties with preemption in light of post-approval risks and regulatory capture); Rabin, Robert L., Reassessing Regulatory Compliance, 88 Geo. L. J. 2049 (2000)Google ScholarPubMed; William Funk et al, The Truth about Torts: Using Agency Preemption to Undercut Consumer Health and Safety, Center for Progressive Reform, Sept. 2007, available at http://www.progressiveregulation.org/articles/Truth_Torts_704.pdf.

8 Sharkey, Catherine M., Federalism in Action: FDA Regulatory Preemption in Pharmaceutical Cases in State Versus Federal Courts 15 J. L. & Pol’y 1013 (2007)Google Scholar.

9 Sharkey, Catherine M., What Riegel Portends for FDA Preemption of State Law Product Liability Claims, 102 Nw. U. L. Rev. 415 (2008)Google Scholar.

10 See Merrill, Thomas, Preemption and Institutional Choice, 102 Nw. U. L. Rev. 727Google Scholar (finding that a lower level of deference should be provided for agency interpretations on preemption to preserve the role of the federal courts in reviewing matters that displace state authority).

11 Nagareda, Richard A., FDA Preemption: When Tort Law Meets the Administrative State, 1 J. Tort L. 4, 54 (2006).Google Scholar

12 Levine v. Wyeth, 944 A.2d 179, 188-89 (Vt. 2006).

13 Id.; see Gilhooley, Addressing Potential Drug Risks, supra note 4, at 132 and 383-84.

14 Brief for the United States as Amicus Curiae Supporting Petitioner at *26, Wyeth v. Levine, No. 06-1249, 2008 WL 2308908 (2008) [hereinafter Government Brief in Wyeth v. Levine].

15 As part of the consultation, the drug sponsor, for example, might have to raise the need for special labeling changes, such as a boxed warning for persistent risks. See infra Part V.B.3; 21 C.F.R. § 201.57(c)(1)(2006).

16 See Preamble, supra note 2, at 3934.

17 21 C.F.R. § 314. 70(c)(6)(iii)(2008).

18 Preamble, supra note 2, at 3936 cl.4. This clause seems broad enough to cover no response as well as a negative response.

19 See infra Part V.B.4-5 (discussing content and matter of disclosures to doctors as well as disclosures in drugs advertised to consumers about talking to their doctor about risk signals under review).

20 See infra Part IV.

21 See Testimony of FDA Commissioner George Larrick: Hearings on Drug Safety Before the Subcomm. of the H. Comm. on Govt. Oper. 2 (1964), reprinted in Peter Barton Hutt, Richard A. Merrill & Lewis A. Grossman, Food and Drug Law 685 (2007) [hereinafter Hutt, Merrill & Grossman] (recognizing that the early period of drug marketing represents “a final step in the testing of the product” and that there is “no way to duplicate fully in clinical trials the great variety of conditions under which a drug will be used when approved.”).

22 Inst. of Med. of the Nat’l Academies, The Future of Drug Safety: Promoting and Protecting the Public Health 11-12, 372-72 (Alina Baciu, Kathleen Stratton & Sheila P. Burke eds. 2006) [hereinafter IOM Report].

23 Id.

24 Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, 121 Sta. 823 (2007); see generally, Gilhooley, Assessing Potential Drug Risks, supra note 4, at 363- 66; infra Part V.C.1.

25 See Hutt, Peter Barton, The State of Science at the Food and Drug Administration, 60 Admin. L. Rev. 431, 432-33 (2008)Google Scholar (arguing that doubling the agency's budget is essential to maintain its scientific role in general); IOM Report, supra note 22 at 13-14 (supporting added revenue for post-approval safety evaluations); Nagareda, supra note 11, at 48 (raising the need for user fees for post-approval reviews). In the case of the drug program, there was a 146% increase in adverse event reports in 10 years but no increase in personnel support. Hutt, supra, at 455. While user fees provide support for reviews to approve new products, the funding for the other core function of the agency declined 29% in three years. Id. at 453-54.

26 See generally Gilhooley, Margaret, Vioxx's History and the Need for Better Procedures and Better Testing, 37 Seton Hall L. Rev. 941 (2007)Google ScholarPubMed (discussing the Vioxx controversy and regulatory response, as well as a proposed regulatory approach to encourage development of needed drugs and more long-term testing).

27 21 U.S.C. § 331(d) (2000); 21 U.S.C. § 355 (2000 & Supp. V 2001-2006).

28 21 U.S.C. §§ 321(n), 331(b) & 352(a)(2000). See Pharm. Mfr. Ass’n. v. FDA, 484 F.Supp. 1179, 1183-84 (D.Del. 1980), aff’d per curiam, 634 F.2d 106 (3d Cir. 1980) (upholding an expansive reading of these provisions as supporting a requirement for patient labeling).

29 21 C.F.R. § 314.70(c)(6)(iii)(A) (2008).

30 21 C.F.R. 201.57(c)(6)(iii)(A) (2008). The rules specifically state that FDA may require boxed warnings for serious warnings, which suggests that only FDA can require boxed warnings and implicitly suggests that other warnings do not have to have prior approval. See 21 C.F.R. § 201.57(c)(1) (2008).

31 Levine v. Wyeth, supra note 12, at 193. For an overview of the significance the FDA labeling can have in malpractice cases, see Morlino v. Medical Center of Ocean County, 706 A.2d 721, 729-30 (N.J. 1998) (holding that deviation from FDA warnings to be insufficient by itself to establish negligence absent expert testimony on the standard of care).

32 Preamble, supra note 2, at 3934-35.

33 Id. at 3935.

34 Id.

35 Id.

36 Id. at 3934.

37 Id.

38 Id. at 3936 cl.4.

39 See T. Merrill, supra note 10.

40 See 73 Fed. Reg. 2848 (Jan. 16, 2008).

41 Id. at 2849.

42 21 C.F.R. § 314.70(a)(6)(iii) (2008).

43 See Sharkey, Federalism in Action, supra note 8 (detailing the differences in acceptance of the regulatory compliance defense); Sharkey, Catherine M., Products Liability Preemption: An Institutional Approach, 76 Geo. Wash. L. Rev. 449 (2008)Google Scholar (discussing the development of the Court's preemption doctrine).

44 Cipollone v. Liggett Group, Inc. 505 U.S. 504, 530 (1992) (finding tort liability preempted by an express preemption of state laws imposing requirements on cigarette promotion).

45 See Geier v. Am. Honda Motor Co., 529 U.S. 861, 866 (2000) (finding preemption appropriate when liability can create uncertainty and conflict with federal objectives taking account of the agency's views); Medtronic v. Lohr, 518 U.S. 470 (1996) (finding by plurality no preemption of general common law duties for grandfathered devices that were not subject to specific pre-market approval with Justice Breyer concurring based on the agency's narrow view of preemption in a regulation); Moreland, Michael P., Tort Reform by Regulation: FDA Preemption of Labeling Claims, 1 J. Health & Life Sciences L. 39, 41 (2007)Google Scholar (tracking shifting views including views of Justice Stevens on the compensatory role of torts and Justice Breyer's views on administrative deference).

46 See Motus v. Pfizer, Inc. 127 F. Supp.2d 1085 (C.D. Cal. 2000); Motus v. Pfizer, Inc. 196 F.Supp.2d 984, 986 (C.D.Cal. 2001) (granting summary judgment on causation grounds), aff’d, 358 F.3d 659 (9th Cir. 2004); Preamble, supra note 2, at 3934-35.

47 Preamble, supra note 2, at 3934-36 (stating FDA's position on preemption in light of product liability cases). See Dorfman, Howard, Quinn, Vivian M. and Brophy, Elizabeth A., Presumption of Innocence: FDA's Authority to Regulate the Specifics of Prescription Drug Labeling and the Preemption Debate, 61 Food & Drug L.J. 585, 593 (2006)Google ScholarPubMed (providing a history of FDA's position on preemption and the potential impact of its position in light of the “crazy quilt” of preemption decisions).

48 Riegel v. Medtronic, Inc., 128 S. Ct. 999, 1005 (2008). The lawsuit sought damages for unspecified design and labeling defects when a doctor used a balloon catheter contrary to the labeling approved by FDA at the time the device was approved.

49 21 U.S.C § 360c(a) (2000).

50 Riegel, 128 S. Ct. at 1007.

51 Id. at 1008.

52 Id. at 1018 (Ginsburg, J., dissenting).

53 Id. at 1011 (Stevens, J., concurring).

54 Warner-Lambert Co. v. Kent, 128 S. Ct. 1168 (2008).

55 Buckman Co. v. Plaintiff's Legal Comm., 531 U.S. 341, 353 (2001).

56 Id.

57 See Kessler & Vladeck, supra note 7, at 480. See infra Part V.B.6 (discussing the relevance of misrepresentations for preemption).

58 See Kessler & Vladeck, supra note 7, at 468 (noting that in passing the FDA Amendments Act Congress demonstrated that it believed the FDA needed greater resources).

59 Preamble, supra note 2 at 3936, cls. 4 & 6 (supporting preemption “unless FDA has made a finding that the sponsor withheld material information”). Buckman, 531 U.S. at 354- 55 (Stevens, J., concurring) (supporting that an exception when the agency made an antecedent finding of fraud).

60 Preamble, supra note 2, at 3933.

61 See supra Part III.A.

62 Levine v. Wyeth, 944 A.2d, at 188, 194.

63 Id. at 182-83.

64 Id. at 183 n.1.

65 Government Brief in Wyeth v. Levine, supra note 14, at *6.

66 Levine v. Wyeth, 944 A.2d at 182.

67 Id. at 187-88.

68 Id. at 189 and 190-95.

69 Id. at 198 (Reiber, C.J. dissenting). The majority also found that the plaintiff's experts testified that the “the label should not have allowed IV push as a means of administration as it was safer to use other means.” Id. at 182.

70 Id. at 198-99.

71 Id. at 189 n.2.

72 21 C.F.R. § 201.57(c)(5).

73 Levine v. Wyeth, 944 A.2d at 188-89.

74 Id. (discussing Wyeth's argument that “FDA prohibited the use of a stronger warning with respect to IV-push administration … .”).

75 Id. at 189. The proposed revision no longer had the statement to use extreme care in the initial sentence. See id. at 183 n.1 for the text of the existing warning and proposed revision.

76 Id. at 189.

77 Preamble, supra note 2, at 3933-96.

78 See Reigel, supra note 3, at 1007. FDA decisions are more accurately described as risk-benefit decision. See Hutt, Merrill & Grossman, supra note 21, at 694-96.

79 See Levine v. Wyeth, 944 A.2d at 194-95 (finding liability without apportionment to be appropriate for multiple tortfeasors under the state's comparative negligence statute even when the lawsuits are separate).

80 Colacicco v. Apotex, Inc., 521 F.3d 253, 271 (3d Cir. 2008).

81 Id.

82 Fellner v. Tri-Union Seafood, 539 F.3d 237, 245 (3d Cir. 2008) (citing United States v. Mead Corp. 533 U.S. 218, 230 (2001), for the test in “relatively formal” proceedings) (concerning the need for mercury warnings on tuna fish).

83 Government Brief in Wyeth v. Levine, supra note 14, at *25. But see infra Part III.B.2 (discussing Wyeth's argument that the reviewer's position established a specific impossibility basis for preemption).

84 Id. at *26.

85 Id.

86 Fellner v. Tri-Union Seafood, 539 F.3d. at 245.

87 See Preamble, supra note 2, at 3934 (describing the existing practice under which “manufacturers typically consult with FDA prior to adding risk information to the labeling” and FDA's position that it “believes” that preemption extends to matters “proposed” to FDA, a term broad enough to encompass consultations).

88 See Task Force on Risk Mgmt., Managing the Risks from Medical Product Use: Creating a Risk Management Framework 43-44 (1999), available at http://www.fda.gov/oc/tfrm/riskmanagement.pdf); Gilhooley, Assessing Potential Drug Risks, supra note 4 at 360-61.

89 In the case of Vioxx, an expert questioned whether the tests needed to establish effectiveness for pain relief were adequate to establish safety for a chronic use drug. F.D.A., Merck, and Vioxx: Putting Patient Safety First? Hearing Before the S. Comm. on Finance, 108th Cong. 50 (2004) [hereafter S. Finance Comm. Hearing] (statement of Dr. Bruce M. Psaty, Professor, Medicine and Epidemiology, University of Washington); Gilhooley, Assessing Potential Drug Risks, supra note 4 at 366-67; Bruce M. Psaty & Carl D. Furberg, Rosigilitazone and Cardiovascular Risk, 356 New Eng. J. Med. 2522, 2524 (2007).

90 21 U.S.C. § 356(b)(1) (2000).

91 Id. at § 356(b)(2).

92 See Gilhooley, Assessing Potential Drug Risks, supra note 4, at 368-69 (noting that the status is given on an agency website; IOM Report, supra note 22, at 55 (citing a 2006 report that 65% of the open post-market commitments “have yet to be started”).

93 See Gilhooley, Assessing Potential Drug Risks, supra note 4, at 368; Hutt, Merrill & Grossman, supra note 21, at 679.

94 See James Bilstead, Surrogate Endpoints, in Hutt, Merrill & Grossman, supra note 21, at 640 (stating the difference between clinical and surrogate indicators).

95 IOM Report, supra note 22, at 107.

96 See Wood, Alastair J.J., A Proposal for Radical Change in the Drug-Approval Process, 355 New Eng. J. Med. 618 (2006)CrossRefGoogle Scholar.

97 To encourage better testing, some advocate providing added non-patent economic incentives for drugs with long-term safety testing and a showing of an improvement over standard therapy. See Alastair J.J. Wood, A Proposal for Radical Change in the Drug-Approval Process, supra note 96, at 618.

98 IOM Report, supra note 22, at 11-12.

99 Id. at 11-12, 171.

100 See Gilhooley, Assessing Potential Drug Risks, supra note 4, at 372-73. The protections for commercial speech cast a cloud over the ability to have an advertising moratorium. See Thompson v. Western States Medical Center, 535 U.S. 357 passim (2002) (holding that § 127(a) of the Food and Drug Administration Modernization Act of 1997 exempting compounded drugs from the FDA's approval process if the providers did not advertise or promote the drugs amounted to an unconstitutional restriction on commercial speech in violation of the First Amendment).

101 See Gilhooley, Vioxx's History, supra note 26 passim.

102 See Gardiner Harris, FDA Official Admits “Lapses” on Vioxx, N.Y. Times, Mar. 2, 2005 at A15 (reporting testimony by an agency official that the warnings initially sought changed during negotiations).

103 Gilhooley, Vioxx's History, supra note 26, at 947.

104 Id.

105 See id. at 948-49.

106 See id. at 950.

107 See supra Part II.C.

108 Preamble, supra note 2, at 3934.

109 21 C.F.R. § 201.57(c)(6) (2008) (“In accordance with [section] 314.70 …, the labeling must be revised to include a warning about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug; a casual relationship need not have been definitely established.”). The CBE rule in § 314.70(c)(6) provides that the agency “may designate a category of changes” for which the holder of the new drug application “may commence distribution of the drug product involved upon receipt by the agency of a supplement for the change,” and provides under subsection (iii)(A) that these “changes include” ones “[t]o add or strengthen a contradiction, warning, precaution or adverse reaction.”

110 See Nagareda, supra note 11, at 24 (“[T]he point of the rules is precisely that some such changes are desirable, without prior FDA approval, in order to improve information about previously-approved drugs–one might say, to prevent the existing labeling from becoming misleading in light of new risk information.”).

111 See Gibson, Brent R. et al., The US Drug Safety System: Role of the Pharmaceutical Industry, 17 Pharmacoepidemiology and Drug Safety, 110–114 (2008)CrossRefGoogle ScholarPubMed (“Pharmaceutical and biotechnology corporations bear the collective responsibility for the therapeutic products they produce.”).

112 See 21 U.S.C. 355(b)(1) (Supp. V 2001-2006) (providing for approval of new drugs based upon applications submitted by the manufacturer with “full reports of investigations” to show whether the drug is safe and effective).

113 See Gilhooley, Vioxx's History, supra note 26, at 946, 958; see also Food and Drug Administration, White Paper on Prescription Drug User Fee Act (PUDFA): Adding Resources and Improving Performance in FDA Review of New Drug Applications (Nov. 10, 2005), reprinted in Hutt, Merrill, & Grossman, supra note 21, at 680-82.

114 See Part IV.C.

115 21 C.F.R. § 201.57(c)(6)(I) (2008).

116 See Gilhooley, Vioxx's History, supra note 26, at 948-50 (noting the difference between FDA and Merck on the need for labeling changes about a cardiovascular risk).

117 21 C.F.R. § 314. 70(c)(6)(iii)(2008).

118 See Gilhooley, Assessing Potential Drug Risks, supra note 4, at 383-85.

119 See IOM Report, supra note 22, at 77-78 (reporting that division directors, office directors, and the Office of New Drugs director “act in a final decision making capacity in most cases”); see also Hutt, Merrill & Grossman, supra note 21, at 20-21.

120 See Hutt, Merrill & Grossman, supra note 21, at 17-20 (reporting that “review and supervision of the working level is attenuated, and in many cases non-existent”).

121 See IOM Report, supra note 22, at 123.

122 See Gilhooley, Assessing Potential Drug Risks, supra note 4, at 388.

123 21 C.F.R. § 10.30 (2008).

124 See supra Part III.C.2.

125 21 C.F.R. § 201.57(c)(1) (2008).

126 Id.

127 21 U.S.C.A. § 355(r) (West Supp. 2008) (added by Food and Drug Administration Amendments Act of 2007. Pub. L. No. 110-85, § 915, 121 Stat. 823, 957 (2007)).

128 See supra Part III.B.2.

129 See Schuck, supra note 6, at 104-05.

130 See id. at 104.

131 See supra Part III.B.1; see also Sharkey, Catherine M., The Fraud Caveat to Agency Preemption, 102 Nw. U. L. Rev. 841, 848-49 (2008)Google Scholar (supporting tort liability as an exception to Buckman when there is an agency finding of fraud).

132 For discussion of the need for additional resources to support the agency's postapproval responsibilities, see Nagareda, supra note 11, at 48 n.178-80; Hutt, supra note 25; IOM Report, supra note 22.

133 See Schuck, supra note 6, at 106-07 (supporting a hyper-heightened pleading requirement).

134 See Nagareda, supra note 11, at 52.

135 See Gilhooley, Assessing Potential Drug Risks, supra note 4, at 387.

136 See IOM report, supra note 22, at 13-14; Nagareda, supra note 11, at 48.

137 The agency has long had the power in the case of misleading labeling to withdraw the drug after a formal hearing, or suspend sale before a hearing in the case of an “imminent hazard.” 21 U.S.C. § 355(e) (2000). In addition, the agency can bring enforcement action in court against misbranded drugs. 21 U.S.C. § 352(a) (2000) (prohibition on misleading statements); 21 U.S.C.A. §§ 332, 334 (West 1999) (authorization of seizures and injunctions). FDAAA provides specific authority to require labeling changes and additional testing that may be enforced through civil money penalties. 21 U.S.C. § 355(o)(1), (o)(3)(A); Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, 121 Stat. 823, 922-23 (2007); see also Gilhooley, Vioxx's History, supra note 26 at 956-57 and 960-62.

138 Judicial Review of informal adjudications can occur with respect to these issues under the Administrative Procedure Act. 5 U.S.C. §§ 555, 706 (2006); see Citizens to Preserve Overton Park v. Volpe, 401 U.S. 402, 420 (1971); Camp v. Pitts, 411 U.S. 138, 142-43 (1973).

139 Cf. Citizens to Preserve Overton Park v. Volpe, 401 U.S. 402 (1971) (supporting a presumption of regularity as well as the need for a thorough review).

140 Kessler & Vladeck, supra note 7, at 465.

141 McDarby v. Merck, 949 A.2d 223, 256 (N.J. Super. Ct. App. Div. 2008).

142 See Funk, supra note 7, at 12; Kessler & Vladeck, supra note 7, at 483.

143 See Issacharoff, Samuel & Sharkey, Catherine M., Backdoor Federalization, 53 U.C.L.A. L. Rev. 1353, 1357 (2006)Google Scholar (describing the Supreme Court as a “willing partner” with Congress in providing federal oversight to state interference with a national market).

144 See Preamble, supra note 2, at 3935; infra Part II.B.

145 See Studdert, David M. et. Al, Medical Monitoring for Pharmaceutical Injuries: Tort Law for the Public's Health?, 289 J. Am. Med. Ass'n 889, 890 (2003)Google ScholarPubMed.

146 See Gilhooley, Vioxx's History, supra note 26, at 951-52 (discussing FDA's decision on applying the findings for Vioxx to other drugs).