1 Martin, Anne et al., Recession Contributes to Slowest Annual Rate of Increase in Health Spending in Five Decades, 30 Health Aff. 11, 11 (2011).CrossRefGoogle ScholarPubMed

2 The Henry J. Kaiser Family Foundation, U.S. Health Care Costs, http://www.kaiseredu.org/Issue-Modules/US-Health-Care-Costs/Background-Brief.aspx (last updated Mar., 2011).

3 Martin et al., supra note 1, at 12.

4 Id. at 18.

5 See infra notes 18-19 and accompanying text.

6 Dresser, Rebecca & Frader, Joel, Off-Label Prescribing: A Call for Heightened Professional and Government Oversight, 37 J.L. Med. & Ethics 476, 477 (2009).Google Scholar

7 See Cohen, Joshua et al., Off-Label Use Reimbursement, 64 Food & Drug L.J. 391, 396 (2009)Google ScholarPubMed (outlining the insurance industry’s process for reimbursing drug claims).

8 Food, Drug, and Cosmetic Act, 21 U.S.C. §§ 301-399 (2006).

9 Id. § 321(p)(1). The FDA drug approval process has received much criticism for its lengthiness. Before a drug maker can submit an Investigational New Drug Application (IND), it must conduct investigations of the drug’s effect on animals to determine if it is safe for human clinical trials. This may take as long as three and a half years. After approval of the IND, the drug must undergo three phases of clinical trials. Phase I trials test toxicity of the drug on humans to determine if it is safe, and takes six to twelve months to complete. Phase II trials test the therapeutic effectiveness on humans suffering from the condition, and takes eighteen months to two years to complete. Phase III consists of clinical trials to further develop effectiveness data, and can last for an average of three years. After completion of the three phases, the drug maker can submit a New Drug Application (NDA) to the FDA, which the agency approves within 180 days. Rossen, Benjamin R., FDA’s Proposed Regulations to Expand Access to Investigational Drugs for Treatment Use: The Status Quo in the Guise of Reform, 64 Food & Drug L.J. 183, 187-88 (2009).Google ScholarPubMed

10 Dresser & Frader, supra note 6, at 477.

11 Carol R. Berry, The Dividing Line Between the Role of the FDA and the Practice of Medicine: A Historical and Current Analysis 2-10 (Jan. 1997) (unpublished paper, Harvard Law School) (on file with Legal Education Document Archive (LEDA), Harvard Law School).

12 Cohen et al., supra note 7, at 392.

13 Stoffelmayr, Kaspar J., Products Liability and “Off-Label” Uses of Prescriptions Drugs, 63 U. Chi. L. Rev. 275, 277 (1996).CrossRefGoogle Scholar

14 In other words, a physician fails to act as would a similar physician in similar circumstances.

15 “[W]e find that a prescription drug’s labeling or its PDR reference, when introduced along with other expert evidence on the standard of care, is admissible to assist the trier-of-fact to determine whether the drug presented an unacceptable risk to the patient.” Richardson v. Miller, 44 S.W.3d 1, 17 (Tenn. Ct. App. 2000).

16 James B. Riley, Jr. & Aaron Basilius, P., Physicians’ Liability for Off-Label Prescriptions, 6 Hematology & Oncology News & Issues 24, 26 (2007).Google Scholar

17 Id. There has been much commentary about the issue of informed consent in off-label prescribing. See, e.g., Ausness, Richard C., “There’s Danger Here, Cherie!”: Liability for the Promotion and Marketing of Drugs and Medical Devices for Off-Label Uses, 73 Brook. L. Rev. 1253 (2008)Google Scholar; Johns, Margaret Z., Informed Consent: Requiring Doctors to Disclose Off-Label Prescriptions and Conflicts of Interest, 58 Hastings L.J. 967 (2007).Google Scholar

18 Radley, David C. et al., Off-Label Prescribing Among Office-Based Physicians, 166 Archives Internal Med. 1021, 1023 (2006).CrossRefGoogle ScholarPubMed

19 Beck, James M. & Azari, Elizabeth D., FDA, Off-Label Use, and Informed Consent: Debunking Myths and Misconceptions, 53 Food & Drug L.J. 71, 80 (1998).Google ScholarPubMed

20 Herrmann, Mark & Bownas, Pearson, Keeping the Label Out of the Case, 103 Nw. U. L. Rev. 477, 478 (2009).Google Scholar

21 Id. at 478-79.

22 Mary Anne Pazanowski, FDA, Legal Experts Discuss Obstacles Facing Pediatric Product Development, 3 BNA Med. Devices L. & Industry Rep. 380 (May 20, 2009).

23 U.S. Food & Drug Ass’n, Guidance for Industry: Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices 3 (Jan. 2009), available at http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0053-gdl.pdf (explaining that off-label uses or treatment regimens “may be important and may even constitute a medically recognized standard of care”).

24 Johns, supra note 17, at 968-69.

25 Herrmann & Bownas, supra note 20, at 479 (estimating that 65% of cancer patients, 70% of kidney dialysis patients, and 80% of AIDS patients engage in off-label use).

26 Henry, Veronica, Off-Label Prescribing Legal Implications, 20 J. Legal Med. 365, 382 (1999).CrossRefGoogle ScholarPubMed

27 Id. at 382.

28 Jeff Minerd, Most Off-Label Drug Use on Iffy Scientific Ground, MedPage Today (May 9, 2006), http://www.medpagetoday.com/PublicHealthPolicy/HealthPolicy/3252.

29 An even greater disparity exists for psychiatric off-label prescriptions, with ninety-six percent of uses having little to no evidential support. Radley et al., supra note 18, at 1021.

30 Rick Nauert, Off-Label Use May Be Off-Track, Psych Central (Aug. 24, 2009), http://psychcentral.com/news/2009/08/24/off-label-use-may-be-off-track/7926.html.

31 Radley et al., supra note 18, at 1021.

32 The FDA approved Actimmune for the treatment of two other rare diseases. Johns, supra note 17, at 969.

33 Id. at 969-70.

34 See id. at 969. Additionally, Actimmune costs approximately $50,000 per year for each of its users.

35 Off-Label Drug Uses Wasting Millions, Raising Health Risks, The Medical News (Mar. 4, 2009, 10:14 PM), http://www.news-medical.net/news/2009/0 3/04/46510.aspx. See also Will Meek, Off-Label Antipsychotic Use, Psych Central (Jan. 21, 2007), http://psychcentral.com/blog/archives/2007/01/21/off-label-antipsychotic-use/.

36 Salbu, Steven R., Off-Label Use, Prescription, and Marketing of FDA-Approved Drugs: An Assessment of Legislative and Regulatory Policy, 51 Fla. L. Rev. 181, 203 (1999).Google Scholar

37 Id.

38 Id.

39 Dresser & Frader, supra note 6, at 477.

40 “Any person who . . . knowingly presents, or causes to be presented, a false or fraudulent claim for payment or approval . . . is liable to the United States Government for a civil penalty.” False Claims Act, 31 U.S.C. § 3729(a)(1) (2006).

41 Crane, Thomas S., The Next Enforcement Wave—Off-Label Marketing of Medical Devices, 21 Health Law. 22, 22 (2009).Google Scholar

42 Stafford, Randall S., Regulating Off-Label Drug Use—Rethinking the Role of the FDA, 358 New Eng. J. Med. 1427, 1428 (2008).CrossRefGoogle Scholar

43 Allergan also sued the Department of Justice, which has been involved in the prosecution of off-label drug promotion. Natasha Singer, Botox Maker’s Suit Cites Free Speech, N.Y. Times, Oct. 3, 2009, at B3.

44 Id.

45 In September 2010, Allergan reached a settlement with the Department of Justice to resolve the criminal and civil claims against the company. Allergan pleaded guilty to a misdemeanor misbranding charge and agreed to pay $600 million. Allergan also agreed to drop its free speech claims. See Jon Kamp & Brent Kendall, Botox Allegations Settled with U.S. for $600 Million, Wall St. J. (Sept. 2, 2010), http://online.wsj.com/article/SB10001424052748703882304575465371767239834.html. The U.S. Supreme Court recently granted certiorari in Sorrel v. IMS Health Inc. to decide whether a Vermont law prohibiting pharmaceutical companies from using prescriber-identifiable data for marketing purposes restricts free trade in truthful information. Robert Barnes, Supreme Court to Hear Drug Data-Mining Case, Wash. Post (Jan. 7, 2011, 10:26 PM), http://www.washingtonpost.com/wp-dyn/content/article/2011/01/07/AR2011010705726.html. Although Sorrel differs in that it involves the treatment of personal patient data, a holding that such restrictions violate the First Amendment increase the likelihood that an Allergan-like constitutional challenge to the off-label marketing ban would be successful.

46 U.S. Gov’t Accountability Office, FDA Faces Challenges Meeting Its Growing Medical Product Responsibilities and Should Develop Complete Estimates of Its Resource Needs 34-35 (2009) (finding that the FDA “cannot do all that is asked of it”).

47 For a more thorough investigation of the Ketek incident, see David B. Ross, The FDA and the Case of Ketek, 356 New Eng. J. Med. 1601 (2007).

48 Brief for David B. Ross, & Stefan P. Kruszewski, as Amici Curiae Supporting Respondent, Wyeth v. Levine, 129 S. Ct. 1187 (2009) (No. 06-1249), 2008 WL 4642106 at *8-15.

49 Wyeth v. Levine, 129 S. Ct. 1187, 1202.

50 See Joseph, John N. et al., Enforcement Related to Off-Label Marketing and Use of Drugs and Devices: Where Have We Been and Where Are We Going?, 2 J. Health & Life Sci. L. 73, 81 (2009)Google ScholarPubMed (noting that private insurers have denied reimbursement for off-label use of drugs).

51 Cohen et al., supra note 7, at 400 (citation omitted).

52 Id. at 397.

53 Id. at 398.

54 Id.

55 Id.

56 See Barry R. Furrow et al., Health Law: Cases, Materials and Problems 122-25 (6th ed. 2008) (discussing state and federal authority to regulate the practice of medicine).

57 Maxwell J. Mehlman, Off-Label Prescribing, The Doctor Will See You Now (May 2005), http://www.thedoctorwillseeyounow.com/content/bioethics/art1971.html/.

58 Under Illinois law, an HMO that provides coverage for FDA approved drugs approved for the treatment of certain types of cancer shall not “exclude coverage of any drug on the basis that the drug has been prescribed for the treatment of a type of cancer for which the drug has not been approved by the federal Food and Drug Administration.” 215 Ill. Comp. Stat. Ann. 125/4-6.3 (West 2009).

59 Tabarrok, Alexander T., Assessing the FDA via the Anomaly of Off-Label Drug Prescribing, 5 Indep. Rev. 25, 35-36 (2000).Google Scholar

60 Doctors Cannot Prescribe Abortion Pill for Off-Label Uses, Ohio Supreme Court Says, 18 BNA Health L. Rep. 920 (July 9, 2009) (discussing the result in Cordray v. Planned Parenthood Cincinnati Region, 911 N.E.2d 871 (Ohio 2009)).

61 See id.

62 Id.

63 Employee Retirement Income Security Act of 1974 (ERISA), Pub. L. No. 93-406, 88 Stat. 829 (codified as amended in scattered sections of 5 U.S.C., 18 U.S.C., 26 U.S.C., 29 U.S.C., and 42 U.S.C.).

64 See Leslie Pickering Francis, Legitimate Expectations, Unreasonable Beliefs, and Legally Mandated Coverage of Experimental Therapy, 1 Ind. Health L. Rev. 213, 234 (2004)Google Scholar (discussing the relationship between ERISA and off-label prescribing).

65 Dresser & Frader, supra note 6, at 483.

66 Id.

67 Stafford, supra note 42, at 1429 (listing reasons why FDA may be reluctant to take a more active role in regulating off-label use).

68 See supra notes 46-49 and accompanying text (discussing FDA’s shortcomings in pharmaceutical regulation due to inadequate resources).

69 Hermann & Bownas, supra note 20, at 483.

70 Id. at 483-84.

71 Id.

72 Cohen et al., supra note 7, at 392. The requirements of a SNDA are just as rigorous as those of the original NDA, requiring Phase II and Phase III safety and effectiveness trials. Oates, Mitchell, Facilitating Informed Medical Treatment Through Production and Disclosure of Research Into Off-Label Uses of Pharmaceuticals, 80 N.Y.U. L. Rev. 1272, 1284-85 (2005).Google Scholar There are benefits of SNDA approval to the drug manufacturer, however, including the ability to freely market the off-label use. Id.

73 Cohen et al., supra note 7, at 392 (noting that SNDA applications may occur infrequently because costly clinical trials may yield unsupportive evidence of safety and effectiveness).

74 See Radley et al., supra note 18, at 1021 (finding that in 2001 approximately seventy-three percent of off-label drug mentions had little or no scientific support).

75 Cohen, Joshua & Wilson, Andrew, New Challenges to Medicare Fighting Beneficiary Access to mAbs, 1 mAbs 56, 56 (2009).CrossRefGoogle Scholar

76 See supra notes 43-45 and accompanying text (discussing Allergan suit and potential impact on FDA’s enforcement authority).

77 Epstein, Richard A., Against Permititis: Why Voluntary Organizations Should Regulate the Use of Cancer Drugs, 94 Minn. L. Rev. 1, 4-5 (2009).Google Scholar

78 Id. at 5-6.

79 Id. at 4 (focusing on experimental cancer drugs rather than off-label uses of approved drugs).

80 Id. at 32.

81 Id. at 33.

82 “These types of intermediaries are commonplace for all serious diseases, serving as a clearinghouse for medical information. Many are managed by families of individuals who have suffered or died from serious diseases. Others are run commercially or by professional medical societies.” Id. at 8. While these voluntary organizations may be either for- or non-profit, Epstein describes them as “typically nonprofit organizations that serve the same basic intermediation function in virtually all markets: to collect, digest, and interpret material for their members in areas where there is an information shortfall. They set best practice standards and convey these standards to their membership on a national and global level.” Id. at 26.

83 Epstein’s model would, however, keep the FDA’s role intact to oversee Phase I trials. Drugs successfully completing Phase I would be regulated by intermediary organizations. Id. at 41.

84 Reed Abelson & Andrew Pollack, Medicare Widens Drugs It Accepts for Cancer, N.Y. Times, Jan. 27, 2009, at A1 (noting that in some cases the reference guides motivating coverage determinations are linked to drug makers).

85 Epstein contends that pursuit of tort damages by patients suffering serious cancer would be a rarity and, thus, such costs would be miniscule. Epstein, supra note 77, at 8.

86 Press Release, Tufts Center for the Study of Drug Development, Three-Quarters of U.S. Health Plans Reimburse for Off-Label Uses of Prescription Drugs (Mar. 10, 2009), available at http://csdd.tufts.edu/files/uploads/mar-apr_pr.pdf (noting that most third-party payors rely on pharmaceutical compedia and/or peer-reviewed literature to inform reimbursement decisions).

87 Cohen et al., supra note 7, at 398.

88 Press Release, supra note 86. Some payors identified specific compendia, such as American Hospital Formulary Service, United States Pharmacopoeia Dispensing Information, American Medical Association Drug Evaluations, Thomson Micromedex DrugDex, Facts and Comparisons, Clinical Pharmacology, and American Pharmaceutical Association Drug Information. Cohen et al., supra note 7.

89 Furrow et al., supra note 56, at 403. These sources include the American Hospital Formulary Service Drug Information, the U.S. Pharmacopoeia Dispensing Information, or two articles from major peer-reviewed journals, or published studies having validated and uncontested data, which support the safety and effectiveness of the proposed use. Id.

90 Abelson & Pollack, supra note 84, at A1.

91 Id.

92 See Roxanne Nelson, Compendia Guiding Off-Label Use of Cancer Drugs Inadequate, Medscape Medical News (Feb. 21, 2009), http://www.medscape.com/viewarticle/588552 (discussing Abernathy’s study and noting inconsistency across compendia).

93 Agency for Healthcare Research & Quality, Dep’t of Health and Human Servs., Compendia for Coverage of Off-Label Uses of Drugs and Biologics in an Anticancer Chemotherapeutic Regimen 3 (2007).

94 Id. at 108-11.

95 Id. at 1 (noting that the Centers for Medicare and Medicaid Services (CMS) commissioned the AHRQ Report to inform potential future coverage determinations).

96 Tom Goss, Off-Label Use of Anticancer Therapies: Physician Prescribing Trends and the Impact of Payer Coverage Policy 3 (2005), available at http://accc-cancer.org/advocacy/pdf/PhRMAstudy.pdf (commissioned by the Association of Community Cancer Centers, the Biotechnology Industry Organization, and the Pharmaceutical Research and Manufacturers of America).

97 Oates, supra note 72, at 1284-85.

98 American Society of Clinical Oncology, Reimbursement for Cancer Treatment: Coverage of Off-Label Drug Indications, 24 J. Clinical Oncology 3206, 3206-07 (2006).CrossRefGoogle Scholar

99 See Medicare: Senator Praises CMS Coding Decision On Reimbursement for Off-Label Avastin, 7 BNA Pharm. L. & Industry Rep. 1287 (Nov. 11, 2009) (describing a CMS coding change permitting physicians to prescribe cancer drugs for off-label uses).

100 See Francis, supra note 64, at 234 (explaining that ERISA preempts state coverage mandates for self-insured employers for off-label drug uses, but that those employers may choose to follow these mandates regardless).

101 American Society of Clinical Oncology, supra note 98, at 3206.

102 Id.

103 At the time of enactment, the Social Security Act recognized the American Hospital Formulary Service-Drug Information, the U.S. Pharmacopoeia-Drug Information, and the DRUGDEX Information System. Id. at 3206-07. The Social Security Act permits the Secretary of Health and Human Services to designate additional compendia (and peer-reviewed medical journals) to provide guidance as to off-label uses of cancer drugs. Id. at 3207. Medicare, for example, has expanded the number of compendia it consults, leading to an expansion of the number of reimbursable cancer drugs. Cohen et al., supra note 7, at 396.

104 Specifically, whether a particular off-label use is medically accepted turns on whether the off-label use is referenced in defined compendia. American Society of Clinical Oncology, supra note 98, at 3207.

105 “In § 1860D-2(e) of the Social Security Act, coverage for off-label uses of drugs reimbursed under the new Part D is defined utilizing the three compendia referenced in the Medicaid law.” Id.

106 See, e.g., Nelson, supra note 92 (noting that “the information used in these compendia is inconsistent, incomplete, and out of date”).

107 American Society of Clinical Oncology, supra note 98, at 3207.

108 Cohen et al., supra note 7, at 396-97.

109 Nelson, supra note 92.

110 Senator Praises CMS Coding Decision, supra note 99.

111 Id.

112 Mehlman, supra note 57 (noting that a number of states have passed laws requiring insurers to pay for off-label uses of approved drugs).

113 Francis, supra note 64, at 235.

114 States requiring insurers to cover off-label drug use for cancer treatment include Arizona, Arkansas, Connecticut, Illinois, Kansas, Maine, Minnesota, Mississippi, Nevada, North Carolina, Ohio, Rhode Island, South Carolina, Tennessee, and Virginia. Id. n.84.

115 S.C. Code Ann. § 38-71-275 (1976).

116 These states include Alabama, Indiana, Maryland, Massachusetts, New Hampshire, New Jersey, North Dakota, Ohio, and Oregon. Francis, supra note 64, at 235 n.85. For example, in Ohio, no policy “shall limit or exclude coverage on the basis that the drug has not been approved by the United States food and drug administration for the treatment of a particular indication for which the drug has been prescribed . . . .” Ohio Rev. Code Ann. § 1751.66 (West 2010).

117 California, Michigan, and South Dakota have enacted this type of mandate. Francis, supra note 64, at 235 n.86.

118 AHCA also limited the off-label uses of Neurontin’s corresponding generic, gabapentin. Douglas, Drew, State to Appeal Ruling That It Must Pay for Off-Label Uses of Epilepsy Medication, 15 BNA Health L. Rep. 306 (Mar. 16, 2006).Google Scholar

119 Id. (describing plaintiffs’ argument that they were entitled to reimbursement under federal Medicaid law because the drugs were listed in a congressionally approved compendia).

120 Id. The state argued that “medically accepted indication” required clinically verifiable data—i.e., two double-blind, placebo-controlled, randomized clinical trials. Id. This standard is equivalent to requirements for FDA approval of a supplemental use of a drug. See supra note 72 and accompanying text.

121 Douglas, supra note 118.

122 Id.

123 See Francis, supra note 64, at 236 n.88 (detailing statutorily imposed evidentiary requirements for off-label coverage mandates and the differences between such requirements).

124 Id. at 234 (describing how state laws governing insurance run afoul of ERISA).

125 Id.

126 Quaresma v. BC Life & Health Ins. Co., 623 F. Supp. 2d 1110, 1135 (2007) (limiting Cal. Health & Safety Code § 1367.21 (West 2010) and Cal. Ins. Code § 10123.195 (West 2010) because they encroach on a relationship regulated by ERISA).

127 See Francis, supra note 64, at 234 “[S]tate mandates do not extend to employers who self-insure their health plans . . . [but] employers nonetheless may follow state mandates voluntarily.”).

128 See Sox, Harold C., Editorial, Evaluating Off-Label Uses of Anticancer Drugs: Time for a Change, 150 Annals of Internal Med. 353, 354 (2009)CrossRefGoogle ScholarPubMed (arguing that the approach where Medicare pays for off-label use of a drug if it is included in a compendia is too low a hurdle and is necessarily inconsistent).

129 Id. (arguing that basing reimbursement on FDA approval is too difficult and too costly).

130 Wyeth, 129 S. Ct. at 1202.

131 Id.

132 Henninger S. Bullock et al., Fifth Circuit, Joining Eighth Circuit, Holds Consumers “Failure to Warn” Claims Against Generic-Drug Makers Not Preempted by Federal Law (Jan. 25, 2010), http://www.mayerbrown.com/publications/article.asp?id=8473&nid=6. In Demahy v. Actavis, the plaintiff alleged that the drug Reglan, manufactured by Actavis, which she used to treat gastric conditions, created a neurological condition. Id. The court did, however, point out that the federal preemption issue has split a number of district courts. Id.

133 American Society of Clinical Oncology, supra note 98, at 3207.

134 Dresser & Frader, supra note 6, at 482.

135 Cohen, et al., supra note 7, at 402.

136 Id.

137 Id.

138 Id. at 402-03.

139 Sox, supra note 128, at 354.

140 Specifically, CMS decided to cover the colorectal agents irinotecan, oxaliplatin, cetuximab, and bevacizumab. Cohen et al., supra note 7, at 403.

141 Id. at 402-03. See also CMS to Cover Warfarin Response Testing Only if Beneficiary in Specific Clinical Trial, 7 BNA Pharm. L. & Industry Rep. 948 (Aug. 14, 2009) for another example of a clinical trial requirement for coverage.

142 Weixel, Nathaniel, Delivery System Reform Makes Treatments More Affordable, J&J Executive Says, 8 BNA Pharm. L. & Industry Rep. 255 (Feb. 19, 2010).Google Scholar

143 See Cohen, supra note 7, at 402-03 (noting the potential for accelerated development of evidence for four cancer drugs).

144 The NCD was originally prompted by safety and spending concerns along with “aggressive marketing practices.” Id. at 403 (citing Stephanie Saul, Medicare Balks at Covering Johnson Heart Drug in Some Cases, N.Y. Times (Dec. 3, 2005), http://www.nytimes.com/2005/12/03/business/03drug.html?_r=2&ref=stephaniesaul]).

145 Oates, supra note 72, at 1303.

146 Best Pharmaceuticals for Children Act (BPCA) of 2002, Pub. L. No. 107-109, 115 Stat. 1408 (2002) (codified as amended in scattered sections of 21 U.S.C. and 42 U.S.C.).

147 Oates, supra note 72, at 1303.

148 Id. at 1304.

149 Id.

150 Id. at 1305.

151 See id. (noting that mandatory pediatric research was not incorporated in the BPCA).

152 Patient Protection and Affordable Care Act of 2010, Pub. L. No. 111-148, 124 Stat. 119 § 6301 (2010). See also Alex Nussbaum et al., Obamacare’s Cost Scalpel, BusinessWeek (Mar. 24, 2010, 11:05 PM), http://www.businessweek.com/magazine/content/10_14/b4172064340424.htm (describing the comparative effectiveness research provisions).

153 Nussbaum et al., supra note 152.

154 Id.

155 Abelson & Pollack, supra note 84, at A1.

156 Epstein, supra note 77, at 21-23.

157 Id. at 17.

158 Id. at 11.

159 Abelson & Pollack, supra note 84, at A1.