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Commercial Speech and Off-Label Drug Uses: What Role for Wide Acceptance, General Recognition and Research Incentives?

Published online by Cambridge University Press:  06 January 2021

Margaret Gilhooley
Margaret Gilhooley*
Affiliation:
Seton Hall Law School
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Abstract

This article provides an overview of how the constitutional protections for commercial speech affect the Food and Drug Administration's (FDA) regulation of drugs, and the emerging issues about the scope of these protections. A federal district court has already found that commercial speech allows manufacturers to distribute reprints of medical articles about a new off-label use of a drug as long as it contains disclosures to prevent deception and to inform readers about the lack of FDA review. This paper summarizes the current agency guidance that accepts the manufacturer's distribution of reprints with disclosures.

Allergan, the maker of Botox, recently maintained in a lawsuit that the First Amendment permits drug companies to provide “truthful information” to doctors about “widely accepted” off-label uses of a drug. While the case was settled as part of a fraud and abuse case on other grounds, extending constitutional protections generally to “widely accepted” uses is not warranted, especially if it covers the use of a drug for a new purpose that needs more proof of efficacy, and that can involve substantial risks.

A health law academic pointed out in an article examining a fraud and abuse case that off-label use of drugs is common, and that practitioners may lack adequate dosage information about the off-label uses. Drug companies may obtain approval of a drug for a narrow use, such as for a specific type of pain, but practitioners use the drug for similar uses based on their experience. The writer maintained that a controlled study may not be necessary to establish efficacy for an expanded use of a drug for pain. Even if this is the case, as discussed below in this paper, added safety risks may exist if the expansion covers a longer period of time and use by a wider number of patients. The protections for commercial speech should not be extended to allow manufacturers to distribute information about practitioner use with a disclosure about the lack of FDA approval. Distributions of information about unapproved uses should not be acceptable unless experts consider the expanded use to be generally recognized as safe and effective based on adequate studies.

The last part of this paper considers the need to develop better research incentives to encourage more testing and post-market risk surveillance by drug makers on off-label uses of their drugs. Violations of the Federal Food Drug and Cosmetic Act (FFDCA) can be considered violations of the False Claims Act, which opens the way to fraud and abuse suits. The scale of penalties involved in these suits may lead to more examination of the scope of FDA regulation and commercial speech protections. Thus this symposium's consideration of these issues is timely and important.

Type
Article
Information
American Journal of Law & Medicine , Volume 37 , Issue 2-3 , June 2011 , pp. 258 - 277
Copyright
Copyright © American Society of Law, Medicine and Ethics and Boston University 2011

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References

1 Food, Drug, and Cosmetic Act, 21 U.S.C. §§ 355(a)-(e) (2006).

2 Thompson v. W. States Med. Ctr., 535 U.S. 357, 376-77 (2002).

3 Wash. Legal Found. v. Friedman, 13 F. Supp. 2d 51, 74 (D.D.C. 1998), amended by sub nom. Wash. Legal Found. v. Henney, 56 F. Supp. 2d 81, 87 (D.D.C. 1999), vacated in part and remanded in part and appeal dismissed, Wash. Legal Found. v. Henney, 202 F.3d 331 (D.D.C. 2000). For the history, see Gilhooley, Margaret, Constitutionalizing Food and Drug Law, 74 Tul. L. Rev. 815, 826-43 (2000).Google Scholar

4 See Legal Status of Approved Labeling for Prescription Drugs; Prescribing for Uses Unapproved by the Food and Drug Administration, 37 Fed. Reg. 16,503, 16,503 (proposed Aug. 15, 1972) (to be codified at 21 C.F.R. pt. 130) (explaining that “the bill did not purport to regulate the practice of medicine as between the physician and the patient”); Peter B. Hutt et al., Food and Drug Law 815-22 (3d ed. 2007).

5 Complaint at 28-33, Allergan v. Food & Drug Admin., No. 1:09-cv-01879-JDB (D.D.C. Jan. 11, 2010) [hereinafter Allergan Complaint].

6 See Natasha Singer, Maker of Botox Settles Inquiry on Off-Label Use, N.Y. Times, Sept. 2, 2010, at A1 (explaining that the reported settlement was $600 million).

7 Food, Drug, and Cosmetic Act §§ 321(p), 355. See infra Part IV.C.

8 Johnson, Sandra H., Polluting Medical Judgment? False Assumptions in the Pursuit of False Claims Regarding Off-Label Prescribing, 9 Minn. J. of L. Sci. & Tech. 61, 66, 73-74 (2008).Google Scholar

9 Id. at 65. See infra Part V.E.

10 Id. at 70. The FFDCA analysis focuses on the indication(s) “intended” by the manufacturer of the drug. Food, Drug, and Cosmetic Act § 321(p)(1).

11 Johnson, supra note 8 at 75-76, n.39.

12 Id. at 114-15; see infra Part III. In 2004, Parke-Davis, the maker of the drug, settled the case for $455 million, which at the time was the largest settlement ever. Id.

13 Id. at 115-21 (stating that it seems “entirely reasonable” for doctors to believe that the drug may be effective for wider neuropathic pain use).

14 Id. at 116.

15 Id. at 114-16.

16 Id. at 65.

17 In 2007, Congress authorized post-approval safety surveillance for newly approved drugs in response to the risks found with Vioxx after it was on the market. Food, Drug, and Cosmetic Act §§ 355(k)(3)-(4). The FDA also received authority to require warnings or additional tests to address post-approval risks. Id. §§ 355(o)(3)(B)-(F); 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, 350-58 (2008)Google Scholar; Gilhooley, Margaret, Vioxx’s History and the Need for Better Procedures and Better Testing, 37 Seton Hall L. Rev. 941 (2007).Google ScholarPubMed

18 Pearson v. Shalala, 164 F.3d 650, 659-60 (D.C. Cir. 1999).

19 For a summary of the strengthened means provided in the healthcare legislation to fight fraud, see Iglehart, John K., The Supercharged Federal Effort to Crack Down on Fraud and Abuse, 29 Health Aff. 1093, 1093-94 (2010)Google ScholarPubMed (steps taken include increasing federal spending to $1.7 billion to combat healthcare fraud, waste, and abuse; “extending the reach of federal laws” against fraud, waste, and abuse; and “tighten[ing] the enrollment process” for Medicare).

20 The high stakes are also dramatically illustrated by the FDA’s prosecution of a company attorney for knowing that a speaker paid by the company presented misleading information in slides to medical practitioners about an off-label use of the drug. See Duff Wilson, Former Glaxo Lawyer Indicted, N.Y. Times Prescriptions Blog (Nov. 9, 2010, 2:25 PM), http://prescriptions.blogs.nytimes.com/2010/11/09/former-glaxo-lawyer-indicted. Her defense is that what she did was “consistent” with “the advice provided her by a nationally prominent law firm.” Id.

21 Osborn, John E., Can I Tell You the Truth? A Comparative Perspective on Regulating Off-Label Scientific and Medical Information?, 10 Yale J. Health Pol’y L. & Ethics 299, 301 (2010).Google ScholarPubMed

22 Id. at 301-03.

23 Id. at 301 n.2 (citing remarks of U.S. Attorney General Eric Holder at the National Health Care Fraud Summit).

24 Id. at 316-25, 353.

25 Id. at 310.

26 Id. at 327-29 (citing effect of the position of the Office of Inspector General of the Department of Health and Human Services); see Johnson, supra note 8, at 114.

27 Va. State Bd. of Pharmacy v. Va. Citizens Consumer Council, 425 U.S. 748, 761-62 (1976).

28 Id. at 770 (Rehnquist, J., dissenting).

29 Thompson v. W. States Med. Ctr., 535 U.S. 357, 370 (2002).

30 See Gilhooley, Margaret, Drug Regulation and the Constitution, 37 U. Rich. L. Rev. 901, 921-23 (2003)Google Scholar (noting that one issue raised by the Supreme Court’s decision in Western States is whether pharmaceutical companies could engage in off-label advertising if the advertising disclaimed FDA approval).

31 Western States, 535 U.S. at 360-61. The general tests were recognized by the Court in Central Hudson Gas & Electric Corp. v. Public Service Commission of New York, 447 U.S. 557 (1980), a case that involved advertising restrictions to discourage expanded use of natural gas when supplies were limited.

32 Food, Drug, and Cosmetic Act § 353a(b)(1)(D).

33 Western States, 535 U.S. at 367.

34 Id. at 371.

35 Id. at 387 (Breyer, J., dissenting).

36 Id. at 371.

37 Id. at 372.

38 Id. at 380 (Breyer, J., dissenting).

39 Id. at 372.

40 Id. at 389 (Breyer, J., dissenting).

41 Id.

42 Virginia Pharmacy, 425 U.S. at 787 (Rehnquist, J., dissenting).

43 Id.

44 Gilhooley, Margaret, Drug Safety and Commercial Speech: Television Advertisements and Reprints on Off-Label Uses, 47 San Diego L. Rev. 845, 866-77 (2010).Google Scholar

45 153 Cong. Rec. S5764 (daily ed. May 9, 2007) (Statement of Sen. Kennedy).

46 See Symposium, Thoughts on Commercial Speech: A Roundtable Discussion, 41 Loy. L.A. L. Rev. 333, 347-48 (2007)Google Scholar; Gilhooley, supra note 44, at 872.

47 Gilhooley, supra note 44, at 894-97.

48 For history, see Gilhooley, supra note 44, at 878-80.

49 Wash. Legal Found. v. Friedman, 13 F. Supp. 2d 51 (D.D.C. 1998), amended by sub nom. Wash. Legal Found. v. Henney, 56 F. Supp. 2d 81, 87 (D.D.C. 1999), vacated in part and appeal dismissed, Wash. Legal Found. v. Henney, 202 F.3d 331 (D.C. Cir. 2000).

50 See Wash. Legal Found., 202 F.3d at 336-37.

51 See Mello, Michelle M. et al., Shifting Terrain in the Regulation of Off-Label Promotion of Pharmaceuticals, 360 New Eng. J. Med. 1557, 1559 (2009).CrossRefGoogle Scholar

52 U.S. Dep’t Health & Human Servs., Food & Drug Admin., 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 (2009), available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm125126.htm [hereinafter Reprint Guidance].

53 Id. at 5.

54 Id. at 3-5.

55 Id. at 4.

56 Allergan Complaint, supra note 5, at 38-40. For a positive view of the Allergan suit and criticism of the Agency’s “near total ban on off-label promotion” as “overly-broad,” see Gregory Conko, Truth or Consequences: The Perils and Protection of Off-Label Drug and Medical Device Promotion, 21 Health Matrix (forthcoming 2011) (manuscript at 36).

57 See Allergan Memorandum of Law in Support of Preliminary Injunction at 7, Allergan Inc. v. U.S. (No. 1:09-cv-01879) (D.D.C. Oct. 1, 2009), available at westlaw.com/result/documenttext.aspx?rs=WLW10.10&ss=CNT&cnt+DOC (citing 42 U.S.C. §§ 1396b(i)(10), 1396r-8(k)(2), 1396(k)(6)) [hereinafter Allergan Memorandum].

58 21 C.F.R. § 314.70(c)(6)(iii) (2010).

59 See Defendant’s Memorandum of Points and Authorities in Support of Motion to Dismiss or for Summary Judgment at 18, Allergan Inc. v. U.S. (No. 1:09-cv-01879) (D.D.C. Mar. 29, 2010).

60 Allergan Memorandum, supra note 57, at 12.

61 Id. at 43.

62 Id. at 4.

63 Id. at 8. The tax alternative would seem to pose considerable practical difficulties.

64 Singer, supra note 6, at A1.

65 Id.

66 Id.

67 Defendant’s Memorandum, supra note 59, at 11.

68 Allergan Memorandum, supra note 57, at 43-44.

69 Weinberger v. Hynson, Westcott & Dunning, Inc., 412 U.S. 609, 632 (1973).

70 Weinberger v. Bentex Pharm. Inc., 412 U.S. 645, 652 (1973).

71 See Professional Labeling of Aspirin, 63 Fed. Reg. 56,802 (Food & Drug Admin Oct. 23, 1998) (issuing a ruling on the appropriate labeling of aspirin). See also Gilhooley, supra note 44, at 886 (discussing what may be viewed as general recognition by experts).

72 Western States, 535 U.S. at 373-76.

73 Gilhooley, Vioxx’s History, supra note 17, at 950.

74 Id. at 953.

75 See Gilhooley, Addressing Potential Drug Risks, supra note 17, at 363-66 (discussing congressional response to FDA interactions with Vioxx).

76 See Food, Drug, and Cosmetic Act § 355(k)(3)(C); Gilhooley, Addressing Potential Drug Risks, supra note 17, at 363 (providing brief summary of surveillance system).

77 Food, Drug, and Cosmetic Act §§ 379h(a)(1)(A)(ii), 379g(6). The user fees support the surveillance system set out in Food & Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, § 905(d), 121 Stat. 823, 949. Companies can be required to take measures to restrict the distribution of a drug or take other steps to reduce harm from use despite warnings on the label. Food, Drug, and Cosmetic Act § 355(o)(4). The amendments also created a Risk Evaluation and Management System to assess the risks. Food, Drug, and Cosmetic Act §§ 355(o)-(p). See Gilhooley, Addressing Potential Drug Risks, supra note 17, at 363-64.

78 Food, Drug, and Cosmetic Act § 355(o)(4).

79 Id. §§ 355(o)-(p).

80 See U.S. Dep’t Health & Human Servs., Food & Drug Admin., Post-Marketing Surveillance Programs, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm090385.htm (last updated Aug. 19, 2009) (noting that post-market surveillance programs are designed to detect adverse events, not adverse events arising from off-label use in particular).

81 Id.

82 Pearson v. Shalala, 164 F.3d 650, 658-60 (D.C. Cir. 1999). See Gilhooley, Drug Safety, supra note 44, at 884-89 (listing factors that can effect the need for disclosures).

83 Although many of the uses were for pain, the fraud and abuse charges involved some uses for very different purposes, such as bipolar and attention deficit disorder. See Johnson supra note 8, at 114-15. Charges also involved improper monetary incentives. Id.

84 Food, Drug, and Cosmetic Act § 321(p)(1) (defining a “new drug” as any drug “not generally recognized . . . as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof”). See Institute of Med., Committee on the Assessment of the U.S. Drug Safety System, Promoting and Protecting the Health of the Public 35 (Alina Baciu et al. eds., 2006), available at http://www.nap.edu/catalog.php?record_id=11750#toc [hereinafter IOM Report].

85 IOM Report, at 33-35 (reporting that the expectation is that the majority of severe toxicities will be detected by high dosage animal studies and the current clinical trials). See U.S. Dep’t of Health & Human Servs., Food & Drug Admin., Managing the Risk from Medical Products Use: Creating a Risk Management Framework 43-46 (1999), available at http://www.fda.gov/downloads/Safety/SafetyofSpecificProducts/UCM180520.pdf; Gilhooley, Vioxx’s History, supra note 17, at 73.

86 See Legal Status of Approved Labeling, supra note 4 (stating that physicians can “vary the conditions of use” of a drug from the use previously approved by the FDA).

87 Johnson, supra note 8, at 71, 81-82.

88 Id. at 69-70.

89 Id. at 99.

90 Id. at 114-15.

91 Id. at 115-16.

92 Radley, David et al., Off-Label Prescribing Among Office-Based Physicians, 166 Archives of Internal Med. 1021, 1025 (2006).CrossRefGoogle ScholarPubMed

93 See Kesselheim, Aaron & Avorn, Jerry, Pharmaceutical Promotion to Physicians and First Amendment Rights, 358 New Eng. J. Med. 1727, 1727 (2008)CrossRefGoogle ScholarPubMed (noting fraud and abuse issues based on off-label uses made for Neurontin for treatment of migraine pain based on medical articles).

94 See infra Part IV.E for a discussion on the need for post-market surveillance.

95 See Johnson, supra note 8, at 64, 69, 73-74.

96 Food, Drug, and Cosmetic Act § 355(j)(5)(F)(iv).

97 See William B. Schultz & Margaret M. Dotzel, Generic Drugs, ANDAs, Section 505(b)(2) NDAs, Patents and Exclusivities, in Food and Drug Law and Regulation 353, 364 (David G. Adams et al. eds., 2008) (“[I]f the exclusivity is for a new use, the generic can market without the new use on its label.”).

98 Bristol-Myers Squibb Co. v. Shalala, 91 F.3d 1493, 1496 (D.C. Cir. 1996). See Lars Noah, Law, Medicine, and Medical Technology: Cases and Materials 869 (2d ed. 2006).

99 Bristol-Myers Squibb Co., 91 F.3d at 1500 (noting that the “Secretary’s interpretation finds unusually strong support in the legislative history”).

100 21 U.S.C. § 355A(b) (2006).

101 Rachel Zimmerman, Child Play: Pharmaceutical Firms Win Big on Plan to Test Adult Drugs on Kids, Wall St. J., Feb. 5, 2001, at A1.

102 See supra Part IV.E.1 and accompanying notes (describing the user-funded surveillance system).

103 See generally Gilhooley, Vioxx’s History, supra note 17.

104 For a more in-depth discussion of this particular solution, see Gilhooley, supra note 44, at 891-94.

105 Research incentives are linked to clinical research. See Schultz & Dotzel, supra note 97, at 364.

106 See Gilhooley, Margaret, Heal the Damage: Prescription Drug Consumer Advertisements and Relative Choices, 38 J. Health L. 1, 24, 26-27 (2005)Google ScholarPubMed (describing one scientist’s opinion that Nexium was “identical” to its predecessor Prilosec).

107 Western States, 535 U.S. at 389.

108 See generally Johnson, supra note 8; infra Part V.