Off-label prescription advertising, the FDA and the first amendment: A study in the values of commercial speech protection

American Journal of Law and Medicine

Volumn 37, Issue 2-3, 2011, Pages 315-357

  Klasmeier, Coleen ^a   Redish, Martin H ^a,b  

^a SIDLEY AUSTIN LLP   (United States)

^b NORTHWESTERN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADVERTIZING; ARTICLE; DRUG INDUSTRY; FOOD AND DRUG ADMINISTRATION; HUMAN; JURISPRUDENCE; LEGAL ASPECT; OFF LABEL DRUG USE; UNITED STATES;

ADVERTISING AS TOPIC; DRUG INDUSTRY; HUMANS; OFF-LABEL USE; SUPREME COURT DECISIONS; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION;

EID: 80051854118     PISSN: 00988588     EISSN: None     Source Type: Journal    
DOI: 10.1177/009885881103700206     Document Type: Article

References (181)

1. Federal Food, Drug, and Cosmetic Act, 21 U.S.C. §§ 335(a), 360(k), 360(e) (2006).
2. See John E. Osborn, 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, 304 (2010) ("[I]n some therapeutic areas off-label uses are the customary, preferred treatments and are publicly declared to be such on patient advocacy group websites and elsewhere").
3. see also Part II.A, infra.
4. The situation is rendered even more bizarre by current FDA practices towards wholly unapproved drugs. See infra text accompanying notes 153-54.
5. See infra Part III.B.
6. See infra Part IV.B.
7. See infra Part III.
8. "Once a drug product has been approved for marketing, a physician may, in treating patients, prescribe the drug for uses not included in the drug's approved labeling." Proposed New Drug, Antibiotic, and Biologic Drug Regulations, 48 Fed. Reg. 26, 733 (proposed June 9, 1983).
9. See also 21 C.F.R. § 312.3(d) (2010) (exemption from FDA regulations for "the use in the practice of medicine for an unlabeled indication of a new drug product approved" by the Agency).
10. The same is true for medical devices. 21 U.S.C. § 396 (2006).
11. According to one authority, off-label uses are "common, can be a source of innovation, and in some settings may represent the standard of care." Donna T. Chen et al., U.S. Physician Knowledge of the FDA-Approved Indications and Evidence Base for Commonly Prescribed Drugs: Results of a National Survey, 18 Pharmacoepidemiology & Drug Safety 1094, 1094 (2009) (footnotes omitted).
12. see also Harold J. DeMonaco et al., The Major Role of Clinicians in the Discovery of Off-Label Drug Therapies, 26(3) Pharmacotherapy 323, 323 (2006) ("[F]or some diseases, such as non-small cell lung cancer and cystic fibrosis, off-label uses are either the only therapies available, or are the therapies of choice.").
13. For example, as far back as 1992 the FDA's Deputy Commissioner for External Affairs conceded that "off-label drug use is often essential to good medical practice, and in some areas-oncology and pediatrics in particular-off-label uses are often considered necessary. In fact, it is on this edge that science and medicine move forward to benefit patients with intractable illness." Brief of the National Spasmodic Torticollis Association, Allergan, Inc. v. United States, Attachment No. 2, CV No. 1:09-01879 (filed Dec. 23, 2009).
14. Carol Scheman, Food & Drug Admin. Comm'r for External Affairs, Prescription Drug Marketing and Promotion-An FDA Perspective, Address before the PMA Public Affairs Section, Mid-Year Meeting, April 15, 1992.
15. Food & Drug Admin., "Off-Label" and Investigational Use of Marketed Drugs, Biologies, and Medical Devices-Information Sheet, FDA.gov, http://www.fda.gov/RegulatoryInformation/default.htm(last visited Apr. 9, 2011).
16. "Buckman Co. v. Plaintiffs' Legal Comm., 531 U.S. 341, 349-51 & n.5 (2001).
17. see also Fran Kritz, FDA Seeks to Add Drugs'New Uses to Labels, Wash. Post, Mar. 29, 1994, at Zll ("In some cases, if you didn't use the drug in the off-label way you'd be guilty of malpractice.").
18. See Paul E. Kalb & Paul E. Greenberg, Legal and Economic Perspectives Concerning U.S. Government Investigations of Alleged Off-Label Promotion by Drug Manufacturers, 27 Pharmacoeconomics 623, 623 (2009) ("Physicians' decisions to prescribe off label are informed by the available scientific literature, and it stands to reason that the more truthful, non-misleading data available, the more informed their decisions will be.").
19. 59 Fed. Reg. 59, 823 (Nov. 18, 1994).
20. United States v. Caputo, 517 F.3d 935, 939 (7th Cir. 2008).
21. See Wash. Legal Found, v. Friedman, 13 F. Supp. 2d. 51 (D.D.C. 1998), .
22. appeal dismissed sub nom. Wash. Legal Found, v. Henney, 202 F.3d 331 (D.C. Cir. 2000).
23. One district court decision, on the basis of questionable reasoning (see discussion infra text accompanying notes 156-57), upheld the ban. Caronia, 576 F. Supp. 2d at 385. In a separate decision, the United States Court of Appeals for the Seventh Circuit ultimately avoided the constitutional issue, but nevertheless raised serious doubts about the ban's constitutionality.
24. United States v. Caputo, 517 F.3d 535 (7th Cir. 2008). On the basis of this scant data, it is reasonable to conclude that as a narrow doctrinal matter, at least, the issue remains an open one.
25. Section 502(a) of the FDCA provides that "A drug . . . shall be deemed to be misbranded-. . . If its labeling is false or misleading in any particular." 21 U.S.C. § 352(a) (2006). Section 502(a) has been invoked with respect to drugs bearing literally false statements as well as drugs marketed with unsubstantiated therapeutic claims. See, e.g., United States v. 4 Cases Slim-Mint Chewing Gum, 300 F.2d 144 (7th Cir. 1962).
26. (affirming trial court denial of new trial in section 502(a) case in which jury found no false or misleading statements in labeling of diet gum); United States v. Articles of Drug, 442 F. Supp. 1236, 1241 (S.D.N.Y. 1978).
27. (drugs violate section 502(a) when they are labeled "100 capsules" but contain only six capsules in each packet). For this provision to apply, a false or misleading statement must appear in a communication that qualifies as "labeling, " which is defined by statute to mean "all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article." 21 U.S.C. § 32l(m) (2006). Under Kordel v. United States, 335 U.S. 345 (1948).
28. to "accompany" an article, matter must supplement or explain the product in connection with its distribution and sale. But "labeling does not include every writing which bears some relation to the product." United States v. 24 Bottles "Sterling Vinegar & Honey Aged in Wood Cider Blended With Finest Honey Contents 1 Pint Prod. Of Sterling Cider Co., Inc., Sterling, Mass, " 338 F.2d 157, 158-59 (2d Cir. 1964).
29. 21 U.S.C. § 355(a) (2006). According to the FDA, "an approved new drug that is marketed for a 'new use' becomes an unapproved new drug with respect to that use." 65 Fed. Reg. 14, 286 (2000). As with section 502(a), this theory would apply only where the off-label statement occurs in a communication that qualifies as "labeling" under the FDCA.
30. 21 U.S.C. § 352(f)(1) (2006). In FDA's view, virtually the only way to avoid violating this provision is to submit a use for FDA review. See 21 C.F.R. § 201.100(c)(2) (2010).
31. See e.g., 59 Fed. Reg. 59, 820 (Nov. 18, 1994) ("Information disseminated by companies in contexts such as scientific and educational meetings, symposia, books, and articles may provide evidence of a regulated product's intended use").
32. 65 Fed. Reg. 14, 286 (2000) ("an approved new drug that is marketed for a 'new use' becomes an unapproved new drug with respect to that use.").
33. Manufacturers did raise First Amendment arguments in enforcement actions during this period, to no effect. During the period in which much of modern food and drug law developed, commercial speech was thought to be without any constitutional protection at all. In the few cases arising under the FDCA in which First Amendment arguments were made, they were summarily rejected.
34. See, e.g., United States v. Articles of Drug, 32 F.R.D. 32 (S.D. 111. 1963).
35. United States v. 8 Cartons, Containing "Plantation 'The Original' etc., Molasses, " 103 F. Supp. 626 (W.D.N.Y. 1951).
36. And legal practitioners did not seriously contend that FDA regulation of labeling and advertising might run afoul of the Free Speech Clause. The first serious examination of the issue in the principal food and drug law review did not appear until 1975, and it concluded, "Government regulation of misbranding and false advertising is clearly constitutional." Thomas H. Christopher, Free Speech and the Regulation of Labeling and Advertising, 30 Food Drug Cosm. L.J. 512, 525 (1975). The author did not even consider the scope of FDA authority to regulate the content of truthful and non-misleading commercial speech.
37. Herbert Ley, FDA Papers, 8 Clinical Pharm. & Therapeutics 749, 749-51 (1967).
38. New Drugs Used For Nonapproved Purposes (Methotrexate for Psoriasis): Hearings Before the Subcomm. of the H. Comm. on Gov't Operations, 92nd Cong. 5 (1971).
39. 37 Fed. Reg. 16, 503 (Aug. 15, 1972).
40. According to David Kessler, FDA "was concerned" about "improper prescribing, " but "was under great pressure from the American Medical Association not to tell the doctor what he or she could prescribe." David A. Kessler, Regulating the Prescribing of Human Drugs for Nonapproved Uses Under the Food, Drug, and Cosmetic Act, 15 Harv. J. on Legis. 693, 698 n.13 (1977). Kessler indicated that FDA "chose to deal with the problem [of off-label prescribing] as an educational matter."
41. FDA's Growing Influence on Your Practice, Med. World News, Mar. 1, 1974, at 46.
42. Gregory J. Bierne, Eternal Vigilance-The Price of Liberty, 222 JAMA 1553, 1553-55 (1972).
43. Sidney A. Shapiro, Limiting Physician Freedom to Prescribe a Drug for Any Purpose: The Need for FDA Regulation, 73 Nw. U. L. Rev. 801, 846 (1979).
44. In 1991, FDA considered and rejected withdrawing the 1972 proposed rule. See 56 Fed. Reg. 42, 668, 42, 669 (Aug. 28, 1991).
45. A 1982 "drug bulletin" issued by FDA emphasized that the Agency regarded off-label use as "accepted medical practice." Food & Drug Admin., Dep't of Health and Human Servs., 12 Food & Drug Admin. Drug Bull. 4, 5 (Apr. 1982).
46. This provision remains in effect, and is currently codified at 21 C.F.R. § 312.2(d) (2010).
47. DDAL, Position on the Concept of Solicited and Unsolicited Requests, Apr. 22, 1982.
48. Investigational New Drug, Antibiotic, and Biological Drug Product Regulations; Treatment Use and Sale, 52 Fed. Reg. 19, 466 (May 22, 1987).
49. 52 Fed. Reg. 8, 798, 8, 833 (Mar. 19, 1987) (to be codified at 21 C.F.R. pt. 312).
50. Div. of Drug Mktg., Adver. & Commc'ns, Ctr. for Drug Evaluations & Research, U.S. Food & Drug Admin., "Drug Company Supported Activities in Scientific or Educational Contexts" (Oct. 26, 1991).
51. See Amended Complaint at 11-15 Wash. Legal Found, v. Kessler (D.D.C. 1995) (Civ. No. 94-1306) (listing examples of FDA refusal to allow distribution of major oncology texts).
52. The Pink Sheet, Prescription Pharm. and Biotechnology, July 13, 1992, at T&G-14.
53. FDA to Target Scientific and Consumer Materials, FDA Advertising and Promotion Manual, Feb. 1993, at 1.
54. See The Pink Sheet, Prescription Pharm. and Biotechnology, Sept. 1994, at T&G-9.
55. Citizen Petition Regarding the Food & Drug Admin.'s Policy on Promotion of Unapproved Uses of Approved Drugs and Devices, 59 Fed. Reg. 59, 820, 59, 823 (Nov. 18, [hereinafter Citizen Petition].
56. Advertising and Promotion, Draft Guidances, 60 Fed. Reg. 62, 471 (Dec. 6, 1995).
57. Advertising and Promotion, Draft Guidance, Republication, 60 Fed. Reg. 63, 384 (Dec. 8, (republication with omitted text).
58. See Advertising and Promotion, Guidances, 61 Fed. Reg. 52, 800 (Oct. 8, 1996).
59. Final Guidance on Industry-Supported Scientific and Educational Activities, 62 Fed. Reg. 64, 074 (Dec. 3, 1997).
60. See, e.g., United States ex rel. Franklin v. Parke-Davis, 147 F. Supp. 2d 39 (D. Mass. 2001).
61. See The Pink Sheet, Prescription Pharm. & Biotechnology, Nov. 27, 1995, at 3.
62. Nancy Benac, FDA Getting Tough On Disguised Drug Promotions, Associated Press, May 30, 1991, available at LexisNexis.
63. C. Adams et al., Risky RX: A Knight-Ridder Investigation, Newspaper article series, Nov. 2-4, 2003.
64. Study Shows Danger to Skin and Gives Hope of a Savior, N.Y. Times, Jan. 25, 1996.
65. See, e.g., Orthopedic Devices: Classification and Reclassification of Pedicle Screw and Spinal Systems, 63 Fed. Reg. 40, 025, 40, 038 (proposed July 27, 1998) (to be codified at 21 C.F.R. pt. 888) ("Because the regulation of [medical] devices is an area of extensive Federal regulation, the agency may regulate the communications at industry-supported scientific and educational activities without violating the First Amendment").
66. Final Guidance on Industry- Supported Scientific and Educational Activities, 62 Fed. Reg. 64, 074, 64, 077 (Dec. 3, 1997) ("As with securities regulation, the Federal Government exerts extensive authority over the sale and promotion of drugs and devices").
67. Food Labeling: General Requirements for Health Claims for Food, 58 Fed. Reg. 2, 478, 2, 525 (proposed Jan. 6, 1993) (to be codified at 21 C.F.R. pts. 20 & 101) ("As with securities, labor, and antitrust regulation, the Government exerts extensive regulatory authority over the economic activity surrounding food and its labeling.").
68. See, e.g., Request for Comment on First Amendment Issues, 67 Fed. Reg. 34, 942, 34, 944 (May 16, 2002) (requesting public comment on "the extent of FDA's ability to regulate speech concerning off-label uses").
69. Decision in Wash. Legal Found, v. Henney, 65 Fed. Reg. 14, 286, 14, 287 (Mar. 16, 2000) ("The D.C. Circuit's decision was based on its conclusion that there is no case or controversy to provide a basis for WLF's facial First Amendment challenge").
70. Letter from Margaret M. Dotzel, Assoc. Comm'r for Policy of Food & Drug Admin., to Daniel J. Popeo & Richard A. Samp, Wash. Legal Found. 1 (Jan. 28, 2002), available at http://www.fda.gov/ohrms/dockets/dailys/02/Jan02/ 013002/01p-0250-pdn0001-01-vol2.pdf.
71. Decision in Wash. Legal Found, v. Henney, 65 Fed. Reg. 14, 286, 14, 287 (Mar. 16, 2000) ("The D.C. Circuit's decision was based on its conclusion that there is no case or controversy to provide a basis for WLF's facial First Amendment challenge").
72. See More Information for Better Patient Care: Hearing of the Comm. on Labor and Human Resources on S. 1477 Before the S. Comm. on Labor and Human Resources, 105th Cong. 64-73 (Feb. 22, 1996) (statement of William B. Schultz, Deputy Comm'r for Policy, Food & Drug Admin.).
73. Margaret A. Hamburg, Comm'r of Food & Drugs, Food & Drug Admin., Remarks at the Massachusetts Medical Society's 2010 Shattuck Lecture: Innovation and the FDA: Past, Present, and Future (May 15, 2010).
74. Linda A. Suydam, Senior Assoc. Comm'r, Food & Drug Admin., Keynote Address at the FDLI Conference on Advertising and Promotion in the New Millennium (Sept. 13, 1999).
75. More Important for Better Patient Care: Hearing of the Comm. on Labor and Human Resources on S. 1477 Before the S. Comm. on Labor and Human Resources, 105th Cong. 64-73 (Feb. 22, 1996) (statement of William B. Schultz, Deputy Comm'r for Policy, Food & Drug Admin.).
76. It is not clear from the Agency's description whether physicians prescribed calcium channel blockers to post-myocardial infarction patients before or after the results of the studies showing lack of benefit had been released.
77. See Donald C. Harrison, Arrhythmia Prophylaxis After Acute Myocardial Infarction: A Decade of Controversy, 2 Cardiovascular Drugs & Therapy 783, 783 (1989).
78. See Gerald v. Naccarelli et al., A Critical Appraisal of the Cardiac Arrhythmia Suppression Trial (CAST), 4 Applied Cardiopulmonary Pathophysiology 9 (1991).
79. See, e.g., Peter H. Held & S. Yusuf, Calcium Antagonists in the Treatment of Ischemic Heart Disease: Myocardial Infarction, 5 Coronary Artery Disease 21 (1994) (reviewing studies of six calcium-channel blockers and finding little benefit in their use post-myocardial infarction).
80. Chris L. Pashos, P.H. Held & S. Yusuf, Effects of β-Blockers and Calcium Channel Blockers in Acute Myocardial Infarction, 14 Eur. Heart J. (SUPP. F) 18, 22 (1993) ("Subgroup analysis revealed that agents which decreased heart rate (verapamil and diltiazem) differed from agents that increased heart rate, which were associated with an excess of deaths and reinfarctions. Subgroup findings like these have to be very carefully interpreted, but subsequent data... appear to reinforce this observation").
81. Merete Vaage-Nilsen et al., Effect of Verapamil on Arrhythmias and Heart Rate During 16 Months Following an Acute Myocardial Infarction, 8 Cardiovascular Drugs & Therapy 147 (1994) ("Verapamil significantly lowered heart rate, prevented supraventricular tachycardia, and reduced VPC [ventricular premature complexes] early after an AMI [acute myocardial infarction].").
82. Food & Drug Admin., U.S. Dep't of Health & Human Servs., Guidance for Industry & FDA Staff: Saline, Silicone Gel, and Alternative Breast Implants 28 (Nov. 2006) ("FDA recommends magnetic resonance imaging (MRI) as the current method of choice for detecting silent rupture of silicone gel-filled breast implants. . . . MRI of the breast should be performed with a dedicated breast coil, with a magnet of at least 1.5 Tesla, and preferably in centers experienced in performing and interpreting this type of examination").
83. see also Anabel Medeiros Scaranelo et al., Evaluation of the Rupture of Silicone Breast Implants by Mammography, Ultrasonography and Magnetic Resonance Imaging in Asymptomatic Patients: Correlation with Surgical Findings, 122 Sao Paulo Med. J. 41, 46 (2004) ("[I]t can be concluded that magnetic resonance imaging with a dedicated breast coil had the highest sensitivity, while the specificity was similar to other methods.").
84. See Debra L. Monticciolo et al., MR Detection of Leakage from Silicone Breast Implants: Value of a Silicone-Selective Pulse Sequence, 163 Am. J. Roentgenology 51, 52 (July 1994) ("A standard circular surface coil with a diameter of 24 cm was placed around each breast imaged").
85. see also Christina Y. Ahn, Residual Silicone Detection Using MRI Following Previous Breast Implant Removal: Case Reports, 19 Aesthetic Plastic Surg. 361, 366 (1995) ("At the present time, the surface coil allows higher resolution and an increased signal to noise. Therefore, if a breast prosthesis rupture or leak is suspected in only one breast, a surface coil would be the coil of choice. Dedicated breast coils are being developed that will allow imaging of both breasts simultaneously as well as of specific areas of the breast for silicone.").
86. See Food & Drug Admin., Dep't of Health & Human Servs., BLA 103000/5000, Approval Letter for BOTOX® Cosmetic 1 (Apr. 14, 2002).
87. 59 Fed. Reg. 59, 825, 59, 825 (Nov. 18, 1994).
88. See 53 Fed. Reg. 41, 516 (Oct. 21, 1988).
89. Federal Food, Drug, and Cosmetic Act § 506, 21 U.S.C. § 356 (2006).
90. 21 U.S.C. § 356(b)(1).
91. See 21 C.F.R. §§ 314.510, 601.21 (2010).
92. See 67 Fed. Reg. 37, 988 (May 31, 2002).
93. Also worth mentioning is the FDA's approach to drug shortages. Although not formalized in a policy as such, the FDA's general practice is to facilitate the importation of unapproved drugs when an approved counterpart has become unavailable, provided the Agency has determined-outside the formal new drug approval process and on an expedited basis-that the substitute product is "safe and effective" and the active ingredient of the substitute is covered by an approved new drug application. See Valerie Jensen et al., FDA's Role in Responding to Drug Shortages, Am. J. Health Sys. Pharmacy 1423, 1423-25 (2002), Questions and Answers on the Propofol Shortage, FDA.gov, http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm209227.htm (last updated Mar. 30, 2011).
94. See Am. Pub. Health Assoc. v. Veneman, 349 F. Supp. 1311, 1315 (D.D.C. 1972) ("[I]t could not be clearer that the Secretary must begin the procedures to withdraw a drug when he concludes that there is no substantial evidence of efficacy.").
95. See Hoffman-LaRoche, Inc. v. Weinberger, 425 F. Supp. 890 (D.D.C. 1975).
96. See Ctr. for Drug Evaluation & Research, Food & Drug Admin., Guidance for FDA Staff and Industry: Marketed Unapproved Drugs-Compliance Policy Guide § 440.100 (2006), available at http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm070290.pdf.
97. See FDA, Information for Healthcare Professionals: New Safety Information for Colchicine (marketed as COLCRYS) (last updated June 4, 2010), www.fda.gov.
98. Open Letter from Janet Woodcock, Dir., Ctr. for Drug Evaluation & Research, Food & Drug Admin. (Mar. 3, 2010), available at http://www.urlpharma.com/files/woodcockletter.pdf.
99. Janet Woodcock & Sarah Okada, Letter to the Editor, Incentives for Drug Development-the Curious Case of Colchicine, 363 N. Eng. J. Med. 1484 (2010).
100. Brief for United States as Amicus Curiae, United States v. Caronia, No. 09-5006, 2010 WL 6351497 (C.A.2).
101. See 36 Fed. Reg. 11, 022 (June 8, 1971).
102. 21 C.F.R. § 201.200(c) (2010).
103. In an amicus brief submitted to the Supreme Court in a securities fraud case late last year, the FDA denied that efficacy data had to reach the level of statistical significance before providing meaningful information about a drug: "A study in which the cure rate for cancer patients who took a drug was twice the cure rate for those who took a placebo could generate meaningful interest even if the results were not statistically significant." Brief for United States as Amicus Curiae Supporting Respondents at 15 n.2, Matrixx Initiatives, Inc. v. Siracusano, No. 09-1156, 2011 U.S. LEXIS 2416 (S. Ct. Mar. 22, 2011), 2011 U.S. S. Ct. Briefs LEXIS 2039 at *15 n.2. Just as the FDA, in the DESI context, recognized that efficacy data were clinically relevant even if they did not satisfy the standard applicable to efficacy assessments in the new drug approval context, so too did the Agency in this case acknowledge that efficacy data could be relevant from an investment perspective. In both situations, the FDA's approach undermines the Agency's assertion in the off-label promotion context that adequate protection of the public health requires unwavering enforcement of the high standards for efficacy data in the 1962 drug amendments.
104. See 21 C.F.R. § 314.520 (2010).
105. Letter from Murray M. Lumpkin, Deputy Ctr. Dir., Review Mgmt., Ctr. for Drug Evaluation & Research, to Steve Thomas, Ph.D., Celgene Corp. (Jul. 16, 1998), available at http://www.accessdata.fda.gov/drugsatfda-docs/appletter/ l998/20785ltr.pdf.
106. Memorandum from Carl Kraus, Med. Officer, Ctr. For Drug Evaluation & Research, to Anne Trontell, Deputy Dir., Office of Drug Safety 2-3 (Jan. 29, 2004), available at http://www.fda.gov/ohrms/DOCKETS/ac/04/briefing/4017Bl- 06b%200verview%20STEPS%20Section%20C%20Tab%207.pdf.
107. See Ctr. for Drug Evaluation & Research, Food & Drug Admin, Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (2005), available at http://www.fda.gov/ downloads/RegulatoryInformation/Guidances/UCMl26834.pdf.
108. Ctr. for Drug Evaluation & Research, Food & Drug Admin., Guidance for Industry: Development and Use of Risk Minimization Action Plans (2005), available at http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM07l6l6.pdf.
109. Ctr. for Drug Evaluation & Research, Food & Drug Admin., Guidance for Industry: Premarketing Risk Assessment (2005), available at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucml26958.pdf.
110. Food & Drug Admin. Amendments Act of 2007, Pub. L. No. 110-85 § 901, 121 Stat. 823, 930 (to be codified at 21 U.S.C. § 355-l(f)(l)(a)(A)).
111. See Press Release, Food & Drug Admin., FDA Announces Withdrawal of Fenfluramine and Dexfenfluramine (Fen-Phen) (Sept. 15, 1997), available at http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInforrnationforPatientsandProviders/ucml79871.htm.
112. See Questions and Answers for Withdrawal of Duract, FDA.gov, http://www.fda.gov/Drugs/ResourcesForYou/Consumers/QuestionsAnswers/ucm073043. htm (last updated Oct. 7, 2010).
113. For a history of Supreme Court protection of commercial speech in its early years, see generally Ronald D. Rotunda, The Commercial Speech Doctrine in the Supreme Court, 1976 U. ILL. L.J. 1080 (1976).
114. See Va. State Bd. of Pharmacy v. Va. Citizens Consumer Council, Inc., 425 U.S. 748 (1976).
115. Ohralik v. Ohio State Bar Ass'n, 436 U.S. 447, 456 (1978).
116. For explication of the argument that commercial speech is deserving of full First Amendment protection, see Martin H. Redish, Money Talks: Speech, Economic Power, and the Values of Democracy 14-62 (2001).
117. See, e.g., Friedman v. Rogers, 440 U.S. 1 (1979).
118. Cent. Hudson Gas & Elec. v. Pub. Serv. Comm'n, 447 U.S. 557 (1980).
119. See infra Part III.B.3.b.
120. 447 U.S. at 566.
121. Edenfield v. Fane, 507 U.S. 761, 770-71 (1993) ("This burden is not satisfied by mere speculation or conjecture; rather a governmental body seeking to sustain a restriction on commercial speech must demonstrate that the harms it recites are real and that its restriction will in fact alleviate them to a material degree.").
122. 447 U.S. at 566.
123. See, e.g., Lorillard Tobacco Co. v. Reilly, 533 U.S. 525, 565 (2001) (state's restrictions of outdoor advertising of tobacco violate fourth prong of Central Hudson).
124. Greater New Orleans Broad. Ass'n v. United States, 527 U.S. 173, 176, 190 (1999) (invalidating federal law prohibiting "some, but by no means all, broadcast advertising of lotteries and casino gambling" because "'[t]he operation of [the challenged statute] and its attendant regulatory regime is so pierced by exemptions and inconsistencies that the Government cannot hope to exonerate it").
125. 44 Liquormart, Inc. v. Rhode Island, 517 U.S. 484, 506 (1996) (invalidating prohibition of liquor price advertising as a means of promoting the government's interest in temperance because "the State has presented no evidence to suggest that its speech prohibition will significantly reduce marketwide consumption") (emphasis in original).
126. Rubin v. Coors Brewing Co., 514 U.S. 476 (1995) (federal law prohibiting beer labels from displaying alcohol content held unconstitutional because under the law distilled spirits are permitted to display their alcohol content).
127. City of Cincinnati v. Discovery Network, Inc., 507 U.S. 410 (1993) (invalidating ban on commercial news racks on city streets in the city by an attempt to improve esthetics, because the remaining non-commercial newspaper racks rendered "marginal indeed" the esthetic benefits gained from the regulation).
128. See, e.g., Thompson v. W. States Med. Ctr., 535 U.S. 357 (2002).
129. 44 Liquormart, 517 U.S. at 484.
130. See 44 Liquormart, 517 U.S. at 518-28 (Thomas, J., concurring).
131. Western States, 535 U.S. at 377 (Thomas, J., concurring).
132. 44 Liquormart, 517 U.S. at 503 (citation omitted).
133. Edenfield v. Fane, 507 U.S. 761 (1993).
134. Western States, 535 U.S. at 374.
135. See, e.g., Zauderer v. Office of Disciplinary Counsel, 471 U.S. 616, 651 (1985).
136. Each of these constitutional justifications can be gleaned from the FDA's rationales for its treatment of off-label promotion. See supra Part II.
137. See infra Part III.B.3.b.
138. See infra Part IV.
139. Brief for the Appellants at 28, Wash. Legal Found, v. Henney, 202 F.3d 331 (D.C. Cir. 2000) (No. 99-5304).
140. See United States v. O'Brien, 391 U.S. 367 (1968).
141. Aaron S. Kesselheim et al., Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints, PLoS Med., Apr. 2001, at 1, 5 ("Complaints alleged that manufacturers also encouraged off-label use through direct financial incentives to physicians").
142. Thompson v. W. States Med. Ctr., 535 U.S. 357 (2002).
143. A. Elizabeth Blackwell & James M. Beck, Drug Manufacturers'First Amendment Right to Advertise and Promote Their Products for Off-Label Use: Avoiding a Pyrrhic Victory, 58 Food & Drug L.J. 439, 445 (2003).
144. See also United States v. Wenger, 427 F.3d 840, 846 n.1 (10th Cir. 2005) ("[T]he Supreme Court has rejected the idea that the power to extensively regulate in a certain area includes the authority to regulate speech without raising First Amendment concerns").
145. United States v. Caronia, 576 F. Supp. 2d 395 (E.D.N.Y. 2008) ("[T]he promotion of off-label uses of an FDA-approved prescription drug is speech, not conduct").
146. Wash. Legal Found, v. Friedman, 13 F. Supp. 2d 51, 59 (D.D.C. 1998) ("This court is hard pressed to believe that the agency is seriously contending that 'promotion' of an activity is conduct and not speech . . .").
147. In the words of one commentator, "[t]he Supreme Court has never accepted the notion that truthful speech can be regulated in order to prevent harm where the sole embodiment of that harm is the speech itself." Richard A. Samp, Courts are Arriving at a Consensus on Food and Drug Administration Speech Regulation, 58 Food & Drug L.J. 313, 324 (2003).
148. Western States, 535 U.S. 357 (2002).
149. See generally 21 U.S.C. § 353a (2000).
150. Western States, 535 U.S. at 374.
151. See Zauderer v. Office of Disciplinary Counsel, 471 U.S. 626 (1985).
152. See Zauderer v. Office of Disciplinary Counsel, 471 U.S. 616, 626 (1985).
153. See, e.g., Greater New Orleans Broad. Ass'n v. United States, 527 U.S. 173 (1999).
154. Rubin v. Coors Brewing Co., 514 U.S. 476 (1995).
155. See, e.g., United States v. Am. Library Ass'n, 539 U.S. 194, 224 (2003) ("Under [the unconstitutional conditions doctrine], 'the Government may not deny a benefit to a person on a basis that infringes his constitutionally protected . . . freedom of speech' even if he has no entitlement to that benefit")
156. (citing Ashcroft v. Free Speech Coalition, 535 U.S. 234, 255 (2002)).
157. U.S. Const, art. I, § 8, cl. 3.
158. U.S. Const, art. I, § 8, cl. 18.
159. See supra text accompanying note 119.
160. See Board of Trs. v. Fox, 492 U.S. 469, 477 (1989).
161. See, e.g., 44 Liquormart, Inc. v. Rhode Island, 517 U.S. 484, 507 (1996) (invalidating prohibition on price advertising of liquor because "[i]t is perfectly obvious that alternative forms of regulation that would not involve any restriction on speech would be more likely to achieve the State's goal of promoting temperance . . .").
162. Lorillard Tobacco Co. v. Reilly, 533 U.S. 525, 565 (2001) (state's restriction of outdoor advertising of tobacco, designed to prevent minors from being exposed to tobacco advertising, violate fourth prong because it unduly interferes with fully protected expression between manufacturers and adult consumers).
163. C. Edwin Baker, Commercial Speech-. A Problem in the Theory of Freedom, 62 Iowa L. Rev. 1 (1976).
164. Robert Post, The Constitutional Status of Commercial Speech, 48 UCLA L. Rev. 1 (2000).
165. See supra text accompanying notes 120-21.
166. See Va. State Bd. of Pharmacy v. Va. Citizens Consumer Council, 425 U.S. 748 (1976).
167. One of us has long been critical of opposition to commercial speech protection. See, e.g., Martin H. Redish, Commercial Speech, First Amendment Intuitionism and the Twilight Zone of Viewpoint Discrimination, 41 Loy. L.A. L. Rev. 67 (2008).
168. Though at the margins the definition of "commercial speech" is subject to some confusion, see, e.g., Kasky v. Nike, Inc., 2 P.3d 1065 (Cal. 2000).
169. it is generally accepted that expression in the form of an advertisement by a profit-making seller that promotes sale of a commercial product or service falls within that definition. See, e.g., Bolger v. Youngs Drug Prods. Corp., 463 U.S. 60 (1983). Whether all manufacturer discussion of its product is properly characterized as commercial speech is beyond the scope of this Article.
170. U.S. Const, art. V (authorizing amendment of the Constitution through a super- majoritarian process).
171. See, e.g., Brandenburg v. Ohio, 395 U.S. 444 (1969) (per curiam).
172. Frederick Schauer, Must Speech Be Special?, 78 Nw. U. L. Rev. 1284 (1984).
173. See Martin H. Redish, The Value of Free Speech, 130 U. Pa. L. Rev. 591 (1982).
174. See Posadas de P.R. Assocs. v. Tourism Co. of P.R., 478 U.S. 328 (1986).
175. For a description of that jurisprudence, see Martin H. Redish, Freedom of Expression: A Critical Analysis 173-212 (1984).
176. 517 U.S. 484 (1996).
177. U.S. Const, art. I, § 8, cl. 3 (Commerce Clause).
178. U.S. Const, art. I, § 8, cl. 18 (Necessary and Proper Clause).
179. While the court in United States v. Caronia, 576 F. Supp. 2d 385, 401 (E.D.N.Y. 2008) reasoned that the federal government lacked such constitutional authority, such a conclusion preposterously ignores the last sixty years of Commerce Clause jurisprudence.
180. See, e.g., Gonzales v. Raich, 545 U.S. 1 (2005) (upholding federal power to criminalize sale of drugs traveling in interstate commerce).
181. Katzenbach v. McClung, 379 U.S. 294 (1964) (upholding Title II of 1964 Civil Rights Act, which prohibited discrimination in restaurants which sell food that traveled in interstate commerce). Whether the FDA itself, under the