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Off-Label Prescription Advertising, the FDA and the First Amendment: A Study in the Values of Commercial Speech Protection

Published online by Cambridge University Press:  06 January 2021

Coleen Klasmeier  and
Martin H. Redish
Coleen Klasmeier
Affiliation:
Sidley Austin LLP, Washington D.C.
Martin H. Redish
Affiliation:
Northwestern University School of Law; Sidley Austin LLP
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Extract

In order to protect the nation from harmful or worthless drugs and devices, the Food and Drug Administration (FDA or the Agency) is legislatively authorized to restrict the sale of prescription drugs or medical devices to those whose efficacy and safety have been reviewed and approved by the Agency. Drugs and devices are approved for a specific medical purpose. In numerous instances, however, the medical profession has discovered that treatments approved for one purpose may also serve other valuable medical purposes. Indeed, on a number of occasions such “off-label” treatments have proven to be essential to the successful treatment of some very serious illnesses.

In these off-label situations, the FDA is faced with a dilemma. On the one hand, off-label use of prescription drug and devices gives rise to a series of major problems for the FDA. While the drug and devices in question have been vetted and approved by the FDA for their designated purpose, at no point has the FDA reviewed the supporting scientific data to determine efficacy for the off-label purpose.

Type
Article
Information
American Journal of Law & Medicine , Volume 37 , Issue 2-3 , June 2011 , pp. 315 - 357
Copyright
Copyright © American Society of Law, Medicine and Ethics and Boston University 2011

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Footnotes

†

The views expressed in this Article are solely those of the authors, and in no way necessarily reflect the views of Sidley Austin LLP or any of its clients. Both authors are involved in the representation of one or more drug manufacturing company clients in matters in which the arguments in this article have been or could be presented to a court or prosecutorial authority, including the Department of Justice and the Food and Drug Administration.

References

1 Federal Food, Drug, and Cosmetic Act, 21 U.S.C. §§ 335(a), 360(k), 360(e) (2006).

2 See 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, 304 (2010)Google ScholarPubMed (“[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 id. at 305 (footnote omitted) (“[I]t is undeniable that off-label prescribing is a critical component of the practice of medicine in America”).

4 See id. at 309; see also Part II.A, infra.

5 The situation is rendered even more bizarre by current FDA practices towards wholly unapproved drugs. See infra text accompanying notes 153-54.

6 See infra Part III.B.

7 See infra Part IV.B.

8 See infra Part III.

9 “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). The FDA disclaims authority to interfere with a doctor’s judgment to prescribe a drug for an unapproved use. Id. 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). The same is true for medical devices. 21 U.S.C. § 396 (2006).

10 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.” Chen, Donna T. 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)CrossRefGoogle ScholarPubMed (footnotes omitted); see also DeMonaco, Harold J. et al., The Major Role of Clinicians in the Discovery of Off-Label Drug Therapies, 26(3) Pharmacotherapy 323, 323 (2006)CrossRefGoogle ScholarPubMed (“[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.”).

11 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).

12 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. Food & Drug Admin., “Off-Label” and Investigational Use of Marketed Drugs, Biologics, and Medical Devices—Information Sheet, FDA.gov, http://www.fda.gov/RegulatoryInformation/default.htm (last visited Apr. 9, 2011).

13 Buckman Co. v. Plaintiffs’ Legal Comm., 531 U.S. 341, 349-51 & n.5 (2001); see also Fran Kritz, FDA Seeks to Add Drugs’ New Uses to Labels, Wash. Post, Mar. 29, 1994, at Z11 (“In some cases, if you didn’t use the drug in the off-label way you’d be guilty of malpractice.”).

14 See Kalb, Paul E. & Greenberg, Paul E., Legal and Economic Perspectives Concerning U.S. Government Investigations of Alleged Off-Label Promotion by Drug Manufacturers, 27 Pharmacoeconomics 623, 623 (2009)CrossRefGoogle ScholarPubMed (“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.”).

15 59 Fed. Reg. 59,823 (Nov. 18, 1994).

16 United States v. Caputo, 517 F.3d 935, 939 (7th Cir. 2008).

17 See Wash. Legal Found. v. Friedman, 13 F. Supp. 2d. 51 (D.D.C. 1998), appeal dismissed sub nom. Wash. Legal Found. v. Henney, 202 F.3d 331 (D.C. Cir. 2000).

18 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. 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.

19 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) (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) (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. § 321(m) (2006). Under Kordel v. United States, 335 U.S. 345 (1948), 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).

20 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.

21 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).

22 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”); 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.”).

23 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. See, e.g., United States v. Articles of Drug, 32 F.R.D. 32 (S.D. Ill. 1963); United States v. 8 Cartons, Containing “Plantation ‘The Original’ etc., Molasses,” 103 F. Supp. 626 (W.D.N.Y. 1951). 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.” Christopher, Thomas H., Free Speech and the Regulation of Labeling and Advertising, 30 Food Drug Cosm. L.J. 512, 525 (1975).Google Scholar The author did not even consider the scope of FDA authority to regulate the content of truthful and non-misleading commercial speech.

24 Ley, Herbert, FDA Papers, 8 Clinical Pharm. & Therapeutics 749, 749-51 (1967).Google ScholarPubMed

25 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).

26 Id. at 1.

27 Id. at 26 (statement of William Goodrich, Chief Counsel, Food & Drug Admin.).

28 Id. at 18.

29 Id. at 58-70.

30 Id. at 66, 67, 70.

31 37 Fed. Reg. 16,503 (Aug. 15, 1972).

32 See id.

33 See id.

34 See id.

35 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.” Kessler, David A., 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).Google Scholar Kessler indicated that FDA “chose to deal with the problem [of off-label prescribing] as an educational matter.”

36 FDA’s Growing Influence on Your Practice, Med. World News, Mar. 1, 1974, at 46; Bierne, Gregory J., Eternal Vigilance—The Price of Liberty, 222 JAMA 1553, 1553-55 (1972).Google Scholar

37 Shapiro, Sidney A., Limiting Physician Freedom to Prescribe a Drug for Any Purpose: The Need for FDA Regulation, 73 Nw. U. L. Rev. 801, 846 (1979).Google Scholar In 1991, FDA considered and rejected withdrawing the 1972 proposed rule. See 56 Fed. Reg. 42,668, 42,669 (Aug. 28, 1991).

38 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).

39 This provision remains in effect, and is currently codified at 21 C.F.R. § 312.2(d) (2010).

40 DDAL, Position on the Concept of Solicited and Unsolicited Requests, Apr. 22, 1982; Investigational New Drug, Antibiotic, and Biological Drug Product Regulations; Treatment Use and Sale, 52 Fed. Reg. 19,466 (May 22, 1987); 52 Fed. Reg. 8,798, 8,833 (Mar. 19, 1987) (to be codified at 21 C.F.R. pt. 312).

41 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).

42 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).

43 The Pink Sheet, Prescription Pharm. and Biotechnology, July 13, 1992, at T&G-14.

44 Id.

45 FDA to Target Scientific and Consumer Materials, FDA Advertising and Promotion Manual, Feb. 1993, at 1.

46 See The Pink Sheet, Prescription Pharm. and Biotechnology, Sept. 1994, at T&G-9.

47 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, 1994) [hereinafter Citizen Petition].

48 Advertising and Promotion, Draft Guidances, 60 Fed. Reg. 62,471 (Dec. 6, 1995); Advertising and Promotion, Draft Guidance, Republication, 60 Fed. Reg. 63,384 (Dec. 8, 1995) (republication with omitted text).

49 See Advertising and Promotion, Guidances, 61 Fed. Reg. 52,800 (Oct. 8, 1996).

50 Final Guidance on Industry-Supported Scientific and Educational Activities, 62 Fed. Reg. 64,074 (Dec. 3, 1997).

51 See, e.g., United States ex rel. Franklin v. Parke-Davis, 147 F. Supp. 2d 39 (D. Mass. 2001).

52 See The Pink Sheet, Prescription Pharm. & Biotechnology, Nov. 27, 1995, at 3; Nancy Benac, FDA Getting Tough On Disguised Drug Promotions, Associated Press, May 30, 1991, available at LexisNexis.

53 Benac, supra note 52.

54 C. Adams et al., Risky RX: A Knight-Ridder Investigation, Newspaper article series, Nov. 2-4, 2003.

55 Study Shows Danger to Skin and Gives Hope of a Savior, N.Y. Times, Jan. 25, 1996.

56 Id.

57 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”); 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”); 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.”).

58 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”); 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”). 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; 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”).

59 See Citizen Petition supra note 47.

60 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.); 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); 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); 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.).

61 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.

62 Id.

63 Id.

64 See Harrison, Donald C., Arrhythmia Prophylaxis After Acute Myocardial Infarction: A Decade of Controversy, 2 Cardiovascular Drugs & Therapy 783, 783 (1989).CrossRefGoogle ScholarPubMed

65 See Naccarelli, Gerald V. et al., A Critical Appraisal of the Cardiac Arrhythmia Suppression Trial (CAST), 4 Applied Cardiopulmonary Pathophysiology 9 (1991).Google Scholar

66 See, e.g., Held, Peter H. & S. Yusuf, Calcium Antagonists in the Treatment of Ischemic Heart Disease: Myocardial Infarction, 5 Coronary Artery Disease 21 (1994)CrossRefGoogle ScholarPubMed (reviewing studies of six calcium-channel blockers and finding little benefit in their use post-myocardial infarction); Pashos, Chris L., Held, P.H. & Yusuf, S., Effects of β-Blockers and Calcium Channel Blockers in Acute Myocardial Infarction, 14 Eur. Heart J. (SUPP. F) 18, 22 (1993)Google Scholar (“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”); 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].”).

67 Citizen Petition, supra note 47, at 59,824 (discussing off-label promotion of the “breast coil” to detect leakage “of the inner gel component of the implant to bodily tissues”).

68 Id.

69 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”); see also Medeiros Scaranelo, Anabel 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)Google Scholar (“[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.”).

70 See Monticciolo, Debra L. 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)CrossRefGoogle ScholarPubMed (“A standard circular surface coil with a diameter of 24 cm was placed around each breast imaged”); see also Ahn, Christina Y., Residual Silicone Detection Using MRI Following Previous Breast Implant Removal: Case Reports, 19 Aesthetic Plastic Surg. 361, 366 (1995)CrossRefGoogle ScholarPubMed (“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.”).

71 Monticciolo et al., supra note 70.

72 See Food & Drug Admin., Dep’t of Health & Human Servs., BLA 103000/5000, Approval Letter for BOTOX® Cosmetic 1 (Apr. 14, 2002).

73 59 Fed. Reg. 59,825, 59,825 (Nov. 18, 1994).

74 See 53 Fed. Reg. 41,516 (Oct. 21, 1988).

75 Federal Food, Drug, and Cosmetic Act § 506, 21 U.S.C. § 356 (2006).

76 21 U.S.C. § 356(b)(1).

77 See 21 C.F.R. §§ 314.510, 601.21 (2010).

78 See 67 Fed. Reg. 37,988 (May 31, 2002).

79 Id. at 37,989.

80 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 Jensen, Valerie et al., FDA’s Role in Responding to Drug Shortages, Am. J. Health Sys. Pharmacy 1423, 1423-25 (2002)CrossRefGoogle Scholar, Questions and Answers on the Propofol Shortage, FDA.gov, http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm209227.htm (last updated Mar. 30, 2011). This practice, like the Agency’s failure to implement DESI, gives the lie to the notion, so frequently articulated in defense of the off-label promotion ban, that the FDCA drug approval process must be applied without compromise or else risk jeopardizing the public’s health. If the process were crucial to patient safety, then the FDA would not simply ignore it in a shortage scenario.

81 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.”).

82 See Hoffman-LaRoche, Inc. v. Weinberger, 425 F. Supp. 890 (D.D.C. 1975).

83 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. Interestingly, in the CPG, FDA dials back its rhetoric about the importance of the new drug approval process, saying only, “The new drug approval . . . process[] play[s] an essential role in ensuring that all drugs are both safe and effective for their intended uses.” Id. at 2 (emphasis added).

84 Id. at 2.

85 Id.

86 Id.

87 Id. at 3. “Some of the specific actions the Agency has taken have been precipitated by evidence of safety or effectiveness problems that has . . . been brought to our attention by outside sources.” Id. at 2. In at least two of these cases, FDA took action only after manufacturers of approved versions of the unlawful products threatened litigation and/or took other action to pressure FDA to implement the new drug approval requirements.

88 See FDA, Information for Healthcare Professionals: New Safety Information for Colchicine (marketed as COLCRYS) (last updated June 4, 2010), www.fda.gov.

89 Id.

90 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.

91 Janet Woodcock & Sarah Okada, Letter to the Editor, Incentives for Drug Development—the Curious Case of Colchicine, 363 N. Eng. J. Med. 1484 (2010).

92 See supra note 18.

93 Brief for United States as Amicus Curiae, United States v. Caronia, No. 09-5006, 2010 WL 6351497 (C.A.2).

94 Id.

95 See 36 Fed. Reg. 11,022 (June 8, 1971).

96 Id. at 11,022-23.

97 21 C.F.R. § 201.200(c) (2010).

98 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.

99 New Drugs Used For Nonapproved Purposes (Methotrexate for Psoriasis), supra note 25, at 19, 57-58.

100 See 21 C.F.R. § 314.520 (2010).

101 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/1998/20785ltr.pdf.

102 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/4017B1-06b%20Overview%20STEPS%20Section%20C%20Tab%207.pdf.

103 Id. at 2.

104 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/UCM126834.pdf; 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/UCM071616.pdf; Ctr. for Drug Evaluation & Research, Food & Drug Admin., Guidance for Industry: Premarketing Risk Assessment (2005), available at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126958.pdf.

105 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. § 355-1(f)(1)(a)(A)).

106 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/PostmarketDrugSafetyInformationforPatientsandProviders/ucm179871.htm.

107 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).

108 For a history of Supreme Court protection of commercial speech in its early years, see generally Rotunda, Ronald D., The Commercial Speech Doctrine in the Supreme Court, 1976 U. Ill. L.J. 1080 (1976).Google Scholar

109 See Va. State Bd. of Pharmacy v. Va. Citizens Consumer Council, Inc., 425 U.S. 748 (1976).

110 Ohralik v. Ohio State Bar Ass’n, 436 U.S. 447, 456 (1978). 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).

111 See, e.g., Friedman v. Rogers, 440 U.S. 1 (1979).

112 Cent. Hudson Gas & Elec. v. Pub. Serv. Comm’n, 447 U.S. 557 (1980).

113 See infra Part III.B.3.b.

114 447 U.S. at 566.

115 Id.

116 Id. at 564.

117 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.”).

118 447 U.S. at 566.

119 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); 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”); 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); 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); 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).

120 See, e.g., Thompson v. W. States Med. Ctr., 535 U.S. 357 (2002). See discussion infra Part III.A.

121 44 Liquormart, 517 U.S. at 484.

122 Id. at 502-03 (citation omitted). Justice Thomas continues to adhere to a view similar to Justice Stevens’s. See 44 Liquormart, 517 U.S. at 518-28 (Thomas, J., concurring); Western States, 535 U.S. at 377 (Thomas, J., concurring).

123 44 Liquormart, 517 U.S. at 503 (citation omitted).

124 Edenfield v. Fane, 507 U.S. 761 (1993).

125 Id. at 767.

126 Western States, 535 U.S. at 374.

127 See, e.g., Zauderer v. Office of Disciplinary Counsel, 471 U.S. 616, 651 (1985).

128 Each of these constitutional justifications can be gleaned from the FDA’s rationales for its treatment of off-label promotion. See supra Part II.

129 See infra Part III.B.3.b.

130 See infra Part IV.

131 Brief for the Appellants at 28, Wash. Legal Found. v. Henney, 202 F.3d 331 (D.C. Cir. 2000) (No. 99-5304).

132 See United States v. O’Brien, 391 U.S. 367 (1968).

133 Kesselheim, Aaron S. et al., Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints, PLoS Med., Apr. 2001, at 1, 5Google Scholar (“Complaints alleged that manufacturers also encouraged off-label use through direct financial incentives to physicians”); see Osborn, supra note 2, at 304.

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

135 Elizabeth Blackwell, A. & Beck, James M., 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).Google Scholar 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”); 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”); 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 . . .”). 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.” Samp, Richard A., Courts are Arriving at a Consensus on Food and Drug Administration Speech Regulation, 58 Food & Drug L.J. 313, 324 (2003).Google Scholar

136 See supra Part III.A.2.

137 See infra Part III.B.3.b.

138 See Osborn, supra note 2, at 305-06. See also infra Part IV.B.2.

139 Western States, 535 U.S. 357 (2002).

140 Id. at 360. See generally 21 U.S.C. § 353a (2000).

141 Western States, 535 U.S. at 374.

142 Id.

143 Id.

144 See supra Part III.A.1.

145 See supra Part II.A. See also Osborn, supra note 2, at 304.

146 See infra Part IV.B.2.

147 See Zauderer v. Office of Disciplinary Counsel, 471 U.S. 626 (1985).

148 For a discussion of FDA’s adoption of a disclaimer-based regime to assure that manufacturer speech about drug efficacy was truthful and non-misleading to physicians, see supra text discussion accompanying note 98.

149 For a discussion of flaws in the FDA’s asserted justifications for the ban on off-label promotion, see supra note 98. See Zauderer v. Office of Disciplinary Counsel, 471 U.S. 616, 626 (1985).

150 See supra text accompanying notes 129-30.

151 See Osborn, supra note 2, at 304.

152 See discussion supra Part II.E.

153 See, e.g., Greater New Orleans Broad. Ass’n v. United States, 527 U.S. 173 (1999); Rubin v. Coors Brewing Co., 514 U.S. 476 (1995).

154 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”) (citing Ashcroft v. Free Speech Coalition, 535 U.S. 234, 255 (2002)).

155 U.S. Const. art. I, § 8, cl. 3.

156 U.S. Const. art. I, § 8, cl. 18.

157 See supra text accompanying note 119.

158 See Board of Trs. v. Fox, 492 U.S. 469, 477 (1989).

159 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 . . .”); 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).

160 C. Edwin Baker, Commercial Speech: A Problem in the Theory of Freedom, 62 Iowa L. Rev. 1 (1976).

161 Robert Post, The Constitutional Status of Commercial Speech, 48 UCLA L. Rev. 1 (2000).

162 See supra text accompanying notes 120-21.

163 See Va. State Bd. of Pharmacy v. Va. Citizens Consumer Council, 425 U.S. 748 (1976).

164 One of us has long been critical of opposition to commercial speech protection. See, e.g., Redish, Martin H., Commercial Speech, First Amendment Intuitionism and the Twilight Zone of Viewpoint Discrimination, 41 Loy. L.A. L. Rev. 67 (2008).Google Scholar

165 See discussion supra Part III.B.3.

166 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), 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.

167 U.S. Const. art. V (authorizing amendment of the Constitution through a super-majoritarian process).

168 It is worth noting that in the specific context of off-label promotion, the speech would be directed at trained members of the medical profession, rather than laymen. Under the logic of this premise of democratic theory, however, it is doubtful that that element should be deemed outcome determinative.

169 See discussion supra Part II.A.

170 See discussion supra Part II.B.

171 It should be emphasized that, even were one to assume the correctness of the FDA’s concern, under controlling commercial speech doctrine the problem could be solved by the far less invasive use of required disclaimers, rather than direct suppression. See discussion supra Part III.B.3.

172 See, e.g., Brandenburg v. Ohio, 395 U.S. 444 (1969) (per curiam).

173 Frederick Schauer, Must Speech Be Special?, 78 Nw. U. L. Rev. 1284 (1984).

174 See Martin H. Redish, The Value of Free Speech, 130 U. Pa. L. Rev. 591 (1982).

175 See Posadas de P.R. Assocs. v. Tourism Co. of P.R., 478 U.S. 328 (1986).

176 For a description of that jurisprudence, see Martin H. Redish, Freedom of Expression: A Critical Analysis 173-212 (1984).

177 517 U.S. 484 (1996).

178 Id. at 509 (“[O]n reflection, we are now persuaded that Posadas erroneously performed the First Amendment analysis . . . [T]he advertising ban [in that case] served to shield the State’s . . . policy from the public scrutiny that more direct, nonspeech regulations would draw.”).

179 See supra text accompanying notes 127-28.

180 See discussion supra Part III.B.

181 As explained earlier, it appears that the rationale for suppressing promotion while simultaneously failing to regulate the activity being promoted originally was grounded largely in political, rather than regulatory, considerations. See discussion supra Part II.D.

182 See supra Part III.B.

183 U.S. Const. art. I, § 8, cl. 3 (Commerce Clause); U.S. Const. art. I, § 8, cl. 18 (Necessary and Proper Clause). 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. See, e.g., Gonzales v. Raich, 545 U.S. 1 (2005) (upholding federal power to criminalize sale of drugs traveling in interstate commerce); 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 current regulatory framework, possesses such authority is wholly irrelevant to the constitutional analysis. If the federal government, as an entity, wishes to require that a prescribed drug be on-label, there is no doubt of its constitutional authority to do so. The government therefore cannot be permitted to suppress expression as an indirect means of achieving its goal, when it has available a perfectly legitimate direct means of achieving the same end.