Off-Label Marketing and the First Amendment

FDA Procedures

Before a drug or medical device can be marketed, its manufacturer must show the FDA that its product is safe and effective for a specified use. To expand the approved uses of a product, the manufacturer must obtain the FDA's authorization.

Neither the Federal Food, Drug, and Cosmetic Act (FDCA) nor FDA regulations define what constitutes unlawful “off-label promotion.” Rather, prosecutors employ the statutory violations of “misbranding” and “adulteration” to prosecute manufacturers' promotion of drugs and devices for unapproved uses. See 21 U.S.C. ” 331(a) and 333(a) (felony and misdemeanor violations). In 1997, Congress passed the FDA Modernization Act (FDAMA), which provided a safe harbor (under certain conditions) for manufacturers to disseminate independent scientific studies and articles that discuss off-label uses that expired in 2006.

In January 2009, the FDA issued a guidance for industry entitled Good Reprint Practices for the Distribution of Medical Journal Articles ' on Unapproved New Uses ' (www.fda.gov/oc/op/goodreprint.html) to aid pharmaceutical and medical device manufacturers in determining what could be publicly distributed. To be eligible for the “safe harbor,” the article must be published by an organization that has an editorial board and fully discloses its conflicts of interest, be peer-reviewed, and “not be in the form of a special supplement or publication” funded in any way by the manufacturer that is the subject of the article. The Good Reprint Practices also state that the publication should not be heavily tied to the drug or device manufacturer. For example, it should not be “primarily distributed” by the manufacturer, written specifically for or at the request of the manufacturer, or “edited or significantly influenced by” the manufacturer. And above all else, the information must not “be false or misleading” or “pose a significant risk to the public health, if relied upon.”

Protected Commercial Speech

More than 30 years ago, the Supreme Court recognized that commercial speech is protected by the First Amendment. Virginia State Bd. of Pharmacy v. Virginia Citizens Consumer Council, Inc., 425 U.S. 748, 762, 765 (1976). Four years later, the Court established a four-part balancing test for evaluating restrictions on commercial speech in Central Hudson Gas & Elec. Corp. v. Public Serv. Comm'n, 447 U.S. 557, 565 (1980): 1) the commercial speech cannot be about “unlawful activity” or “misleading”; 2) the government interest in regulation must be “substantial”; 3) the regulation must “directly advance” the government interest; and 4) the regulation cannot be broader than necessary.

In Thompson v. Western States Medical Center, 535 U.S. 357 (2002), a group of licensed pharmacies challenged, on First Amendment grounds, two provisions of the FDAMA regarding the marketing of compounded drugs prepared by combining or mixing ingredients to create a medication tailored to the individual needs of a patient. The pharmacists had solicited prescriptions from doctors and advertised the availability of compound drugs ' activities prohibited by the FDAMA because the compound product did not go through the FDA approval process. The Court held that the FDA's restrictions on promotion violated the First Amendment because they were broader than necessary to serve the government's interest.

Scientific Articles and Conferences

The Supreme Court's 2002 holding in Western States was partly foreshadowed by the D. C. Circuit in Washington Legal Foundation v. Friedman, 13 F. Supp. 2d 51, 55 (D.D.C. 1998), vacated on other grounds, Washington Legal Found. v. Henney, 202 F.3d 331 (D.C. Cir. 2000). The panel struck down the FDA prohibitions, finding a preference for the dissemination of more information, rather than less, in order that health care professionals, who may lawfully use drugs and devices off-label, can form their own opinions about them. The court rejected the government's circular argument that, because promoting an “off-label” use is “illegal,” the commercial speech doctrine is inapplicable. To have accepted the FDA's position would, in the court's view, have “eviscerated” First Amendment protections.

The issue of when scientific information loses its protected status was addressed in United States v. Harkonen, No. C 08-00164 MHP, 2009 WL 1578712 (N.D. Cal. June 4, 2009), where the Chief Executive Officer of InterMune was prosecuted for off-label marketing and promotion of the drug Actimmune'. After Actimmune' was approved by the FDA for specific pediatric diseases, InterMune conducted clinical trials on its effectiveness against an unrelated lung disease that occurs mainly in adults. Under the CEO's direction, it then issued a press release touting the clinical trial as a successful treatment for adult use. The court upheld the sufficiency of the indictment because the press release was not “a peer-reviewed publication,” “refers to a specific commercial product on the market,” and might be shown at trial to be false and misleading.

Recently, Allergan, Inc. challenged FDA restrictions on off-label
promotion as unconstitutional and invalid under the First Amendment. Allergan, Inc., v. United States, Civ. Action No. 09-1879 (D.D.C Oct. 1, 2009). Allergan is the distributor of Botox', a prescription drug that is FDA-approved to treat several conditions, but it is also frequently used by doctors off label to treat other conditions. In a motion filed on Jan. 15, 2010, Allergan argues that the “FDA's regulations criminalize off-label speech in sweeping terms, and nothing in those regulations (or the Act) limits the reach of criminal liability to speech that is 'promotional.'”

Allergan and other litigating manufacturers stress that neither the FDCA nor FDA regulations define the term “promotion,” and that the FDA's Guidance pronouncements and other interpretative statements lack the force of law. An illustration of the ambiguity created is found in 21 U.S.C. ' 360aaa-6, which allows a manufacturer to answer questions asked by a health care practitioner. The statute does not state that a manufacturer may not initiate a discussion with the practitioner. Although any “prohibited conduct must, for criminal purposes, be set forth with clarity in the regulations” or the statute itself, see M. Kraus & Bros., Inc. v. United States, 327 U.S. 614, 622 (1946), similar challenges have not been successful, even when coupled with First Amendment issues. See United States v. Caputo, 517 F.3d 935 (7th Cir. 2008).

Conclusion

The absence of a clear statutory and regulatory framework for manufacturers makes off-label marketing a murky and treacherous area. Manufacturers are left with the dilemma that they can discuss off-label information so long as they do not “promote” off-label uses. Deciding where to draw the line is risky for manufacturers of generic and branded medical products alike. It remains to be seen if the Supreme Court's expansive view of First Amendment rights also applies to the area of commercial speech and off-label promotion.

Jonathan S. Feld ([email protected]), a member of this newsletter's Board of Editors, is a Partner at Katten Muchin Rosenman LLP, where he focuses on civil and criminal enforcement matters. Laura A. Brake is an associate in the firm's Litigation Department.

Prosecutions for “off-label marketing” by manufacturers have become an important component of the government's health care initiative. “Off-label” usage of prescription drugs and medical devices refers to using a product for a purpose that is not specified in the labeling approved by the Food and Drug Administration (FDA). Manufacturers are prohibited from promoting off-label uses of their products, but health care providers may prescribe or use them as they choose, whether or not the use fits within the FDA-approved “label.” 21 U.S.C. ' 396.

Government fines and criminal prosecutions against manufacturers for promoting “off-label” uses have surged, especially for pharmaceuticals. In 2009 alone, the Department of Justice (DOJ) announced the largest health care fraud settlement in U.S. history ' a $2.3-billion settlement with Pfizer arising from the off-label promotion of certain pharmaceutical products. Eli Lilly, Bristol-Myers Squibb, and Novartis have also entered into multi-million-dollar settlements. AstraZeneca agreed in April 2010 to a $520 million settlement in connection with off-label marketing.

Pharmaceutical and medical device manufacturers have argued that FDA restrictions on off-label promotion infringe their First Amendments rights. While First Amendment defenses are difficult, two recent cases have placed this issue back in the spotlight. United States v. Harkonen, No. C 08-00164 MHP, 2009 WL 1578712 (N.D. Cal. June 4, 2009), a criminal prosecution, and Allergan, Inc. v. United States, No. 09-1879 (JDB) (D.D.C. Oct. 1, 2009), a civil case that is awaiting decision. Further, the expansive interpretation of the First Amendment protections in recent Supreme Court decisions, albeit in different settings, may further re-energize this defense.

FDA Procedures

Before a drug or medical device can be marketed, its manufacturer must show the FDA that its product is safe and effective for a specified use. To expand the approved uses of a product, the manufacturer must obtain the FDA's authorization.

Neither the Federal Food, Drug, and Cosmetic Act (FDCA) nor FDA regulations define what constitutes unlawful “off-label promotion.” Rather, prosecutors employ the statutory violations of “misbranding” and “adulteration” to prosecute manufacturers' promotion of drugs and devices for unapproved uses. See 21 U.S.C. ” 331(a) and 333(a) (felony and misdemeanor violations). In 1997, Congress passed the FDA Modernization Act (FDAMA), which provided a safe harbor (under certain conditions) for manufacturers to disseminate independent scientific studies and articles that discuss off-label uses that expired in 2006.

In January 2009, the FDA issued a guidance for industry entitled Good Reprint Practices for the Distribution of Medical Journal Articles ' on Unapproved New Uses ' (www.fda.gov/oc/op/goodreprint.html) to aid pharmaceutical and medical device manufacturers in determining what could be publicly distributed. To be eligible for the “safe harbor,” the article must be published by an organization that has an editorial board and fully discloses its conflicts of interest, be peer-reviewed, and “not be in the form of a special supplement or publication” funded in any way by the manufacturer that is the subject of the article. The Good Reprint Practices also state that the publication should not be heavily tied to the drug or device manufacturer. For example, it should not be “primarily distributed” by the manufacturer, written specifically for or at the request of the manufacturer, or “edited or significantly influenced by” the manufacturer. And above all else, the information must not “be false or misleading” or “pose a significant risk to the public health, if relied upon.”

Protected Commercial Speech

More than 30 years ago, the Supreme Court recognized that commercial speech is protected by the First Amendment. Virginia State Bd. of Pharmacy v. Virginia Citizens Consumer Council, Inc. , 425 U.S. 748, 762, 765 (1976). Four years later, the Court established a four-part balancing test for evaluating restrictions on commercial speech in Central Hudson Gas & Elec. Corp. v. Public Serv. Comm'n , 447 U.S. 557, 565 (1980): 1) the commercial speech cannot be about “unlawful activity” or “misleading”; 2) the government interest in regulation must be “substantial”; 3) the regulation must “directly advance” the government interest; and 4) the regulation cannot be broader than necessary.

In Thompson v. Western States Medical Center , 535 U.S. 357 (2002), a group of licensed pharmacies challenged, on First Amendment grounds, two provisions of the FDAMA regarding the marketing of compounded drugs prepared by combining or mixing ingredients to create a medication tailored to the individual needs of a patient. The pharmacists had solicited prescriptions from doctors and advertised the availability of compound drugs ' activities prohibited by the FDAMA because the compound product did not go through the FDA approval process. The Court held that the FDA's restrictions on promotion violated the First Amendment because they were broader than necessary to serve the government's interest.

Scientific Articles and Conferences

The Supreme Court's 2002 holding in Western States was partly foreshadowed by the D. C. Circuit in Washington Legal Foundation v. Friedman , 13 F. Supp. 2d 51, 55 (D.D.C. 1998), vacated on other grounds, Washington Legal Found. v. Henney , 202 F.3d 331 (D.C. Cir. 2000). The panel struck down the FDA prohibitions, finding a preference for the dissemination of more information, rather than less, in order that health care professionals, who may lawfully use drugs and devices off-label, can form their own opinions about them. The court rejected the government's circular argument that, because promoting an “off-label” use is “illegal,” the commercial speech doctrine is inapplicable. To have accepted the FDA's position would, in the court's view, have “eviscerated” First Amendment protections.

The issue of when scientific information loses its protected status was addressed in United States v. Harkonen, No. C 08-00164 MHP, 2009 WL 1578712 (N.D. Cal. June 4, 2009), where the Chief Executive Officer of InterMune was prosecuted for off-label marketing and promotion of the drug Actimmune'. After Actimmune' was approved by the FDA for specific pediatric diseases, InterMune conducted clinical trials on its effectiveness against an unrelated lung disease that occurs mainly in adults. Under the CEO's direction, it then issued a press release touting the clinical trial as a successful treatment for adult use. The court upheld the sufficiency of the indictment because the press release was not “a peer-reviewed publication,” “refers to a specific commercial product on the market,” and might be shown at trial to be false and misleading.

Recently, Allergan, Inc. challenged FDA restrictions on off-label
promotion as unconstitutional and invalid under the First Amendment. Allergan, Inc., v. United States, Civ. Action No. 09-1879 (D.D.C Oct. 1, 2009). Allergan is the distributor of Botox', a prescription drug that is FDA-approved to treat several conditions, but it is also frequently used by doctors off label to treat other conditions. In a motion filed on Jan. 15, 2010, Allergan argues that the “FDA's regulations criminalize off-label speech in sweeping terms, and nothing in those regulations (or the Act) limits the reach of criminal liability to speech that is 'promotional.'”

Allergan and other litigating manufacturers stress that neither the FDCA nor FDA regulations define the term “promotion,” and that the FDA's Guidance pronouncements and other interpretative statements lack the force of law. An illustration of the ambiguity created is found in 21 U.S.C. ' 360aaa-6, which allows a manufacturer to answer questions asked by a health care practitioner. The statute does not state that a manufacturer may not initiate a discussion with the practitioner. Although any “prohibited conduct must, for criminal purposes, be set forth with clarity in the regulations” or the statute itself, see M. Kraus & Bros., Inc. v. United States , 327 U.S. 614, 622 (1946), similar challenges have not been successful, even when coupled with First Amendment issues. See United States v. Caputo , 517 F.3d 935 (7th Cir. 2008).

Conclusion

The absence of a clear statutory and regulatory framework for manufacturers makes off-label marketing a murky and treacherous area. Manufacturers are left with the dilemma that they can discuss off-label information so long as they do not “promote” off-label uses. Deciding where to draw the line is risky for manufacturers of generic and branded medical products alike. It remains to be seen if the Supreme Court's expansive view of First Amendment rights also applies to the area of commercial speech and off-label promotion.

Jonathan S. Feld ([email protected]), a member of this newsletter's Board of Editors, is a Partner at Katten Muchin Rosenman LLP, where he focuses on civil and criminal enforcement matters. Laura A. Brake is an associate in the firm's Litigation Department.