For years, the U.S. Food and Drug Administration (FDA) has taken the position that a medical device (or drug) manufacturer that promotes an FDA-approved device (or drug) for an unapproved use violates the Federal Food, Drug, and Cosmetic Act (FDCA). Such off-label promotion, the FDA maintains, misbrands¹ the product. According to the FDA, off-label promotion circumvents the regulatory approval process designed to ensure that medical devices and drugs are safe and effective, thereby endangering the public.

The FDA's position often brings the agency into conflict with the regulated industry that wishes to disseminate and inform prescribing physicians about beneficial off-label uses for their products. Manufacturers have long cited legitimate reasons for disseminating truthful and non-misleading off-label promotion—for instance, that such promotion helps doctors make informed medical decisions, that these informed decisions directly benefit patients, and that in some cases off-label use is the standard of care in treating patients. Manufacturers have also raised the defense that the FDA's prohibition on truthful and non-misleading off-label promotion violates their First Amendment commercial free speech rights.²

Government actions for misbranding and other alleged violations of federal healthcare laws (e.g., the False Claims Act³ and the Federal Anti-Kickback Statute⁴) are increasing. Moreover, the penalties for a conviction can be significant. For example, misbranding convictions can result in fines, criminal convictions (including felony convictions), and jail time. Both companies and individuals (e.g., corporate officers) may be tried and convicted for misbranding violations. Whether truthful and non-misleading off-label promotion constitutes misbranding is therefore an important question with far-reaching consequences.

Recent cases, including the 2015 Amarin⁵ district court decision, have made it clear that at least some federal courts side with the regulated industry. For example, the Amarin court held that its "considered and firm view is that . . . the FDA may not bring [a misbranding] action based on truthful promotional speech alone, consistent with the First Amendment."⁶

A further important development along these lines recently occurred in the ongoing criminal case involving a medical device manufacturer and its CEO in U.S.A. v. Vascular Solutions, Inc. & Howard C. Root.⁷ Vascular Solutions and its CEO Howard Root were each charged with four counts of adulteration, four counts of misbranding, and felony conspiracy to: introduce adulterated medical devices into interstate commerce, introduce misbranded medical devices into interstate commerce, and defraud the United States by concealing the sale of the allegedly adulterated and misbranded medical devices.⁸

In the Vascular Solutions proposed jury instructions, the Department of Justice (DOJ) acknowledged⁹ that it "is also not a crime for a device company or its representatives to give doctors wholly truthful and non-misleading information about the unapproved use of a device."¹⁰

While this represents a significant step in the evolution of government's misbranding jurisprudence understanding, companies and their corporate officers should approach off-label promotion with caution for many reasons:

• First, holdings like Amarin have limited geographic reach. Amarin is a federal district court holding in the Southern District of New York. Should the government bring a misbranding case in a different federal district court, that district court could come to a different conclusion—i.e., that truthful and non-misleading off-label promotion is not protected by the First Amendment.
• Second, false and misleading off-label promotion is not afforded a First Amendment safe harbor.
• Third, whether off-label promotion is truthful and non-misleading will be decided on a case-by-case basis by a court that takes into consideration the unique facts of the off-label promotion.
• Fourth, whether something is truthful and non-misleading can be time dependent. Off-label promotion that is presently truthful and non-misleading may become false, misleading, or both at some future point. For example, several months after starting to promote off-label, a peer-reviewed study could publish in a major medical journal that directly refutes the basis for the off-label promotion, potentially rendering the off-label promotion false and misleading as of the date of the study's publication.
• Fifth, it is possible to satisfy one requirement but not the other—e.g., a court could find an off-label promotion to be truthful but also misleading.

Going forward, the FDA may shift its focus toward attempting to prove that off-label promotions are misleading. It may be possible for the FDA to make a misleading allegation stick even when the off-label promotion is truthful, such as in situations including:

• when using a peer-reviewed publication for off-label promotion, failing to disclose if any publication author has a financial interest in the device or in the publication;
• neglecting to inform, during the off-label promotion, of any significant risks or safety concerns known to the company and relating to the unapproved use;
• failing to provide the approved labeling with the off-label promotion;
• omitting provision of a comprehensive list discussing contrary authorities to the off-label use; or
• failing to state, when applicable, that the FDA declined to approve the device for the off-label use.

Conclusion

Companies should take a cautious approach to off-label promotion that minimizes the risk of the FDA and DOJ concluding that the off-label promotion is false, misleading, or both. Recommended practices include:

• comprehensive training of all employees in sales and marketing;
• implementing standard operating procedures requiring formal review and approval of all promotional materials;
• establishing a promotional review committee that will be responsible for review and approval of all promotional materials; and
• strictly adhering to FDA guidance regarding good reprint practices and responses to unsolicited requests for information.

¹ 21 U.S.C. § 352. "A device . . . shall be deemed to be misbranded . . .if its labeling is false or misleading in any particular . . . " "Unless its labeling bears (1) adequate directions for use . . ." (Emphasis added.) Adequate directions for use are determined by the intended use(s) of, e.g., the manufacturer.

21 C.F.R. § 801.4 recites in part that:

The words intended uses . . . refer to the objective intent of the persons legally responsible for the labeling of devices . . . This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives.

Thus, the FDA reasons that an off-label promotion is an intended use. The intended use, which has not—by definition—been FDA approved, does not have adequate directions for use on the device's label, and the device is therefore misbranded.

² The commercial free speech doctrine limits government (e.g., FDA) free speech restriction when the free speech has economic motivation (e.g., to sell a medical device). Under the U.S. Supreme Court's Central Hudson judicial review standard, government restriction of commercial free speech is unconstitutional if the speech discusses a lawful activity and is truthful and non-misleading unless:

• the government's interest is substantial;
• the regulation directly advances that substantial interest; and
• the regulation is not more extensive than necessary.

Central Hudson Gas and Elec. Corp. v. Pub. Serv. Comm'n of New York, 447 U.S. 557, 566 (1980). In practice, the third test prong is most often not met by the government.

³ 31 U.S.C. §§ 3729-3733.

⁴ 42 U.S.C. § 1320a-7(b).

⁵ Amarin Pharma, Inc. v. U.S. Food and Drug Administration, 1:15-cv-03588-PAE (SDNY 2015).

⁶ Id. at 45.

⁷ For a layman's summary of the criminal indictment, see J. Carlson, "Vascular Solutions CEO indicted by Texas grand jury," Star Tribune, Nov. 13, 2014; available electronically at: http://www.startribune.com/vascular-solutions-ceo-indicted-on-conspiracy-other-charges/282618741/, last accessed Jan. 25, 2016.

⁸ The conspiracy charges are detailed at pages 9-21 and constitute the bulk of the 23-page indictment.

⁹ To the authors' knowledge, this is the first time the DOJ has acknowledged that truthful and non-misleading off-label promotion, on its own, does not constitute misbranding.

¹⁰ Proposed Jury Instructions, U.S.A. v. Vascular Solutions, Inc. & Howard C. Root, Criminal No. SA:14-CR-926-RCL, filed Jan 7, 2016.