First Amendment Challenges to the FDA’s Authority to Regulate Off-label Promotion

​​​The FDA’s long-standing authority to prohibit off-label promotion of pharmaceuticals has recently been questioned under free speech challenges, one of which has already succeeded in a United States District Court. Oftentimes, drugs that receive FDA approval for treating specific medical conditions are found to be effective in treating additional ailments. Such “off-label use” can be quite effective and its practice is fairly prevalent.  In fact, over half of all cancer drugs are used off-label.  Furthermore, physicians are allowed to prescribe drugs for off-label use and in some cases such methods would be considered best practices. However, issues arise when pharmaceutical manufacturers market or promote their products for off-label uses, i.e. those that may be safe and beneficial, but have not yet received FDA approval.

The FDA prohibits companies from advertising or promoting drugs for off-label uses, regardless of the drug’s efficacy or safety. If manufacturers market or promote off-label uses, they risk liability under 21 U.S.C. § 331(a), which prohibits “[t]he introduction or delivery for introduction into interstate commerce of any food, drug, device, tobacco product, or cosmetic that is adulterated or misbranded”, and under 21 U.S.C. § 333(a) the FDA may impose up to one year in prison and up $1,000 in fines per occurrence. Penalties may be increased to up to three years and $10,000 in fines if there was “intent to defraud or mislead” or if the manufacturer is a repeat offender.

Under 21 U.S.C § 352, a drug is “misbranded” if labeling “does not contain adequate directions for use.”  The FDA defines “adequate directions for use” in 21 C.F.R. § 201.5 as “directions under which the lay[person] can use a drug safely and for the purposes for which it is intended”. “Intended use” is defined as “the objective intent of the persons legally responsible for the labeling of drugs”, which may be shown by “oral or written statements” and “the circumstances that the article is. . . . offered and used for a purpose for which it is neither labeled nor advertised.” Accordingly, manufacturers may not promote previously approved drugs for non-approved use until they have undergone the clinical testing required by the FDA. 

On August 7, 2015 the United States District Court of the Southern District of New York granted a preliminary injunction in favor of Amarin Corporation plc, a pharmaceutical manufacturer. The Court held that Amarin “may engage in truthful and non-misleading speech promoting the off-label use of Vascepa. . . . and such speech may not form the basis of a prosecution for misbranding”. It further held that Amarin’s promotion was sufficiently truthful and non-misleading.

Vascepa is a heart medication derived from fish oil that was originally approved by the FDA for treating adult patients with “very high triglyceride” levels (i.e. those whose triglycerides exceed 500 mg/dL of blood). Amarin also sought approval to treat adults with triglyceride levels between 200 and 499 mg/dL who are also taking statins (“persistently high triglycerides”). An FDA-approved study showed that Vascepa was effective in reducing triglycerides these levels, and according to the Court is “undisputed[ly]” safe relying on Vascepa’s current application in very high triglyceride patients and the FDA’s approval for public use of a chemically similar dietary supplement.

After the FDA refused to approve Vascepa’s “secondary use” in persistently high triglyceride patients, and had warned Amarin from using the results of an FDA approved study in promoting Vascepa’s secondary use to doctors, Amarin and four doctors filed a complaint to enjoin the FDA under the First Amendment. Amarin and the doctors argued that prohibiting manufacturers from releasing the results of reliable studies to doctors violated free speech principles. The Court agreed with Amarin, citing United States v. Caronia, a Second Circuit case, which held that free speech principles prevented FDA from criminalizing the truthful promotion of off-label uses. The main thrust of the Court’s holding is that manufacturers are able to provide this information of off-label use to doctors when it is truthful, from reliable studies, and non-misleading.

In response to Amarin’s victory, another manufacturer, Pacira, filed a complaint in the same District Court as Amarin.  Pacira’s drug EXPAREL is FDA-approved for post-surgery pain relief after bunionectomies and hemorrhoidectomies. However, the drug has been shown to be an effective pain reliever in other surgeries. Pacira’s primary argument is that the promotion is not off-label because it was approved for general post-surgical use, while the FDA contends such approved use is limited to those situations that were studied, i.e. bunionectomies and hemorrhoidectomies.  Alternatively, Pacira argues that providing information to physicians from other studies falls under the Amarin exception in that it is truthful and non-misleading.  

Going forward, it is unclear whether the FDA will appeal the Amarin decision. Given that the case would be appealed to the Second Circuit Court of Appeals, which decided Caronia, the case used to support the Amarin decision, the FDA may be apprehensive about their chances. However, the FDA has a lot to lose because its ability to prohibit off-label promotion has been a major tool in regulating manufacturers abilities to promote drugs for wider uses, and accordingly increase their profits.

Further implications of the decision are also unclear. While the decision is a temporary victory for pharmaceutical companies, it is doubtful that manufacturers in other jurisdictions will start testing the waters of off-label promotion. It seems unlikely that manufactures in other jurisdictions will begin promoting truthful off-label uses before favorable decisions are made in their own jurisdictions. One objection to the Amarin decision is that it practically allows courts, rather than the FDA, to decide whether certain uses of a drug are objectively safe. Further, it remains unclear whether manufacturers will be able to use successful studies to market off-label use to the public.

Joe Gregorio is a third year law student at DePaul University College of Law. Joe is a managing editor of the E-Pulse; editor of articles, notes, and comments for The DePaul Law Review; and co-chair of Outreach and Recruitment for the Jaharis Health Law Institute. His current interests are in health care regulation, specifically in drugs and devices, fraud and abuse, and health care delivery.​​​