Amarin Pharma v. U.S. Food and Drug Administration: Excerpts

On Aug. 7, US District Judge Paul Engelmayer granted a preliminary injunction to Amarin Pharma, proscribing FDA from filing a “misbranding” action against Amarin, should it provide “truthful and non-misleading” information to physicians promoting the off-label use of its approved drug, Vascepa (icosapent ethyl, derived from fish oil) for patients with persistently high triglycerides. The closely watched case presents a dramatic and significant threat to FDA’s existing framework for policing off-label promotion—and activity for which, in recent years, companies ranging from GlaxoSmithKline to Abbott Labs to Allergan, among others, have paid billions in fines. Following are excerpts from the ruling (Case 1:15-cv-03588-PAE; certain citations in these excerpts have been removed):

In United States v. Caronia, 703 F.3d 149 (2d Cir. 2012), the Court of Appeals for the Second Circuit vacated a pharmaceutical sales representative’s conviction for conspiring to introduce a misbranded drug into interstate commerce, in violation of 21 U.S.C. §§ 331(a) and 333(a)(l). The conviction was based on Caronia’s having promoted a drug for “off-label use,” that is, a use other than the one approved by FDA. Caronia’s conduct to promote the off-label use, however, had consisted solely of truthful and non-misleading speech. The Second Circuit held that, to avoid infringing the First Amendment, the misbranding provisions of the Federal Food, Drug and Cosmetic Act (the “FDCA”) must be construed “as not prohibiting and criminalizing the truthful off-label promotion of FDA-approved prescription drugs” where the off-label use itself is lawful.

This case grows out of the decision in Caronia and involves the same misbranding provisions. Plaintiff Amarin Pharma, Inc. manufactures a triglyceride-lowering drug, Vascepa. FDA has approved Vascepa for one use, but doctors have widely, and lawfully, prescribed it for another. Amarin wishes to make truthful statements to doctors relating to Vascepa’s off-label use. The specific statements Amarin seeks to make are derived largely from an FDA-approved study of Vascepa’s off-label use, and from writings by FDA itself on that subject. Amarin therefore contends, and FDA largely but not wholly concedes, that the statements Amarin seeks to make are truthful and non-misleading. However, FDA, recognizing that Amarin’s purpose in making these statements would be to promote an unapproved use of Vascepa, has threatened to bring misbranding charges against Amarin (and, presumably, its employees) if it does so.

In this action, Amarin claims that FDA’s threat of a misbranding action is chilling it from engaging in constitutionally protected truthful speech. Amarin seeks preliminary relief to ensure its ability to engage in truthful and non-misleading speech free from the threat of a misbranding action. For the reasons that follow, the Court grants such relief.

Vacating the conviction, the Second Circuit held that a manufacturer’s speech promoting off-label use is constitutionally protected commercial speech, and that the First Amendment places limits on a misbranding prosecution to the extent it is based on the truthful promotion of FDA-approved drugs for off-label use. Applying the principle of constitutional avoidance, the Circuit held that the FDCA’s misbranding provisions could not be construed “to criminalize the simple promotion of a drug’s off-label use by pharmaceutical manufacturers and their representatives because such a construction—and a conviction obtained under [this] application of the FDCA—would run afoul of the First Amendment.” Thus, the Circuit held, “[t]he government cannot prosecute pharmaceutical manufacturers and their representatives under the FDCA for speech promoting the lawful, off-label use of an FDA-approved drug.”

Later, the Court reviews Caronia in detail because, unlike Amarin, and unlike much secondary commentary, FDA reads that decision narrowly, and as turning on the particular circumstances of Caronia’s trial. FDA thereby reads Caronia to preserve for the Government the ability to bring a misbranding action… This reading of Caronia is reflected in the position FDA has taken in this case.

In February 2014, FDA responded to Caronia by issuing updated draft guidance as to the dissemination of scientific or medical journal articles. FDA authorized manufacturers to distribute such articles relating to unapproved uses of drugs, under certain conditions. When a manufacturer distributes journal articles that include information on off-label uses of its drug, FDA stated, it will not use the fact of such distribution as evidence of the manufacturer’s intent that the drug be used for an unapproved use, provided that the manufacturer makes certain disclosures with the articles. But, FDA has stated, if a sales representative characterizes an article to suggest that a drug is safe or effective for an unapproved use, the agency may use such speech as evidence that the manufacturer intended to promote that use.

Separately, in June 2014, FDA agreed, in response to a citizen petition, to conduct a “comprehensive review [of its] regulatory regime governing communications about medical products,” with the intent to issue, within a year, new guidance regarding such issues. As of this decision, no such guidance has been issued. During this litigation, FDA told Amarin that “new guidance will be forthcoming,” but at the argument on July 7, 2015, FDA declined to state what the status or timetable is with respect to such guidance.

FDA argues that protecting truthful speech aimed at promoting off-label drug use is “a frontal assault...on the framework for new drug approval that Congress created in 1962,” because allowing a manufacturer to promote such use “has the potential to eviscerate [the] FDA drug approval regime.” The short answer is that the FDCA’s drug-approval framework predates modern First Amendment law respecting commercial speech. The Supreme Court held in Central Hudson (1980) that the First Amendment gives qualified protection to commercial speech and in Sorrell (2011) that pharmaceutical marketing qualifies as such speech. It follows that the provisions of a 1962 statute that implicates such speech, such as the FDCA’s misbranding provisions, today must be considered, and to the extent ambiguous construed, in light of contemporary First Amendment law, under which truthful and nonmisleading commercial speech is constitutionally protected, subject to the Central Hudson framework.

The Second Circuit’s decision in Caronia reflected a careful Central Hudson analysis.

And the Circuit, in Caronia, identified alternative, and less speech-restrictive means for FDA to achieve its objectives. FDA’s quarrel is, therefore, ultimately, with Caronia. Notably, however, despite a vigorous dissent to the effect that the panel majority had “call[ed] into question the very foundations of our century-old system of drug regulation,” (Livingston, J., dissenting), the Government neither sought rehearing nor petitioned for certiorari in Caronia. (Ed: a footnote here states that “This Court cannot override the Second Circuit’s definitive construction of the misbranding statute.”)

A final observation: Although FDA cannot require a manufacturer to choreograph its truthful promotional speech to conform to the agency’s specifications, there is practical wisdom to much of FDA’s guidance, including that a manufacturer vet and script in advance its statements about a drug’s off-label use. A manufacturer that leaves its sales force at liberty to converse unscripted with doctors about off-label use of an approved drug invites a misbranding action if false or misleading (e.g., one-sided or incomplete) representations result. Caronia leaves FDA free to act against such lapses. A manufacturer may also conclude that it is prudent to consult with FDA before promoting off-label use. Reasonable minds may differ over whether a given statement is misleading in context; and developments in science or medicine may make a once-benign statement misleading. Prior consultation with FDA may prove a helpful prophylactic, and may avert misbranding charges where FDA and the manufacturer would take different views of a statement. In the end, however, if the speech at issue is found truthful and non-misleading, under Caronia, it may not serve as the basis for a misbranding action.

The response:

At press time, FDA had not issued a response to the ruling, which could be appealed; between this case and the earlier Caronia case, the subject might be heading eventually for the Supreme Court. The Eastern District rulings are binding in New York, Vermont and Connecticut.

Amarin issued a press release stating that “Based on today’s ruling Amarin plans to begin promotional activities consistent with the opinion as soon as possible.”