On August 7, 2015, the U.S. District Court for the Southern District of New York invoked the First Amendment, granting Amarin Pharma, Inc. (Amarin) preliminary protection against federal criminal prosecution for misbranding and allowing Amarin to promote its drug, Vascepa, for off-label use through certain truthful, non-misleading speech.1 In so ruling, Judge Engelmayer applied the Second Circuit’s widely cited precedent in Caronia, which overturned a conviction under the same statutory provision.2 The extension of the much-scrutinized Caronia rule to a novel procedural posture raises important considerations for compliance officers and other staff in the pharmaceutical industry.

Factual Background

In 2012, Amarin obtained FDA approval for Vascepa to treat adults with “very high” triglycerides (defined as over 500 mg/dL of blood). Very high triglycerides are associated with increased risk of cardiovascular disease, so drugs that reduce triglycerides were expected to reduce the risk of cardiovascular events. Vascepa is a purified Omega-3 fatty acid product, derived from fish oil. Similar products are marketed directly to consumers by other companies under the FDA’s less-stringent dietary supplement regulations.

Amarin sought approval for Vascepa to treat adults with lower but still-high triglyceride levels (200 to 499 mg/dL) who are already being treated with statins for cholesterol (“persistently high” triglycerides). Vascepa passed an additional clinical trial in 2013, but the FDA withheld approval because studies using other, unrelated triglyceride-reducing drugs found that reduced triglycerides did not reduce the risk of cardiovascular events. FDA delayed approval pending the outcome of yet another study in which Amarin was already participating, designed to test directly Vascepa’s impact on risk of cardiovascular events. FDA warned Amarin not to promote Vascepa off-label, or risk prosecution.

Legal Background

The Food, Drug, and Cosmetic Act (FDCA) contains a criminal provision against selling (in interstate commerce) any drug that is “misbranded,”3 which the FDCA defines as lacking “adequate directions for use.”4 FDA regulation interprets as “adequate” directions that a layperson can use to take the drug safely “for the purposes for which it is intended.”5 The same regulations interpret “intended use” as the “objective intent” of the manufacturer, as demonstrated by oral and written statements and whether the drug is “offered and used for a purpose for which it is neither labeled nor advertised” with the manufacturer’s knowledge.6 The FDA takes the position that off-label promotion alters the “intended use” of the drug, rendering a drug misbranded.

The FDA has further taken the position that the truthfulness of the off-label promotion is irrelevant, since the prosecution is for the misbranded sales, not the promotional speech. In U.S. v. Caronia, however, the Second Circuit overturned the misbranding conviction of Alfred Caronia, a pharmaceutical representative, on First Amendment grounds.7 After looking closely at the trial record, the Second Circuit determined that in effect, Caronia had been convicted solely on the basis of his speech. Applying the Central Hudson test8for commercial free speech, the Second Circuit found that the misbranding offense would violate the First Amendment, because it fails to directly advance the government interest in safe and effective pharmaceutical use, and is not narrowly drawn to restrict speech by the minimal degree necessary to advance that interest.9 The Second Circuit interpreted the FDCA misbranding provision consistent with the First Amendment, to exempt truthful, non-misleading speech that promotes an off-label use.10

Amarin Sues for Injunctive or Declaratory Relief

On May 7, 2015, Amarin brought an “as-applied” First Amendment challenge to the FDA’s position concerning Amarin’s prospective off-label promotion of Vascepa. Citing Caronia, Amarin argued that its First Amendment right to free speech was chilled by the threat of criminal prosecution. While final decision on the merits is pending, Amarin requested either a preliminary injunction against prosecution or a declaration that its planned promotional speech – a textual statement appended to the complaint – would not violate the misbranding provision. In opposition, the FDA attempted to distinguish Caronia, arguing that the misbranding statute in the abstract punished conduct of selling misbranded drugs, and that the Caronia decision only rejected as unconstitutional the prosecution’s strategy against Alfred Caronia, which impermissibly focused on his promotional speech rather than the sales.11 While maintaining the authority to prosecute even truthful and non-misleading off-label promotions, the FDA also proposed modifications to Amarin’s proposed text, offering assurances against prosecution if those modifications were adopted.

The Amarin Decision

In granting Amarin the requested relief, the Court rejected the FDA’s attempt to limitCaronia to its facts and concluded that the impact of the Caronia ruling was broader in scope. The Court ruled that the misbranding statute itself, not the wording of the prosecution’s case, is what criminalizes speech. The Court’s interpretation prevents the government from evading constitutional protections on truthful and non-misleading promotional speech by simply emphasizing the non-speech aspects of the offense.

The Court was not persuaded by the FDA’s efforts to defend its regulatory framework. As the Court noted, the FDCA’s misbranding provision dates to 1962, and the Supreme Court’s entire commercial speech doctrine is of a newer vintage. “The short answer is that the FDCA’s drug-approval framework predates modern First Amendment law respecting commercial speech.”12

Having decided that Caronia applied to Amarin’s situation, the Court unsurprisingly found that Amarin was likely to succeed on the merits and granted the preliminary relief sought. The court declared first that Amarin may engage in truthful, non-misleading off-label promotion of Vascepa for treating “persistently high triglycerides” without fear of misbranding prosecution, and second that certain specific text was truthful and non-misleading.

The approved text, however, is not the one that Amarin proposed. The Court modified Amarin’s proposal extensively. In some places, the Court added phrases that the FDA had suggested. In other places, the Court took Amarin’s proposal unaltered. Most remarkably, in the crucial passage concerning the drug’s impact on risk of cardiovascular event, the Court constructed a paragraph borrowing phrases from both Amarin’s and the FDA’s proposals but also including entirely new material supplied by the Court.13 Until the Court enters a final judgment or modifies its preliminary relief, only this approved text is safe from prosecution for misbranding.

Putting Amarin in Context

The Amarin decision required Judge Engelmayer to undertake a weighty proactive task: crafting a non-misleading message that the manufacturer could use to promote the proposed off-label use. The court’s approach arguably demands a high degree of confidence in the conclusion that this approved text is truthful and not misleading – and that the promoted use is safe. It is difficult to imagine the court adopting the same approach if the drug’s safety were at all in dispute, because the risk of harm to patients might bear more heavily on the public interest prong of the preliminary injunction analysis.14 Even in this case where the FDA conceded that Vascepa was safe, the court warned that its provisional remedy was “based on the present record,” and contingent on “changed circumstances” in scientific understanding.15

First Amendment Implications

From one First Amendment perspective, Amarin offers a cure that is perhaps worse than the disease. Amarin sought judicial approval for a specific text before actually using the speech, arguably acquiescing to a form of “prior restraint.” As the Court noted, “the FDA cannot require a manufacturer to choreograph its truthful promotional speech to conform to the agency’s specifications,” yet this opinion requires that the speech be choreographed to the Court’s specifications.16 If pre-emptive suits like this one become de rigueur, seeking judicial pre-clearance to market off-label, this practice itself could be viewed as in effect ad hoc censorship, enforced by the peril of criminal prosecution.

Implications for the False Claims Act

Beyond criminal misbranding prosecutions, the government can pursue off-label promotions for civil damages and penalties as violations of the False Claims Act (FCA). The FCA gives the government (or a “relator”: a whistleblower suing on behalf of the government) a civil claim against a defendant who obtains payment from the government by presenting a false claim for payment, by causing such a false claim to be presented, or by using or causing the use of a false record in making a claim.17 With few exceptions, off-label uses are not covered by Medicare, Medicaid, or other government payers, so the government has sued manufacturers for promoting off-label use of prescription drugs; specifically, for causing doctors and pharmacists to present claims for payment for drugs not covered by the government program, thereby rendering the claims “false”.

A pair of recent FCA cases against off-label promoters rejected the First Amendment defense.18 In both cases, however, the relators survived a motion to dismiss simply by pleading that the promotional speech was in fact false or misleading.19 Under the first step of the Central Hudson analysis, the allegation that the speech was false or misleading puts the speech entirely outside First Amendment protection, at least at the pleadings stage, where the court must treat allegations as true.

In Parke-Davis, an earlier FCA case, the court rejected a defense that “impermissible off-label promotion does not necessarily include a false statement or fraudulent conduct.”20The court observed that the FCA violation arises from the submission of a claim to the government and not solely from the promotional speech itself.21 This distinction of the speech from the allegedly improper conduct is noteworthy, because Amarin and Caronialooked past the sales that nominally constitute the FDCA “misbranding” violation to give constitutional protection to the promotional speech.22 The Parke-Davis court suggested in dicta, without mentioning the First Amendment, that a “much closer question would be presented if the allegations involved only the unlawful—yet truthful—promotion of off-label uses . . . without any fraudulent representations by the manufacturer.”23 This dictum suggests that the logic of Caronia and the Free Speech defense might extend to FCA cases or to cases where the government has asserted FCA and FDCA misbranding claims in tandem.

The Narrow Path Forward

To many observers, Amarin opens a straight but ultimately narrow pathway for promoting off-label use. Only entirely truthful and non-misleading statements can be protected from prosecution. Although the Court’s declaration protects all truthful and non-misleading off-label promotion of Vascepa, only the approved text, as modified by the court, has been declared truthful and non-misleading. Any statement beyond the approved “textual statements” is potentially subject to criminal prosecution. If the pre-clearance of text through declaratory relief becomes standard procedure, compliance personnel will have to continue to vigilantly oversee and monitor the statements of drug sales representatives and others to ensure that their statements adhere to the script; any oral or written statement augmenting or otherwise deviating from the approved text might only increase the risk of prosecution. Underscoring this warning to the industry, the Court cautions that: “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.”24