United States: Amarin And FDA Agree To Landmark Settlement On Off-Label Promotion

On March 8, 2016, Amarin Pharma, Inc. reached a noteworthy settlement in its lawsuit against the U.S. Food and Drug Administration ("FDA") to protect its First Amendment right to promote the drug Vascepa for nonapproved, off-label uses. Amarin Pharma, Inc. v. FDA (S.D.N.Y. No. 15-cv-3588) (Engelmayer, J.). Earlier, Judge Engelmayer had granted a preliminary injunction blocking the FDA from pursuing a misbranding suit against Amarin for the company's off-label promotion. This recent settlement now brings the litigation to a close—signaling a potential softening in the FDA's stance on off-label promotion and, potentially, a more active role for the courts in determining when off-label promotion is permitted.

Case Background

The FDA approved Vascepa (icosapent ethyl) capsules to reduce triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. The original approval was based on a single phase 3 clinical trial of patients with "very high" triglycerides, which was conducted under a Special Protocol Assessment ("SPA") agreement with the FDA. An SPA indicates FDA agreement that a study will support the approval of a drug product's application if the study is conducted in accordance with the protocol and achieves the agreed-upon objectives. Subsequently, Amarin designed and entered an SPA with the FDA to evaluate the effect of Vascepa on triglyceride levels among statin-treated patients with "persistently high" triglycerides (>200 and <500 mg/dL) in a single phase 3 clinical investigation. Amarin also agreed to conduct a cardiovascular outcomes trial on these patients.

Amarin submitted a supplemental application in February 2013, requesting FDA approval for use of Vascepa in patients with persistently high triglycerides. The application detailed the data from the studies conducted pursuant to the SPA, which met the primary endpoint, a significant secondary endpoint, and the obligations associated with the cardiovascular outcomes study. Often, SPA compliance leads to approval. Not here, however. Instead, the FDA seemed to have second thoughts about the underlying science. Specifically, the FDA did not feel the data sufficiently supported the drug's use in patients with persistently high triglycerides and rescinded the SPA, an extremely rare occurrence. In a Complete Response Letter, the agency stated that it needed additional data before it could approve the second use. It also warned Amarin that any effort to promote Vascepa for the unapproved use could constitute misbranding under the Food, Drug & Cosmetic Act.

Ten days after receiving the letter, Amarin sued the FDA. The company claimed that the First Amendment protected its right to tell doctors and other health care professionals about the data suggesting that Vascepa could be used to treat "persistently high" triglycerides. According to Amarin's complaint, the FDA's threat of a misbranding prosecution for the truthful, nonmisleading promotion of an off-label use had an impermissible chilling effect on the company's constitutionally protected speech. Amarin sought a preliminary injunction barring the FDA from pursuing such a claim.

The August 7, 2015 Ruling

In granting Amarin's motion for a preliminary injunction, Judge Engelmayer relied heavily on the U.S. Court of Appeals for the Second Circuit's ruling in United States v. Caronia. Caronia held that the First Amendment prohibited the government from criminally prosecuting an individual for the truthful, nonmisleading promotion of a drug for off-label uses. In Amarin's case, the government essentially sought to limit Caronia to its particular facts and procedural posture, focusing on improper instructions and other statements made to the jury there. But Judge Engelmayer read Caronia to more broadly disallow any and all misbranding prosecutions for truthful, nonmisleading off-label promotion, because, in the Second Circuit's view, the government lacked sufficient justification to prohibit such speech.

Judge Engelmayer then held that certain communications proposed by Amarin were indeed truthful and nonmisleading. For certain other communications, Judge Engelmayer provided revisions that would make the statements truthful and nonmisleading. But, he emphasized that his rulings were based only on the information before him: "A statement that is fair and balanced today may become incomplete or otherwise misleading in the future as new studies are done and new data is acquired."

Because Judge Engelmayer's ruling was only a decision on a motion for a preliminary injunction, it did not provide any final relief. In addition, the FDA was free to appeal to the Second Circuit. Shortly after the ruling was issued, however, Amarin and the FDA announced that they were discussing a potential settlement.

The March 8, 2016 Settlement

In the settlement—a stipulation that Judge Engelmayer has already approved—the government "agree[d] to be bound by the Court's conclusion that Amarin may engage in truthful and non-misleading speech promoting the off-label use of Vascepa ... and, under Caronia, such speech may not form the basis of a prosecution for misbranding." In addition, the government agreed that Amarin's proposed statements, as modified by the court's August 2015 ruling, were "truthful and non-misleading."

The settlement also sets forth a new procedure through which Amarin can seek preapproval of off-label promotional communications. In addition to the generally available FDA review procedures for promotional materials, Amarin may propose up to two communications per year about the off-label use of Vascepa to the FDA—allowing Amarin to reduce the risk that a particular communication would be seen as misleading. (Presumably, this process would be used for communications that do more than, for example, merely distribute a study published in a credible, peer-reviewed journal, where there would seem to be less potential for a dispute over the communication's propriety.) After receiving the proposed communication, the FDA has 60 days to respond with any concerns. If the parties cannot settle any disagreements on their own, either party may ask Judge Engelmayer to resolve the dispute. This special process will be in place through 2020.

Significance of the Settlement

The Amarin settlement is notable for at least two reasons. First, it may signal that the FDA is softening its approach to off-label promotion. In the settlement, the agency waived its right to appeal Judge Engelmayer's decision. Moreover, the settlement green-lighted not only the speech specifically approved by Judge Engelmayer but also all future "truthful and non-misleading" off-label promotion of Vascepa. This effectively endorses a broad reading of Caronia, which is something the government may have difficulty walking back.

That said, companies should proceed with caution: The settlement is, of course, an agreement with Amarin alone. And the settlement explicitly states that truthful and nonmisleading speech cannot be the basis for a misbranding prosecution "under Caronia," perhaps to preserve the government's ability to argue for a different result outside the Second Circuit (i.e., where Caronia is not binding). Still, this settlement should be useful to parties engaged in truthful and nonmisleading off-label promotion nationwide.

Second, the settlement provides that a court should resolve any disputes between Amarin and the FDA over whether proposed communications about off-label uses are permissible. This sort of ongoing judicial oversight is unusual. It remains to be seen whether other judges will have a similar appetite for such a role.

The settlement (like the First Amendment) protects only truthful and nonmisleading communications. As the settlement states, "Amarin bears the responsibility, going forward, of assuring that its communications to doctors regarding off-label use of Vascepa remain truthful and non-misleading." Given that new studies and new data can conceivably make older, once-proper communications misleading, Amarin's duty to make sure its communications "remain truthful and non-misleading" should not be taken lightly.

Nonetheless, by any measure, the Amarin settlement is a major milestone for the First Amendment's protection of truthful and nonmisleading off-label promotion.

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Laura F. Laemmle-Weidenfeld
Colleen Heisey
Stephen G. Sozio
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