The Compliance Implications of Amarin’s Off-Label Marketing Win in the Second Circuit

By Darren Jones

By: Darren Jones, Dakota Gallivan, John Thorpe

In early August, the FDA’s power to regulate pharmaceutical off-label marketing took another hit.  Amarin, an Irish bio-pharmaceutical company, won a First Amendment case against the FDA relating to the off-label promotion of their cardiovascular health drug, Vascepa. The FDA previously approved Vascepa for the treatment of individuals with very high levels of triglyceride in their blood. Subsequently, Amarin discovered that physicians were also prescribing Vascepa for patients with lower, but “persistently high”, triglyceride levels. To obtain FDA approval for Vascepa’s use in this expanded population of patients, Amarin conducted a second FDA-approved, phase 3 clinical trial, named the ANCHOR trial. The ANCHOR trial showed that Vascepa was effective at reducing triglyceride blood levels in the expanded population.

As reported by Thomas Sullivan at Policy and Medicine, Amarin hoped to encourage Vascepa’s use in the expanded population through the pro-active dissemination of the ANCHOR  study in combination with the presentation of related evidence and the assertion that “supportive but not conclusive research shows… EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease.”

Unfortunately, this plan ran afoul of the FDA. After Amarin submitted its supplemental new drug application for the use of Vascepa in the expanded population set, a FDA special Advisory Committee assigned to review the ANCHOR study found that a number of high-profile cardiovascular trials called into question whether the reduction of triglyceride levels in individuals with persistently high levels actually reduced overall cardiovascular risk. The Committee voted 9-2 to withhold approval for Vascepa’s second proposed indication. The FDA subsequently sent Amarin a Complete Response Letter that included a warning for Amarin: any attempt to market Vascepa for its proposed second indication could constitute misbranding under the Federal Food, Drug, and Cosmetic Act (FDCA).

This letter prompted Amarin’s successful lawsuit against the FDA, which aimed at lifting the FDA’s threat to bring misbranding charges. The case was heard in the Manhattan Federal District Court of Judge Paul Engelmayer.

Judge Engelmayer granted Amarin injunctive relief from the FDA’s threat of civil charges. His decision built on precedent created by the U.S. v. Coronia case from the Second Circuit Court of Appeals. Coronia focused on off-label statements made by a pharmaceutical sales rep from Orphan Medical, a specialty pharmaceutical company. The Court ruled that as long as the sales rep’s off-label statements were true, he could not be prosecuted for talking about an unapproved use. In the Amarin case, Judge Engelmayer transferred this logic from an individual sales rep to a pharmaceutical company. His opinion holds that as long as Amarin’s off-label statements about Vascepa are true and not misleading, they are protected from the specter of FDA prosecution. Judge Engelmayer stated that the FDA “may not bring an action based on truthful promotional speech alone, consistent with the First Amendment.”

The FDCA prohibits pharmaceutical companies from selling “misbranded” drugs. The FDA requires that pharmaceutical companies limit statements relating to the promotion of their drugs to each drugs’ “intended use” (or the use for which the drug was approved). To promote a drug for a non-FDA approved use, the FDA requires additional clinical trials. Coronia, and now the Amarin case, challenge this regulatory limitation on speech and may be bellwethers for a coming revision of the FDA’s off-label regulatory and enforcement policy.

The FDA has yet to indicate whether it will appeal the Amarin case. Without an appeal, and considering the favorable precedent, drug companies could choose to initiate similar law suits in the Second Circuit on a drug by drug basis should the FDA refuse to modify its off-label enforcement policies.  While the FDA has indicated a willingness to update its guidelines, it has not done so to date. It has also yet to hold a meeting it said it would this summer focusing on the issue of free speech and off-label marketing.  However, after the Amarin case, and now that pharmaceutical companies have a viable legal option to challenge the FDA, the FDA’s slow pace regarding the development of new regulatory guidelines will likely accelerate.

In the meantime, restrictions on the proactive dissemination of off-label medical information still have teeth. For pharmaceutical manufacturers, Judge Engelmayer stressed that the First Amendment’s free speech protections do not cover false or misleading commercial speech. This means that without robust compliance oversight, pharmaceutical companies risk losing First Amendment protection if their sales force goes too far off scrip t.

Now, more than ever, pharmaceutical companies will need to place an increased emphasis on certifying the veracity of the clinical studies they use to educate or inform health care providers. They also must verify the outputs of their studies. To do this, pharmaceutical companies will need to ensure that their scientific and medical review processes follow recognized best practices and are subject to clear and consistent control methodologies. But the buck doesn’t stop there.

Considerable risk also remains in the translational processes within pharmaceuticals that boil down scientific findings into commercial messages for sales and marketing teams to use in the field. It is important to remember that ensuring the veracity of the scientific study used to support off-label messaging does not ensure that the messaging itself is wholly supported by the study and not misleading, especially when it is delivered by individual sales reps in the field.

In other words, Coronia and the Amarin case should not be viewed as an invitation to immediately open the floodgates to the pro-active dissemination of true off-label information. Rather, pharmaceutical companies should invest in the development of mature processes surrounding and bridging the entire medical information and marketing processes: from the initial validation and review of a clinical study to the translation of the study into appropriate and accurate messaging for sales and marketing teams to, finally, the deployment of the information to health care providers.

Lastly, it is important to remember that Coronia and the Amarin case only act as legal precedent within the Second Circuit. Other federal circuits could rule differently with similar facts. As of today, it is unclear whether the FDA would want to risk creating a split between the circuits through further litigation. A split could presage a visit to the Supreme Court, and, given the Court’s recent rulings in favor of corporate free speech, the FDA would likely face an uphill climb to convince a majority of the justices to rule in their favor.

Sources and Supplemental Reading:
Amarin Pharma, Inc. v. FDA
U.S. v. Caronia
Amarin Wins Preliminary Injunction Against FDA to Promote Truthful Off-Label Promotion, Thomas Sullivan at Policy and Medicine
A Victory for Amarin Further Erodes FDA Regulation of Off-label Promotion, David Gibbons at FDA Law Blog
Breaking News – Amarin Hits First Amendment Home Run Off FDA, Drug and Device Law Blog
Amarin Case Could Unleash a Flood of Off-Label Promos, Tracy Staton at Fierce PharmaMarketing