Amarin is an important US district court opinion affirming the importance of the Second Circuit’s Caronia decision and finding that pharmaceutical and medical device companies have a constitutionally protected right to provide truthful and non-misleading information regarding off-label uses of their products.
The US District Court for the Southern District of New York ruled against the Food and Drug Administration (FDA) and upheld the rights of a pharmaceutical manufacturer to make truthful and non-misleading statements regarding off-label uses of its FDA-approved drug, including the right to affirmatively make those statements through sales representatives to healthcare providers, following the US Court of Appeals for the Second Circuit’s landmark opinion in United States v. Caronia.
The court held that plaintiff drug manufacturer Amarin Pharma Inc. (Amarin) may make truthful and non-misleading statements to doctors regarding off-label uses of its FDA-approved drug Vascepa and that such speech may not form the basis of a prosecution for misbranding. Relying heavily on Caronia, US District Judge Paul A. Engelmayer granted Amarin’s motion for preliminary relief against the FDA, stating that, without relief, Amarin’s “First Amendment rights [would] be chilled by the threat of a misbranding action.”
COURT REJECTS FDA’S READING OF CARONIA
In Amarin, FDA argued strongly for its interpretation of Caronia, asserting that FDA is able to bring a misbranding action against a manufacturer or its representative where the conduct at issue consists solely of truthful and non-misleading speech promoting an off-label use of an approved drug. The court squarely rejected that interpretation: “The [c]ourt’s considered and firm view is that, under Caronia¸ the FDA may not bring such an action based on truthful promotional speech alone, consistent with the First Amendment.” FDA also argued that the Caronia decision was limited to the facts of that particular case, but the court similarly rejected that argument. This important decision further solidifies the free speech protections afforded to drug manufacturers that wish to provide truthful and non-misleading information to doctors about their drugs for off-label uses, particularly in light of contemporary First Amendment law, which has developed and is set forth in Central Hudson Gas and Electric Corp. v. Public Service Communication of New York, 447 U.S. 557 (1980).
AMARIN CITES STUDIES AND THE FDA’S COMPLETE RESPONSE LETTER TO SUPPORT ITS OFF-LABEL USE
Amarin manufactures Vascepa, a pure eicosapentaenoic omega-3 fatty-acid drug currently approved by FDA to reduce triglyceride levels in adult patients with very high triglycerides. Physicians also widely, and lawfully, prescribe Vascepa for patients with “persistently” high triglycerides. To support a requested label change, Amarin conducted a study, called ANCHOR, to evaluate Vascepa for patients with persistently high triglyceride levels who were already on statin therapy. The ANCHOR study showed that Vascepa produced a statistically significant decrease in triglyceride levels in persons with persistently high triglycerides. Amarin sought a new indication based on the ANCHOR study results, but in an April 27, 2015 Complete Response Letter, FDA refused approval for the new indication and rejected Amarin’s request to incorporate ANCHOR data into Vascepa’s labeling. FDA’s letter stated that Vascepa “may be considered to be misbranded under the [Federal Food, Drug, and Cosmetic Act (FDCA)] if it is marketed with this change before approval of this supplemental application.”
Amarin sought relief from potential prosecution for use of general and specific statements about the results of the ANCHOR study. After its complaint, Janet Woodcock, director of FDA’s Center for Drug and Evaluation and Research, issued a letter setting out FDA’s position on Amarin’s proposed statements. In that letter, FDA made important concessions about certain communications, noting that many already fell within existing FDA guidance for distribution of reprints. Although the FDA letter sought to moot the dispute altogether, Amarin rejected some of FDA’s proposed additional restrictions and conditions. By issuing the letter to the court and noting approaches to make the communications non-misleading (e.g., use of disclaimers), FDA provided industry with a roadmap to construct non-misleading speech. Nevertheless, the court deemed the case ripe because Amarin faced a “non-extinguished threat of a misbranding prosecution.”
COURT TO FDA: YOU’RE CHILLING AMARIN’S RIGHT TO DISCUSS THE TRUTHFUL SCIENCE ON ITS PRODUCT
In opposing Amarin’s request for an injunction, FDA raised three primary arguments, all of which were rejected. First, it argued that Amarin’s suit was a “frontal assault . . . on the framework for new drug approval that Congress created in 1962.” The court dismissed this concern, holding that the FDCA statute from 1962 must be considered in light of more recent First Amendment law that protects truthful and non-misleading commercial speech. Second, the court argued that only certain truthful and not-misleading statements could be protected. The court rejected this argument on the basis that the Caronia holding applied across the board to all truthful and not-misleading speech and that Caronia specifically reached proactive oral statements by a drug manufacturer’s sales representatives. Third, FDA argued that it could use truthful and non-misleading statements to establish intent to promote off-label uses. The court declined to consider that argument as “beside the point,” writing “Amarin’s lawsuit is directed instead to the act requirement—the situation in which a misbranding action takes aim at truthful, non-misleading speech. And Caronia construed the misbranding statute, categorically, not to reach a manufacturer or its representative under those circumstances.”
To be clear, neither Caronia nor Amarin foreclose the potential for prosecutions related to off-label marketing. The court explicitly addressed two important limitations on Caronia that remain unchanged. First, that “the First Amendment does not protect false or misleading commercial speech.” And, second, that “the First Amendment protects expression, not conduct.” On this second limitation, the court further wrote “[a] manufacturer that engages in non-communicative activities to promote off-label use cannot use the First Amendment as a shield. Caronia holds protected, and outside the reach of the FDCA’s misbranding provisions, off-label promotion only where it wholly consists of truthful and non-misleading speech.”
Amarin marks an important development post-Caronia and serves as an important affirmation of the right to truthful and non-misleading statements made to promote pharmaceuticals. This decision, if upheld, will cause pharmaceutical and medical device companies to reconsider the scope of promotion distributed for their products. Because the FDA still can take enforcement action against a company for off-label promotion that is inaccurate or misleading, if a company decides to rely on the decision before any potential appeal is resolved, it is critical for the company to ensure that the off-label communications are truthful and non-misleading.
Examples of Protected Activities
- Sales representatives and others (medical science liaisons, nurse educators, and other field personnel) can initiate discussions and “promote” off-label uses of drugs through truthful and non-misleading statements, which contain adequate disclaimers.
- Speech covered by this right can be either oral or written and in the form of articles, reprints, guidelines, or other truthful, scientifically accurate, and non-misleading statements.
- Reprints and other information do not necessarily need to be on a specific product at issue, because the court agreed that articles on the effect of eicosapentaenoic and docosahexaenoic omega-3 fatty acids, the active ingredients in Vascepa, could be distributed.
- Companies can summarize articles or use other formats as long as the summary is accurate and factual and not misleading (including through material omission).
- Truthful and non-misleading speech is protected, and the venue is not a decisive factor—however, the government may consider the circumstances surrounding a communication to determine if there is noncommunicative conduct that should be evaluated in considering potential misbranding arguments.
- Importantly, if the speech is considered promotion and is written, it will need to be submitted to FDA in a signed form 2253 consistent with 21 CFR 314.81(b)(3)(i).
- As the court noted, companies can seek FDA views on whether the off-label use speech is misleading through FDA’s current prelaunch and advisory comments processes; obviously, that will be a strategic decision for each company and may require companies to create decision tree standard operating procedures for when FDA review is requested.
Examples of Activities That Are Outside the Scope of Amarin
- False or misleading speech that can arise from inaccuracies, inappropriate bias, omissions of material information, dated information, or absence of disclaimers.
- Knowing and willful noncommunicative activities intended to improperly induce off-label use, such as activities ordinarily subject to the Medicare Anti-Kickback Statute.