By Ryan Abbott
Government regulation of off-label promotion by pharmaceutical companies is now an important First Amendment issue. The Food and Drug Administration (FDA) has historically restricted truthful and non-misleading speech by pharmaceutical companies under the Food, Drug and Cosmetic Act (FDCA). The FDCA prohibits introducing “misbranded” products into interstate commerce. The FDA has interpreted this to prohibit pharmaceutical companies recommending uses not already approved by the agency (these uses appear in a drug’s labeling). Drugs promoted for unapproved uses may also be considered “new” drugs which require FDA approval. Pharmaceutical companies can also face liability under the False Claims Act for off-label promotion.
United States v. Caronia was the first time the FDCA’s misbranding provisions were successfully challenged under the First Amendment. In 2012, the Second Circuit held that the FDA’s regulations failed the test for commercial speech announced in Central Hudson. Namely, the Court held that restricting truthful speech did not directly advance a government interest (rather, the regulations paternalistically prevented dissemination of truthful information), and the Court held that the FDA’s regulations were more extensive than necessary. The Court did not even analyze the regulations under the test announced in Sorrell v. IMS Health, decided by the Supreme Court in 2011, which held that heightened scrutiny was warranted where restrictions are content- and speaker-based. The FDA did not seek en banc review or writ of certiorari.
Almost immediately, the case was heralded as a landmark decision that would have a profound impact on drug regulation. However, that has yet to occur. Since the case was decided the FDA has already generated large settlements with companies like Amgen for violating agency regulations on off-label promotion. That may be because of uncertainty regarding Caronia’s reach, and because for large companies a relatively cheap settlement makes more sense than risking felony indictments and exclusion from government programs. For the agency’s part, it has tried to avoid fully vetting constitutional issues surrounding its regulations. The FDA stated after Caronia that the ruling would not alter its enforcement policy. Although, the agency has stated it is developing new guidances concerning off-label promotion.
The newest development in this story came last month in Amarin vs. United States. District Court Judge Paul Engelmayer issued a preliminary injunction against the FDA, holding that the pharmaceutical company Amarin has a First Amendment right to be free from a misbranding action based on truthful and non-misleading speech promoting off-label use. The case concerned Amarin’s drug Vascepa, which is an omega-3 fatty acid obtained from fish oil used to control triglycerides.
The FDA initially approved Vascepa to treat “very high” triglyceride levels, and entered into an agreement (a special protocol assessment) with Amarin to approve the drug for treatment of “persistently high” triglyceride levels pending the outcome of additional research. The FDA wanted Amarin to conduct two studies as part of the supplemental approval process: the “ANCHOR” study to show that Vascepa would reduce triglyceride levels, and the “REDUCE-IT” trial to show that Vascepa would reduce the risk of cardiovascular events (such as heart attacks). The ANCHOR study successfully established that Vascepa lowers triglyceride levels in individuals on statin therapy with persistently high triglyceride levels. After the results of the ANCHOR study were available, and pursuant to its agreement with the agency, Amarin moved to seek FDA approval for its second indication (in a supplemental new drug application [sNDA]) while the REDUCE-IT trial was underway. However, between the time of the agency’s agreement with Amarin and the sNDA, new research had demonstrated that other drugs known to be effective at reducing cholesterol levels, fenofibrates and niacin, did not reduce cardiovascular risk. For example, niacin has long been prescribed to raise HDL levels (“good cholesterol”) on the basis that low HDL is associated with an increased risk of cardiovascular events. Only recently has research shown that raising HDL with niacin does not appear to affect the underlying cardiovascular risk. The FDA’s advisory panel decided that this same phenomenon might well apply to Vascepa, and refused to approve the sNDA until the results of the REDUCE-IT trial were available. After all, the purpose of prescribing drugs to lower triglyceride levels is to reduce the risk of cardiovascular events.
After Amarin filed for its preliminary injunction, the FDA attempted to moot the district court case by approving most of the statements Amarin wanted to make (largely statements that Vascepa reduces triglyceride levels without claims to reductions in cardiovascular risk), approving some of the company’s proposed materials for distribution, and noting that new agency guidance on off-label promotion is forthcoming. However, Amarin argued it still had areas of disagreement with the agency over statements it could make, and that and the company continued to fear prosecution.
The FDA proposed that Caronia should apply narrowly, because it was fact-specific to the circumstances of that one case, and that Caronia does not restrict the agency from bringing a misbranding action where conduct consists solely of truthful and non-misleading speech. The District Court disagreed, holding that the FDA may not prohibit truthful, non-misleading speech about off-label use.
This is an important case because it supports industry claims that FDA regulation of off-label promotion falls under the same protection as commercial speech generally. For that matter, the case gives further momentum to claims that government regulations are overreaching in drug regulation as a whole, and in a number of other areas (e.g., securities regulations).
This is also likely to be a good test case for industry, because Vascepa is relatively safe and Amarin has strong support for the claims it wanted to make. In fact, as the active ingredient in Vascepa is just a fatty acid, the drug could also be sold without prescription as a dietary supplement. Interestingly, if marketed as a dietary supplement, Amarin would have been able to claim that, “Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary artery disease.” Vascepa is unlike the drug in Caronia, Xyrem, which has some very serious potential risks. In fact, the pharmaceutical representative being prosecuted in Caronia had even been recorded stating that Xyrem had been used successfully in children as young as 14, despite a black box warning that Xyrem’s safety and effectiveness had not been established in people under that age of 16.
While the ruling in Amarin is consistent with the evolution of protections afforded to commercial speech generally, it has some troubling public health implications. Richard Epstein and I have debated the case for and against the FDA’s regulations for off-label drug use here and written about it here.
If the FDA is no longer able to restrict truthful, non-misleading off-label promotion, the agency may need to adapt and rely more on informational regulation. Ian Ayres and I have proposed a tiered labeling system that would allow the agency to have more flexibility in this respect, and I have previously proposed that the agency should attempt to engage third parties historically removed from the drug approval process (e.g., insurers) to leverage additional resources. For readers interested in learning more about these issues, I spoke about Caronia, Amarin, and FDA regulation of off-label promotion last week on TWIHL (http://twihl.com).