Off-Label Promotion and Product Liability

Vascepa is approved as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia. These patients would also be treated with statins. The product is composed of pure eicosapentaenoic acid (EPA), an omega-3 fatty acid. Amarin wanted to promote the product for a wider group of patients than approved, e.g., patients treated with statins with high but not very high triglyceride levels. This is an “off-label” use. The company sought to make health care professionals aware of clinical study results concerning the efficacy of the drug in certain patients, which the FDA had questioned, but with qualified statements, such as: “Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease.”

Amarin was prepared to provide additional information, such as a selection of peer-reviewed scientific articles on the potential effect of EPA on the reduction of the risk of coronary heart disease. It was also willing to include disclosures and disclaimers to doctors, such as that the drug had not been approved for certain uses, among other qualifiers.

According to Amarin, the FDA intimated that the dissemination of such information would be off-label (because the drug was only approved to treat very high triglyceride levels) and would misbrand the drug product, potentially resulting in enforcement action. The FDA (after convening an advisory panel) did not approve the drug product for the additional indication. Thus, Amarin took the preemptive step of seeking a preliminary injunction.

Amarin claimed that the statements were truthful and non-misleading speech, and thus should be protected by the First Amendment, citing a previous U.S. Court of Appeals for the Second Circuit decision (the 2012 United States v. Caronia case). In a June 5 letter, perhaps intended to make the case moot, the FDA noted during the court proceeding that it would not consider the dissemination to be evidence of misbranding if the company met certain conditions. The FDA indicated it did not have concerns with much of the information the company proposed to communicate. Amarin was willing to agree to some, but not all, of the FDA-requested disclosures.

Highlights of the Amarin Decision

The district court said that the FDA June 5 letter did not make the case moot, because Amarin had not agreed to all of the conditions and, thus, the letter continued to expose the company to potential FDA enforcement action. The court noted, “Because Amarin faces a non-extinguished threat of a misbranding prosecution for speech it proposes to undertake as to Vascepa, there remains a live case or controversy.”

The court, citing Caronia, said that the government cannot prosecute companies and their representatives under the Federal Food, Drug, and Cosmetic Act for truthful, non-misleading discussion, even if that discussion is about off-label uses: “The Court'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.” According to the court, unlike the FDA's contention, the Caronia decision was not limited to the facts of that specific case.

The court also held that Amarin may engage in truthful and non-misleading speech promoting off-label use of Vascepa, and that such speech may not form the basis of a prosecution for misbranding.

Further:

• The FDA failed to persuade the court that its regulation of off-label promotion should be exempt from First Amendment scrutiny.
• The court recognized that the FDA has a substantial interest in protecting consumers from potentially ineffective drugs, and encouraging companies to utilize the drug approval process to include new uses in the product label. However, the court said that the FDA could have used less restrictive approaches to accomplish its goals. In this case, Amarin's proposed statements and disclaimers, with possible tweaks to explain the status and limitations of the research, might have made the statement not misleading. As a result, the court enjoined the FDA from considering the off-label communications to be evidence of misbranding.
• The district court rejected the FDA's position that, for prescription drugs, any such communications should be supported by “significant scientific agreement.”
• The decision made clear that false or misleading statements are not protected speech. In addition, the government could prosecute non-communicative, unlawful promotional activities (e.g., rewarding doctors for prescribing a product for off-label uses). The court said that Caronia protects off-label promotion “where it wholly consists of truthful and non-misleading speech.”

Because the agency can take enforcement action against misleading statements (e.g., one-sided or incomplete), companies should consider voluntary restrictions or appropriate qualifiers.

The court offered a “final observation”:

Although the FDA cannot require a manufacturer to choreograph its truthful promotional speech to conform to the agency's specifications, there is practical wisdom to much of the FDA's guidance, including that a manufacturer vet and script in advance its statements about a drug's off-label use. A manufacturer that leaves its sales force at liberty to converse unscripted with doctors and off-label use of an approved drug invites a misbranding action if false or misleading (e.g., one-sided or incomplete) representations result. Caronia leaves the FDA free to act against such lapses. A manufacturer may also conclude that it is prudent to consult with the FDA before promoting off-label use. Reasonable minds may differ over whether a given statement is misleading in context; and developments in science or medicine may make a once-benign statement misleading. Prior consultation with the FDA may prove a helpful prophylactic, and may avert misbranding charges where the FDA and the manufacturer would take different views of a statement.

Another Potential Loss?

Fresh off its loss in the Amarin court decision concerning off-label promotion, the agency again finds itself the defendant in a similar lawsuit concerning whether it can silence a company's truthful and non-misleading communications about off-label uses. This time, it is Pacira Pharmaceuticals, Inc. challenging the FDA's authority. Perhaps not surprisingly, Pacira brought its challenge in the U.S. District Court for the Southern District of New York, the same forum where the FDA lost the Amarin case, hoping for a similar result.

Here are some background facts:

• Pacira has approval to market its prescription drug, Exparel' (bupivacaine liposome injectable suspension), for single-dose administration into a surgical site to produce post-surgical analgesia.
• In September 2014, the FDA issued a Warning Letter to Pacira, contending that the company promoted its product for pain relief in surgeries not listed on the label ' i.e. , unapproved and off-label uses ' and, thus, misbranded the product. The FDA has since removed the Warning Letter from its website.
• Pacira cites its First Amendment free speech rights to promote its product in a truthful and non-misleading manner (Amarin made similar arguments). The company maintains that the information presented is, indeed, consistent with the approved, on-label indication.
• The company also claims that, under the Due Process Clause of the Fifth Amendment, the FDA must establish rules that expressly notify it of the prohibitions for a particular drug. Pacira asserts that it has a broad, approved indication and, after three years post-approval, the FDA attempted to limit promotion of the product beyond two specific indications ' surgeries for bunions and hemorrhoids. Pacira contends that the agency's regulations as applied to the company are vague. In addition, it alleges that the FDA failed to provide fair notice about what Pacira could lawfully promote and what it considered to be prohibited, thus representing a retroactive, ex-post-facto penalty.
• Pacira alleges that the FDA violated the Administrative Procedure Act when it attempted to narrow what the company believes was a broad indication, and where it had supporting clinical data for the claims promoted, without following regulatory rules to modify the drug's label.
• In the Complaint, Pacira claims it sought to meet with the FDA to better understand the agency's interpretation, but to no avail. The FDA ultimately issued a close-out letter to Pacira, indicating that it considered the Warning Letter issue to be resolved.
• Pacira's Complaint seeks declaratory relief and a preliminary and/or permanent injunction to prevent the FDA from taking enforcement action that could violate the company's legal rights.

The FDA has not said much, if anything, post- Amarin, except it is public knowledge that Amarin and the FDA are discussing settlement options. We believe the agency is struggling to find a balance whereby it can maintain its jurisdictional authority to take enforcement action against what it perceives to be unlawful promotion, while possibly conceding some authority when the off-label information is truthful and not misleading.

Conclusion

In light of recent developments, many companies are re-evaluating potential off-label promotional dissemination approaches. The courts have not given carte-blanche power to manufacturers to promote off-label. The information must still be truthful and not misleading, which might require prominent disclosures, disqualifiers, or limitations in promotional pieces, among other things. It bears repeating that the Federal Food, Drug, and Cosmetic Act provides that, in determining whether a promotion is misleading, it must be taken into account (among other things) not only representations made or suggested, but also “the extent to which the labeling or advertising fails to reveal facts material in the light of such representations or material with respect to consequences which may result from the use of the article to which the labeling or advertising relates under the conditions of use prescribed in the labeling, or advertising thereof or under such conditions of use as are customary or usual.”

A company's Promotional Review Committee must remain the gatekeeper. Furthermore, non-FDA-related issues, such as product liability exposure, must be considered and not discounted or dismissed. A jury might not be as forgiving if little Johnny or Grandma is injured as a result of a product's off-label use, which could be traced back to a manufacturer's promotional efforts.

It is important that the cases settled and pending are fact-specific, and that each is focused in one jurisdiction (Connecticut, New York or Vermont). While it might be possible to create product information, even if off-label, that will pass legal scrutiny, it is important to remember that the “truthful and not misleading” standard seems to be the norm, however that might be interpreted. So, a company should recognize that this broad standard might be beneficial in an FDA sense (allowing more freedom to distribute) but, potentially, problematic to a company named as a defendant in a product liability lawsuit (where a judge and jury might impose a strict and narrow interpretation favoring an injured party).

In sum, distribution of an off-label piece, without internal review, is not advisable, notwithstanding the potential FDA opportunities, when one factors in possible product liability exposure.

Alan G. Minsk,' a member of this newsletter's Board of Editors, is a partner and practice leader of Arnall, Golden, Gregory LLP's Food and Drug Practice. He focuses his practice on advising pharmaceutical, biologic, medical device, cosmetic and food companies, on all legal and regulatory matters relating to the FDA and DEA.