Earlier this month, the FDA reached a settlement with Amarin Pharma that expressly allows Amarin to promote its prescription fish-oil product, Vascepa, for unapproved uses. The , which includes use of a voluntary procedure for Amarin to pre-clear future promotional claims with the FDA, marks a turning point for the regulation of drug advertising and promotional activity in the U.S. by easing FDA's long held and staunchly defended restrictions on drug marketing.
The Amarin case, it should be noted, involved a unique set of facts that strongly supported Amarin's statements that the federal district court considered not misleading about Vascepa's unapproved uses.
For one, Amarin successfully completed a phase III clinical study demonstrating the effectiveness of Vascepa in lowering triglyceride levels in patients with persistently high triglycerides who were still on statin therapy. This study was conducted under a Special Protocol Agreement (SPA) entered with the FDA, under which the agency agreed to approve Vascepa for this indication if Amarin satisfied certain requirements. These requirements included meeting prespecified endpoints and enrolling at least 50% of patients for an outcomes trial to examine whether Vascepa would also reduce cardiovascular event in patients with persistently high triglycerides. Amarin met the pre-specified endpoints for the SPA trial and met the enrollment criteria for the outcomes trial.
FDA's About-Face
Thus, Amarin believed it had satisfied FDA's SPA requirements for approval of Vascepa for the second indication. However, with the affirmation of an advisory committee, FDA concluded the endpoints previously agreed upon did not establish that the lower triglyceride levels in patients with persistently high triglycerides led to fewer cardiovascular events. FDA then rescinded its SPA, a rare occurrence, and refused to approve Amarin's supplemental application for the expanded indication; instead, FDA asked for more data.
In addition, the FDA warned Amarin that any promotion of Vascepa for the treatment of persistently high triglycerides would render Vascepa misbranded. Based on this "threat," Amarin brought its suit against FDA. It was with this background that the court came to examine whether Amarin's proposed statements and disclosures to accompany promotion of Vascepa for this unapproved use would be false or misleading. After a detailed review, the court agreed that most of Amarin's proposed statements would ensure that its promotion of Vascepa would not be false or misleading.
In the settlement agreement, Amarin agreed to be bound by its proposed statements and disclosures as reviewed by the Court. Specifically, Amarin agreed to disseminate the results of the studies supporting the unapproved uses with the following statement:
"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 also agreed to distribute reprints of relevant peer-reviewed scientific publications. More importantly, Amarin agreed to make relevant "contemporaneous disclosures" to physicians, including:
- "FDA has not approved Vascepa to reduce the risk of coronary heart disease."
- "FDA has not approved Vascepa for the treatment of statin-treated patients with mixed dyslipidemia and high triglyceride levels."
- "The effect of Vascepa on the risk of cardiovascular mortality and morbidity has not been determined."
- "A cardiovascular outcomes study of Vascepa designed to evaluate the efficacy of Vascepa in reducing cardiovascular mortality and morbidity in a high risk patient population on statin therapy is currently underway."
- "Vascepa may not be eligible for reimbursement under government healthcare programs, such as Medicare or Medicaid, to reduce the risk of coronary heart disease or for treatment of statin-treated patients with mixed dyslipidemia and high (>200 mg/dL and <500 mg/dL) triglyceride levels. We encourage you to check that for yourself."
Impact on Off-Label Prosecutions
The Amarin settlement agreement also signals the acceptance by federal authorities that an earlier decision in United States v. Caronia establishes that off-label promotion through truthful and nonmisleading verbal statements, standing alone, cannot form the basis of criminal charges for misbranding.
With the Amarin settlement, regulation of off-label promotion takes the next step: Not only are Amarin sales representatives free from prosecution for truthful and nonmisleading off-label promotion of Vascepa, the FDA has agreed to review such off-label communications up to twice a year upon Amarin's voluntary submission to confirm as much.
After the Amarin court sent FDA and the company into the settlement negotiations, two less-publicized cases have been brought and resolved in which the companies' off-label promotion has been permitted.
First, Pacira Pharmaceuticals settled its by reaching an agreement on a labeling change that effectively affirmed Pacira's promotion of its analgesic drug, Exparel, for use in various surgeries rather than in only the two specific surgeries studied in the clinical trials supporting the drug's approval. Pacira, like Amarin, had unique and compelling facts supporting Pacira's expanded promotion. Specifically, FDA had approved Exparel as a surgical analgesic without specifying the types of surgeries in the indications for use. Instead, the directions for use of the drug covered only the two types of surgeries. Upon being sued, with the Amarin court having just issued its ruling, FDA agreed to revise the labeling to provide directions for use for various surgeries and thus permit promotion for such uses.
Most recently, a federal jury in Texas found Vascular Solution, manufacturer of a medical device intended for ablation of superficial veins, based on a conclusion that the promotion was true and not misleading.
So where will off-label prosecution go from here? While only time will tell, a good guess would be that criminal misbranding prosecutions will focus on blatantly false statements and nonspeech evidence of intent to misbrand -- such as internal marketing plans showing intended uses of a drug that do not match the label directions, and incentive compensation plans that are designed for uses of a drug that do not match label directions.
To avoid misleading promotion, statements about off-label uses should be carefully crafted with disclosures and qualifying statements. As the Amarin court noted, "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 in the end. ..."
, and , are partners in the law firm , whose clients include pharmaceutical and medical device companies.
Kupchyk, of Foley Hoag's Washington, D.C. office, is an FDA lawyer who advises biotechnology, medical device, and pharmaceutical companies, as well as healthcare providers and institutions, researchers, and investors on FDA-related matters. Adelman, of the firm's Boston office, has over a decade of state and federal prosecutorial experience in her counsel of corporations, officers, directors, and other individuals in government investigations -- including criminal, civil, regulatory, and Congressional investigations -- and related complex civil litigations.