An Uninformative Truth: The Logic of Amarin’s Off-Label Promotion

March An Uninformative Truth: The Logic of Amarin's Off-Label Promotion Spencer Phillips Hey 0 1 Aaron S. Kesselheim 0 1 0 1 The Program On Regulation , Therapeutics, And Law (PORTAL) , Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston , Massachusetts, United States of America, 2 The Harvard Center for Bioethics, Harvard Medical School , Boston, Massachusetts , United States of America 1 Abbreviations: CVD , cardiovascular disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FDA , United States Food and Drug Administration; LDL, low-density lipoprotein Provenance: Not commissioned; externally peerreviewed The United States Food and Drug Administration (FDA) generally does not permit pharmaceutical manufacturers to promote their products for non-FDA-approved (“off-label”) indications. A lawsuit filed by Amarin Pharmaceutical in May 2015 sought permission to distribute off-label statements relating to its product Vascepa, because it argued that those statements were “truthful and non-misleading” and that the First Amendment's protection of commercial speech gave it the right to make those statements. In August 2015, a federal court agreed with Amarin. We argue that Amarin's argument is faulty, because the so-called “truthful and nonmisleading” statement is a tautology-that is, it is only truthful because of its logical construction-not because it is consistent with the state of scientific evidence. Since the off-label marketing statement is actually misleading when viewed from this perspective, the federal court's conclusion was incorrect. We propose that informativeness in asserting scientific facts, rather than truthfulness, ought to be the gold standard for evaluating commercial speech about pharmaceuticals. - OPEN ACCESS Funding: ASK is supported by the Laura and John Arnold Foundation, the FDA, and the Harvard Program in Therapeutic Science, and is a Greenwall Faculty Scholar in Bioethics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: ASK reports serving as an expert witness in an investor lawsuit against Amgen relating to marketing practices. ASK is a member of the Editorial Board of PLOS Medicine. In May of 2015, a small Irish pharmaceutical manufacturer, Amarin, caused a major stir when it preemptively filed suit against the United States Food and Drug Administration (FDA) to ensure that it could distribute certain statements about its prescription pill Vascepa, composed of an esterified form of the omega-3 fatty acid eicosapentaenoic acid (EPA), derived from fish oil [ 1 ]. Vascepa had already been FDA-approved in 2012 to treat “very high” levels of triglycerides (>500 mg/dL), which was expected to prevent pancreatitis. However, Amarin wished to market the product to physicians for patients with moderate triglyceride levels ( 200 mg/dL and <500 mg/dL) to reduce those patients’ risk of cardiovascular disease (CVD)—an “offlabel” indication that the FDA had not approved. Fearing that the FDA would treat this action as criminal misbranding, Amarin launched its lawsuit, and in August, a federal court agreed with Amarin, claiming that the First Amendment protected its commercial speech rights to make claims about its product that were “truthful and non-misleading” [2]. While this was not the first (or even the most recent) court case to undermine the FDA’s authority to regulate how pharmaceutical companies promote their products [ 3–5 ], it is unusual for its close examination of the essential truthfulness of the claims at issue. Here, we argue that the central claim for which Amarin sought legal relief has essentially no truth content and is therefore only likely to serve the company’s economic interest on the presumption that it will be misinterpreted. We will then argue that even setting aside the vacuousness of this particular claim, Amarin’s interpretation of the scientific evidence that it considers to support its claim relies on a problematic circularity of reasoning. Fish Oil Derivatives and Cardiovascular Disease In July 2009, while Vascepa was still in development, the FDA and Amarin established a formal agreement in which the FDA acknowledged that it would approve Vascepa as a treatment of moderately high triglyceride levels provided that Amarin completed a clinical trial demonstrating that Vascepa reduced persistently high triglyceride levels among statin-treated patients. This study, called ANCHOR, was initiated in 2009 and took approximately 4 years to complete. It showed that for patients already taking a statin, Vascepa produced significantly lower triglyceride levels relative to placebo [ 6 ]. While ANCHOR was underway, however, circumstances changed. Clinical trials involving the non-statin cholesterol-lowering drugs niacin [ 7,8 ] and fenofibrates [9] were completed (...truncated)