Free Speech and Pharmaceutical Regulation—Fishy Business

Recent research has not been kind to fish oil salesmen, or the value of ω-3 fatty acid supplements for the secondary prevention of cardiovascular disease.¹ Amarin Corporation, in particular, has been hit hard. The company’s only approved product is icosapent ethyl (Vascepa), a prescription-based derivative of fish oil. In 2012, the US Food and Drug Administration (FDA) approved the drug to treat patients with very high triglyceride levels, but the company has long wanted to promote its use in a much larger group of patients: those with lower triglyceride levels and cardiovascular disease who were already being treated with statins. In 2013, an FDA advisory committee voted 9 to 2 against approval for this use, in part because several recent studies of other drugs with similar effects on blood lipids showed no clinical benefit when they were added to statins.² Amarin’s stock price plummeted, and investors brought suit claiming that they had been misled about the promise of the drug.

In May 2015, Amarin struck back, suing the FDA in US district court in Manhattan, arguing that the First Amendment gives the company the right to market its drug for this broader group of people despite the lack of regulatory approval and the lack of evidence of an outcomes benefit for patients.⁴ The company's argument hit at the heart of the drug regulatory system in the United States. For decades, that system has required companies that want to promote pharmaceutical products for new uses to first prove to the FDA that the drugs are safe and effective for these uses. Amarin argued that this system is unconstitutional, and that companies should instead be allowed to market their products in any way that a judge would consider to be neither false nor misleading. Amarin relied in particular on a recent and much criticized judgment from a federal appeals court, US v Caronia.³ That 2012 decision came close to declaring the FDA’s prohibition of off-label marketing unconstitutional, citing recent Supreme Court cases that have strengthened constitutional protections for commercial speech.

In August 2015, the judge in the Amarin case,⁴ relying largely on the Caronia ruling, handed the company a major victory. He ruled that the company could market Vascepa for the desired broader population, and make many of the very claims that the FDA views as misleading—claims such as “supportive but not conclusive research” shows that the drug “may reduce the risk of coronary heart disease.” As of December 2015, the FDA had not decided whether to appeal or settle the case.

The stakes are high indeed: the Amarin precedent, if it holds, has the potential to unleash a flood of misleading marketing to physicians. Under Amarin, if a company wants to market its drug off-label, it need only convince a judge, not the FDA, that its claims are not “false or misleading.” In effect, the decision replaces drug regulators with judges—whose expertise in science and medical research varies considerably—when off-label promotion is concerned. The judge in Amarin saw the problem clearly: “You're talking to somebody who has difficulty using a toaster,” he said at the hearing. “I’m the last person who should opine on this.”⁵

It is not merely that most judges lack the requisite training to effectively assess complex drug claims. They also lack access to the necessary data, and the tools that regulators have to evaluate and shape that data. When a company seeks approval from the FDA for a new indication for a marketed drug, it must submit extensive clinical research and trial data, as well as details about the trial design. FDA scientists can therefore reanalyze the data, detect flaws in protocols and case reports, and, when necessary, reject trial results or require more information. A recent FDA review conducted after safety concerns were raised about rosiglitazone (Avandia), for example, involved manual reviews of forms and efforts to collect additional data for hundreds of trial participants and revealed important new facts, including 8 deaths that had not previously been recorded.⁶

The most insidious aspect of the Amarin decision, therefore, is that it undermines the structures that encourage companies to produce high-quality clinical evidence to support new uses of drugs. If the decision stands, companies with a drug approved for one use will have to produce only enough evidence to convince a judge, not the FDA, to market it for additional indications. To be effective, a company’s marketing must also influence the prescribing patterns of physicians. Although physicians are a more sophisticated audience, they are not in a position to substitute for regulators. Relatively few have training in research methods. Those who do have such training lack access to comprehensive clinical trial data and rely heavily on the published literature, which is skewed toward positive results.⁷ In addition, there is a strong and specific association between pharmaceutical marketing and physician behavior, independent of the evidence supporting the products.⁸

The Amarin decision—if it is neither modified nor reversed—may well put patients, and the evidence base for medical practice, at risk. Drugs that are prescribed for unproven indications can cause serious harm. For example, tiagabine (Gabitril), a medication to reduce the frequency of seizures in patients with epilepsy, can cause seizures when used off-label for other indications.⁹ Risk-benefit ratios also shift when new uses are contemplated: a drug whose adverse effects may be acceptable when used to treat patients with serious illness may cause more harm than benefit if used to treat healthier patients. Even a drug that is safe, but ineffective, can be harmful, for example if it is used instead of an effective intervention. Because health care budgets are limited, spending on ineffective treatments also squanders money that might be better spent elsewhere.

Does our constitutional commitment to free speech really require this result? Not if the traditional legal standard for commercial speech protection prevails. Commercial speech serves an “informational function”¹⁰ and can be regulated to ensure that the public has access to accurate information. The FDA serves exactly this end. The agency aims not to censor company speech, but to foster the development of accurate and reliable information, and channel that information into settings where it can be rigorously evaluated. For example, companies are not prohibited from marketing outright. They may make marketing claims if they provide adequate supportive evidence to the FDA. Nor are companies prohibited from conducting research, and publishing such research—whether meeting FDA standards or not—in the medical literature. Indeed, this is encouraged, and companies can distribute reprints of studies directly to physicians, if the publications have certain indicia of reliability, such as having undergone peer review.

The FDA did not appeal the ruling in the Caronia case. The ongoing settlement negotiations in Amarin suggest that the agency may not yet wish to take its chances in the higher courts in this case. At some point, however, the FDA will have to either take the underlying issue about off-label marketing up the chain, to the Supreme Court itself, or lose a key aspect of its regulatory authority by a thousand cuts. If and when the FDA finally takes a stand, it will need the help of experts who can help judges understand our drug regulatory system and render vivid the acute dangers of deregulation where medicines are concerned.

Corresponding Author: Amy Kapczynski, JD, Yale Law School, 127 Wall St, New Haven, CT 05611 (amy.kapczynski@yale.edu).

Published Online: February 1, 2016. doi:10.1001/jamainternmed.2015.8155.

Conflict of Interest Disclosures: None reported.