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Since 1962, the US Food and Drug Administration (FDA) has required companies to establish, with adequate and well-controlled clinical trials, a drug’s safety and efficacy for each intended use and has prohibited the “offlabel” promotion of drugs. For companies to market an approved medicine for new indications, they must first conduct trials and submit data to establish safety and efficacy, as was the case for the initial approval. The FDA’s approach to off-label promotion is in jeopardy, however. In response to recent US Supreme Court decisions strengthening First Amendment protection for companies, the pharmaceutical industry has framed offlabel marketing as a free speech right. Drug companies have won several important court cases that have weakened the FDA’s authority to regulate off-label marketing. Although the legal issue—whether the FDA’s restrictions on off-label marketing are unconstitutional— remains unresolved, the agency has initiated a comprehensive review of its approach to off-label marketing. On November 9 and 10, 2016, the FDA will convene a public hearing to address “its regulations and policies governing firms’ communications about unapproved uses of approved/cleared medical products.”1 The Food, Drug, and Cosmetic Act grants the FDA the authority to approve drugs for specific indications and to prohibit the sale of “misbranded” drugs. When used for a new condition or population, a drug’s riskbenefit ratio may change, or new safety considerations may emerge. By requiring studies before permitting marketing of new uses, the FDA gives companies incentives to produce the needed evidence for sound medical decisions. Off-label uses can be clinically appropriate, and physicians are free to prescribe medicines off-label. To help facilitate well-informed decisions, the FDA has created safe harbors that allow companies to communicate about potential new uses with physicians. Under current FDA guidance, drug companies may respond to unsolicited questions from physicians and proactively circulate peer-reviewed journal articles about off-label uses if the articles are based on adequate and wellcontrolled studies.2,3 Recently, companies have begun to challenge this framework for communicating with clinicians about offlabel uses of drugs. Some have argued that more extensive marketing is not merely good policy, but a constitutionally protected right. In a watershed 2012 case, United States v Caronia, the US Court of Appeals for the Second Circuit in New York sided with the industry. In that case, a pharmaceutical detailer had promoted sodium oxybate (Xyrem), approved to treat narcolepsy, for off-label uses, including chronic pain, and a jury convicted him of misbranding the drug. In a 2 to 1 decision, the appellate court vacated the conviction on First Amendment grounds.4 The court ruled that the government could not prosecute the detailer simply for making off-label promotional statements, but was also careful not to entirely strike down the FDA’s authority to regulate off-label promotion. It suggested that the FDA might have prevailed if it had treated promotional speech merely as evidence of criminal conduct (namely, the selling of a misbranded drug) and not as criminal itself. This draws on a well-established rule that the use of speech as evidence to prove criminal conduct does not violate, or even implicate, the First Amendment. This rule in fact sustains the FDA’s authority to forbid the marketing of entirely unapproved drugs. A company that markets an unapproved drug cannot defend its actions by arguing that its treatment claims are constitutionally protected speech.5 In 2015, a US district court in Manhattan went beyond Caronia, in a case involving Amarin Pharmaceuticals.6 The trial judge concluded that drug companies have a First Amendment right to market any off-label use to physicians as long their statements are not false or misleading.7 The judge barred the FDA from using such promotional statements as evidence of misbranding, effectively rejecting the legal argument that was left open by the Caronia case. On this logic, once a drug is approved for any indication, it can be promoted to physicians for any use as long as a judge, not the FDA, views the marketing to be truthful and nonmisleading. But judges are not experts in trial design, pharmaceutical regulation, or the evaluation of medical evidence, and the effects of drugs cannot be known unless they are carefully studied. The Amarin decision invites a world where companies no longer pursue broad clinical indications for new drugs but instead seek the narrowest possible indication for approval and then market the drug for any new use for which there is some evidence, no matter how weak. Companies would no longer have to conduct rigorous trials and submit, to the FDA, data demonstrating the safety and efficacy of new uses. Such an approach would compromise the future evidence base for medicines, expose patients to a greater risk of adverse events, and increase pharmaceutical spending without evidence that the expenditures would help improve patients’ health.8 VIEWPOINT