Medicolegal Sidebar: Free Speech Rights Versus Off-Label Use

In the United States, physicians can use a medical device or drug for an off-label use if they believe that such use is in the best interest of their patient. Off-label use is a legal practice whereby a drug that is approved by the U.S. Food and Drug Administration (FDA) for one indication is instead used to treat a different condition that the FDA has not explicitly authorized.

If off-label use is common—and it is [9]—then why does “labeling” matter? While off-label use by physicians is permitted, it is illegal for pharmaceutical companies and device manufacturers to promote and market their products for off-label use. Off-label marketing can invoke large settlements. One example occurred in May 2012 when Abbott Laboratories agreed to pay a USD 500 million fine to settle liability arising from the company’s illegal promotion of its prescription drug, Depakote, for off-label use [5]. Abbott pleaded guilty to assigning a special sales force to illegally promote Depakote for the purpose of controlling agitation in elderly patients with dementia in nursing homes—an off-label indication.

Physicians, by contrast, are free to make up their own minds about how to use drugs and devices in their practices, but only up to a point. To limit legal liability, physicians contemplating off-label use of a drug or device need to discuss their decisions in the context of a risk-benefit analysis with their patients as part of the informed consent process [2]. But do the obligations of physicians (and others, including pharmaceutical representatives) under existing law pertaining to off-label uses come into tension with their rights to free speech? If so, what does the law have to say about this?

U.S. v Caronia

A legal ruling titled U.S. v Caronia [8] changed the regulatory landscape for pharmaceutical manufacturers and severely curtailed the FDA’s authority over the off-label promotion of drugs. In 2002, the U.S. FDA approved Xyrem, a drug with gamma-hydroxybutyrate (GHB) as its active ingredient, to treat cataplexy (a sudden muscular weakness) in patients who have narcolepsy. Later, the FDA also approved Xyrem to treat patients with narcolepsy with excessive daytime sleepiness, a neurologic disorder related to dysfunctional sleep-wake cycles. Xyrem had known side effects, including depression, seizures, coma, and even death. These were serious enough to require an FDA black box warning on the package insert for Xyrem, indicating a very high level of concern for potential permanent or fatal side effects of the drug.

Alfred Caronia worked as a sales rep for Orphan Medical, Inc., the company that made Xyrem. Caronia’s salary was based on his sales volume. Caronia started Orphan Medical’s speaker programs for Xyrem, enlisting and paying physicians to talk to their peers about Xyrem and its effectiveness against cataplexy and narcolepsy. Orphan Medical hired Dr. Peter Gleason to promote Xyrem through those speaker programs. The company policy specified that if a physician inquired about the off-label uses for Xyrem, the rep should not respond. Instead, a medical request form would be filled out and sent to Orphan Medical, which would then forward information to the inquiring physician.

In 2005, the federal government suspected that Caronia and Gleason were illegally promoting Xyrem for off-label uses such as fibromyalgia, muscle disorders, EDS, chronic pain, and fatigue. The government hired Dr. Stephen Charno as a cooperator and had him pose as a physician potentially interested in prescribing Xyrem. In taped conversations, the government collected the evidence needed to show that Caronia and Gleason had conspired to promote Xyrem for off-label uses. In subsequent U.S. District Court proceedings, both defendants pled guilty [7].

Before trial however, Caronia filed a pre-trial motion seeking dismissal of the charges, arguing that the FDA’s actions unconstitutionally restricted his right to free speech under the First Amendment. Caronia’s position was that, because of the First Amendment, the FDA could not prohibit his promotion of a legally-approved drug for off-label use if the promotion was truthful and non-misleading, and where others (such as physicians) were allowed to engage in such conduct. The District Court was unpersuaded by this line of reasoning and rejected Caronia’s motion. Even so, the Court acknowledged that Caronia’s motion raised constitutional issues that were “very much unsettled, not only in this circuit but nationwide” [7].

Legal Proceedings

Upon Caronia’s appeal, in December 2012, the U.S. Court of Appeals for the Second Circuit returned a landmark 2-1 decision by a three-judge panel [8], vacating Caronia’s conviction and clarifying that the government cannot prosecute pharmaceutical manufacturers and their sales reps under the FDA for the truthful and non-misleading off-label promotion of an FDA-approved drug.

The Second Circuit Court’s split-decision reasoning relied, in part, on a previous U.S. Supreme Court ruling that also invoked free speech. In the 2011 legal case titled Sorrell v IMS Health Inc. [4], a 2007 Vermont law had banned the use of prescriber-identifiable data for marketing or promoting a prescription drug without the consent of the prescriber. The law was passed to protect physician prescribing history from intrusive pharmaceutical marketers. As plaintiff, IMS Health was one of three companies that collected such data for a trade group, and it challenged the Vermont law under First Amendment grounds.

The U.S. District Court for Vermont upheld the law, and IMS Health appealed to the U.S. Court of Appeals for the Second Circuit, who reversed the decision. Faced with an injunction, the Vermont Attorney General filed for review by the U.S. Supreme Court. In affirming the lower court, Justice Anthony Kennedy remarked that “Vermont's statute, which imposes content- and speaker-based burdens on protected expression, is subject to heightened judicial scrutiny” [4]. By rejecting Vermont’s claim that the law was necessary to improve public healthcare, the Court held that the law, however well-intentioned, impermissibly infringed upon the First Amendment rights of IMS Health.

Interpretation: Aftermath of Caronia

The FDA chose not to appeal the Caronia ruling to the U.S. Supreme Court, possibly because of concerns that a conservative U.S. Supreme Court during the Trump administration would end up affirming Caronia and further undermine the FDA’s regulatory role. In our view, the FDA’s reluctance to take on Caronia was justified—in light of its earlier ruling in Sorrell, the Supreme Court probably would have ruled in favor of Caronia’s free speech right to talk about the lawful off-label uses of Xyrem, regardless of who was in the White House.

Subsequent legal rulings have applied Caronia and eased the regulatory landscape for pharmaceutical companies. In one case [1], the FDA sought to prosecute Amarin, a small company that marketed its Vascepa brand fish oil capsules as effective in reducing triglycerides. Amarin sought approval for an expanded indication, but the FDA found deficiencies in Amarin’s clinical trial and denied it. Amarin sued the FDA, arguing its free speech right allowed it to promote Vascepa regardless for an off-label, non-FDA approved use. The Court issued an injunction against the FDA, and the parties eventually came to a settlement in 2016, marking yet another milestone victory in favor of the free speech rights of pharmaceutical manufacturers.

Since Caronia, the FDA has avoided prosecuting individual sales reps for off-label drug promotion. Instead, the government has targeted promotional messaging that is false, misleading, or for uses that are not medically necessary. To do this, the FDA has invoked the civil False Claims Act. One example is that of Bayer Corporation who, in 2022, paid a USD 40 million fine to resolve violations of the False Claims Act when internal whistleblowers alleged that the company was paying kickbacks to hospitals and physicians to boost usage of its drugs Trasylol and Avelox, which were promoted for off-label uses that were neither reasonable nor necessary, resulting in false claims submitted to Medicare and Medicaid [6].

Conclusion

Since the Caronia legal ruling, medical device and pharmaceutical sales reps have enjoyed far more latitude to present and discuss the off-label uses of an FDA-approved product and to hand out literature describing non-FDA approved utilization. Courts have been less accommodating, however, when it comes to physicians asserting their free speech rights to defend certain medical practices. An example is offering the so-called conversion or reparative therapies to LGBTQ youth. After the California and New Jersey legislatures passed bans on such practices, physicians in those states sued, arguing that patient-physician discussions were protected speech under the First Amendment. The U.S. Court of Appeals for the Third Circuit and the U.S. Court of Appeals for the Ninth Circuit disagreed. The Courts upheld the bans and clarified that the State interest in protecting its citizens from ineffective or harmful medical practices was compelling enough to overcome physician free speech rights [3].

In the case of orthopaedic surgeons, relying on the sales representative to find out whether or not a device is approved for a specific indication is not an option. It falls upon individual practitioners to familiarize themselves with the regulatory status of a device and, if off-label use is contemplated, engage the shared decision-making process in discussions with patients. Shared decision-making means letting the patient know that a drug or device will be used in an off-label manner, and clarifying that off-label use means that the FDA testing standards for patient safety have not been met or even investigated. Afterward, orthopaedic surgeons must ensure that proper documentation of this patient discussion and shared decision-making process is part of the medical record.