Physicians have the authority to prescribe drugs for any reason they believe will benefit the patient, regardless of whether the use is on- or off-label. Off-label prescription is neither illegal nor unethical when based on the best available evidence.
By contrast, off-label promotion—unlike off-label use—has heretofore invited legal liability including criminal charges, penalties under the False Claims Act, and misbranding actions by the Food and Drug Administration (FDA). Opponents of off-label promotion argue that the off-label uses have not passed scrutiny by the FDA, the chief regulatory body charged with ensuring both efficacy and safety for specific indications of drugs.
In recent years, however, the trend toward heightened constitutional protection of commercial speech in the health care arena has opened up opportunities for off-label promotion without threat of liability. Proponents of both off-label drug promotion and expanded protection of commercial speech argue that, in an era of increasing transparency in health information, citizens have a right to know about any evidence that a drug might be effective for a particular off-label use.
The recent settlement between the FDA and Amarin Corporation, a pharmaceutical company with one approved product, Vascepa® (icosapent ethyl), a fish oil product that lowers serum triglyceride levels, is the most recent example of this trend. The settlement permits Amarin to engage in truthful and non-misleading promotion of Vascepa for an off-label use. Though the settlement applies only to this case, it marks a significant change in FDA policy on off-label drug promotion. Additionally, the optional preclearance procedure for off-label promotion introduced by the FDA in the settlement could have important implications for the regulation of other promotional activities, such as direct-to-consumer advertising.
First Amendment Litigation in Pharmaceutical Promotion
The 2002 Supreme Court case Thompson v. Western States Medical Center extended First Amendment commercial-speech protection to compounding pharmacies, a subset of pharmaceutical providers, for the first time. In this case, the compounding pharmacy wanted to promote its products and challenged FDA rules prohibiting the solicitation of prescriptions for, and the advertising of, compounded drugs. In a narrow five-four decision written by Justice Sandra Day O’Connor, the Court held that the relevant FDA rules violated the compounding pharmacy’s First Amendment right to free speech.
The dissent, concerned that a strict application of commercial free speech would hinder the “legislative or regulatory decision about the best way to protect the health and safety of the American public,” called for a more lenient application of the Constitution that “reflects the need for distinctions among contexts . . . and forms of speech.” Justice Stephen Breyer, writing for the dissent, distinguished between advertisements for the ability to compound drugs, which he believed were constitutional, from those advertisements for individual compounds, which he believed were unconstitutional, and argued that the statutory objective was best served by the FDA advertising restrictions.
In 2012, the Second Circuit Court of Appeals further expanded First Amendment commercial speech protection in the realm of pharmaceutical marketing in United States v. Caronia. The court overturned a pharmaceutical sales representative’s conviction arising from a recording of his promotion of off-label use of Xyrem (sodium oxybate) to a group of doctors. Xyrem was approved for the indication of excessive daytime sleepiness, but Caronia promoted it for insomnia and fibromyalgia. The court held that convicting the sales representative for off-label marketing that was not untruthful or misleading violated his First Amendment rights. In contrast, off-label promotion that is untruthful and misleading would be fraudulent, and thus not protected by the First Amendment.
This decision signaled a change in the court’s treatment of off-label drug promotion that has led directly to the Amarin decision.
Amarin Pharma Inc. v. U.S. Food and Drug Administration
After a successful clinical trial (MARINE), Amarin received FDA approval for Vascepa in patients with triglyceride levels of 500 mg/dl or greater. The subsequent ANCHOR study, which was designed in conjunction with the FDA pursuant to a Special Protocol Agreement (sNDA), examined Vascepa in patients with triglyceride levels mg/dl but mg/dl. The trial met its primary endpoint of triglyceride lowering, so a successful supplemental new drug application was almost certain. In October 2013, however, the FDA rejected the sNDA on the grounds that lowered triglycerides in this range were not tangibly connected to a lower risk of cardiac events.
In an unusual move, Amarin filed suit against the FDA on the grounds that it had a First Amendment right to state the facts demonstrating that Vascepa lowered triglycerides, and previous evidence showing a positive link between lowered triglycerides and reduced cardiovascular risk. Amarin sought to prevent the FDA from bringing an enforcement action against the company for disseminating information about the ANCHOR study (including reprints of peer-reviewed publications and textual disclosures) to health care professionals.
In granting a motion for a preliminary injunction, Judge Engelmayer of the Southern District of New York recognized that the unusually extensive regulatory history confirmed the truthfulness of Amarin’s statements about the off-label use of Vascepa. Specifically, the FDA had approved the ANCHOR study—the evidentiary basis for the off-label claims—and affirmed in writing that Vascepa was proven effective in lowering triglycerides. Accordingly, Amarin was able to base the proposed off-label promotion “almost entirely on statements by the FDA itself.” The court found that, consistent with the First Amendment, the FDA could not bring a misbranding action “based on truthful promotional speech alone.” The FDA chose not to appeal the decision, fearing a wider-reaching decision at the court of appeals.
In March 2016, Amarin Pharmaceuticals and the FDA reached a settlement agreement resolving the issues in the initial complaint. The agreement binds the FDA to the specific conclusion in the 2015 decision by Judge Engelmayer affirming Amarin’s ability to disseminate off-label communications, including journal reprints, to health care professionals, as long as the communications are “truthful and non-misleading.”
The parties agreed that such speech would not serve as the basis for a misbranding prosecution. Thus it appears as though the FDA will tolerate off-label promotion by a drug sales representative if the drug has been approved by the FDA for another indication, and the off-label use the company promotes is supported by evidence.
In a notable feature of the settlement, the FDA provided Amarin with an optional preclearance process for new off-label promotion of drugs. It is possible, but unlikely, that this settlement extends to other forms or content of communications. For example, whether the holding extends beyond drug detailing to promotions such as direct-to-consumer advertising will only be settled through either preclearance with the FDA or in future litigation.
Though the settlement only applies to Amarin, this provision has symbolic importance: the agency has finally “spoken” about where it is willing to compromise in the sphere of off-label promotion. In doing so, it has departed significantly from its traditional position on the issue. The agency has seemingly agreed to refrain from bringing misbranding actions against truthful, non-misleading off-label promotion, and has shifted the burden onto the company to ensure the communications meet the standard. While the settlement applies only to Amarin’s off-label promotion of Vascepa, its potential reach is vast.
The settlement does not extend to Amarin, or other drug companies, a carte blanche for off-label promotion, but it may provide guidance on FDA thinking on this issue, and serve as a template for companies hoping to promote off-label uses. Indeed, since the Amarin case, the FDA has been more lenient in pursuing off-branding and promotional disputes.
For example, Pacira Pharmaceuticals sued the FDA on First Amendment grounds similar to those used in the Amarin case after receiving a warning letter notifying Pacira that Exparel (bupivacaine liposome injectable suspension used for postsurgical pain control) was misbranded. Pacira sued in order to promote Exparel for use in injection sites not tested in clinical studies using what it claimed was truthful and non-misleading speech. In response, the FDA withdrew its warning letter and quickly settled the dispute in December 2015.
First Amendment approaches based on the Amarin case also gained traction in at least one judicial proceeding for off-label medical device promotion. Vascular Solutions, Inc., and its CEO, Howard Root, encouraged Vascular Solutions’ salespeople to promote uses of the Vari-Lase Short Kit beyond uses contained in the FDA-approved label indications. Federal prosecutors in the case agreed to a jury instruction stipulating that it is “not a crime for a device company or its representatives to give doctors wholly truthful and nonmisleading information about the unapproved use of a device.” Both Vascular Solutions and the CEO, Howard Root, were acquitted of the charges.
The Future of Off-Label Promotion
For proponents of off-label promotion, the Amarin settlement and the trend towards increased allowance of off-label promotion it represents are a victory. They argue that allowing pharmaceutical companies to communicate truthful, non-misleading information to treating physicians opens the flow of information, ensures that doctors are informed of all options, and makes off-label treatments available to patients.
Opponents of off-label promotion draw a distinction between a physician’s decision to prescribe a drug for an off-label use and a pharmaceutical company’s promotion of that off-label use. They argue that promoting a drug for off-label use inappropriately exposes patients to risk, whereas an individual doctor would make a treatment decision based on clinical data, experience, and an individualized assessment of patient need.
Given the competing interests of patient health, access to information, drug safety, and the financial interest of the pharmaceutical industry, the FDA should have complete authority to provide guidance for off-label promotion in order to ensure the safety and efficacy of drugs. Regardless of one’s view of the practice, using the First Amendment to sort out difficult questions of off-label promotion skirts the deeper questions about these competing interests. If the outcome in Amarin extends to direct-to-consumer advertising, or to claims with an inconclusive scientific basis, it threatens to undercut the mandate of and trust in the FDA. Undoubtedly we can anticipate further case law to delineate proper uses of the First Amendment in this context. The courts ought to exercise discretion and sound judgment, keeping the health of the public in mind as the ultimate goal.