Off-label marketing: free speech or illegal promotion?BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f320 (Published 22 January 2013) Cite this as: BMJ 2013;346:f320
When Alfred Caronia worked a decade ago as a sales representative for Orphan Medical—now part of Jazz Pharmaceuticals—he marketed sodium oxybate for cataplexy but also promoted the drug for other unapproved uses. In 2008 he was convicted of introducing a misbranded drug into interstate commerce for talking up unapproved uses. However, his conviction was overturned by a US appeals court panel last month after he successfully argued that his First Amendment rights were violated because the federal government failed to prove his remarks were false or misleading, potentially opening the doors for increased off-label marketing.
Off-label marketing is hardly new, of course. Physicians in the US are free to prescribe medications for uses not approved in product labeling, but the federal government has successfully reached settlements with dozens of drug makers for violating the Food, Drug and Cosmetic Act, which prevents them marketing a drug for unapproved uses. Recently, though, there has been some push back.
Several drug makers have filed lawsuits against the US Food and Drug Administration to argue that the agency is stifling commercial speech. Par Pharmaceutical, for instance, contended that its right to convey “truthful” information to physicians is protected by the First Amendment yet is thwarted by FDA regulation. The lawsuit is pending.
And so the Caronia decision capped an increasingly intense debate about the rights of drug makers to discuss use of their medicines for specific purposes, even when these uses are not approved by the FDA. And the ruling quickly sparked debate about the extent to which off-label marketing might now become more pervasive and what the FDA might do in response.
The court ruling is the latest chapter in a saga that extends back half a century, when the US Congress enacted an amendment to the Food, Drug and Cosmetic Act to demand proof of safe and effective drugs from manufacturers. This came in response to the thalidomide scandal, in which children were born with birth defects after their mothers took the drug for morning sickness during pregnancy.
The amendment crystallised existing concerns about the promotion of products for uses that were not approved by the FDA. But its passage enshrined the agency’s authority to regulate off-label speech because it makes it illegal to directly or indirectly distribute into interstate commerce a drug that is adulterated or misbranded.
For years, the FDA has considered a drug to be misbranded if the labeling does not include adequate instructions for use. And a drug is considered adulterated if the labeling includes information that has not been approved by the agency. Even though the act never mentions the words “off label,” the FDA’s authority to regulate off-label activities, including speech, flows from this language.
The US Department of Justice has used the amendment to pursue civil and criminal charges for off-label marketing. Numerous drug makers have reached settlements with the federal government—and in many cases, with state governments—for promoting their medicines for unapproved uses. Notable payments include a $3bn (£1.9bn; €2.2bn) settlement reached by GlaxoSmithKline, although the payout covers more than off-label marketing activity; $2.3bn paid by Pfizer in 2009 in connection with off-label marketing of several medicines; and $1.4bn paid by Eli Lilly in connection with illegally promoting the antipsychotic drug olanzapine.
The number of companies that have reached settlements over off-label marketing has grown so long that a spokesman for the Department of Justice says the FDA does not keep track and could not offer a comprehensive rundown. But the laundry list is testimony to the pervasive nature of this sort of marketing and the determination of regulators and prosecutors to attempt to reign in the industry.
Effect of the ruling
Now, though, the recent court ruling is raising questions about whether off-label marketing will suddenly accelerate. Opinion is divided about this because the decision was made by a three justice panel rather than the full appeal court. However, the FDA has decided not to seek a re-hearing before the appeals court.
“The government has determined not to seek further review,” an FDA spokeswoman says. “FDA does not believe that the Caronia decision will significantly affect the agency’s enforcement of the drug misbranding provisions of the FD&C [Food, Drug and Cosmetic] Act. The decision does not strike down any provision of the FD&C Act or its implementing regulations, nor does it find a conflict between the act’s misbranding provisions and the First Amendment or call into question the validity of the act’s drug approval framework.”
Some speculate that the FDA has let the ruling stand because the decision holds only for the Second Circuit, which covers New York, Connecticut, and Vermont. The agency will therefore be free to continue pursuing marketing violations in other parts of the country while it settles on a legal strategy.
“Off-label promotion in jurisdictions outside the Second Circuit remains subject to the risk of FDA enforcement action, assuming the agency elects to initiate enforcement action and declines to follow the decision in Caronia elsewhere,” says Arnie Friede, a former FDA associate chief counsel and former senior corporate counsel at Pfizer.
Other experts note that the agency may want to convince the solicitor general that the appeals court decision cannot be lived with and push for a review before the Supreme Court. Of course, this approach may take some time to crystallize, making it likely that the pharmaceutical industry will take a wait and see approach.
“My guess is that you won’t see a lot [of off-label marketing activity] in the near term— say the next year or more—until you see more clarity about what may happen next,” says Chad Landmon, who chairs the FDA practice group at law firm Axxin, Veltrop and Harkinder. “I think [the pharmaceutical industry] will be reluctant to change their activity until they see how this plays out.”
By the same token, few expect a sudden burst of direct-to-physician or direct-to-consumer advertising that contains off-label marketing messages. “I think it is mistaken to believe that pharmaceutical companies will put the off-label horse before the final judicial cart comes along,” says Friede.
Although there is no certainty that the Caronia ruling will stand, the decision makes it likely that the FDA and the Department of Justice will have to reformulate their approach to off-label marketing and focus only on those cases where they can prove that false or misleading information was knowingly conveyed to healthcare providers.
The appeals court panel in the Caronia case noted that free speech, in the context of off-label marketing, does not extend to activities that include false or misleading statements. This leaves the door open to continued prosecution. “There is nothing in [the] Caronia [ruling] that precludes the government from pursuing charges that labeling or advertising for a prescription drug is false or misleading,” says Friede.
Several attorneys, for instance, say that this has always been a litmus test, of sorts, for federal prosecutors who want to ensure that the details contained in underlying whistleblower cases have evidence that can hold up in court. For this reason, it seems likely that the Department of Justice will continue to pursue such cases.
“My experience handling numerous whistleblower cases is that the government wants proof not only of off-label marketing but of false and misleading statements and conduct. For example, affirmative statements about adverse events, lies about findings in clinical trials, ghostwritten articles that were intentionally misleading,” says Steve Sheller, a lawyer who has represented numerous whistleblowers.
Adds Friede: “In most off-label actions, there are usually many documents, often in the thousands and even millions, that demonstrate a company’s intention to promote off-label, the ensuing training of sales reps to promote off-label, and subsequent off-label statements by sales reps. Evidence of this sort goes well beyond the simple off-label promotional statements of the kind in Caronia.”
That may be so, but if the ruling stands, the pharmaceutical industry is expected to get a boost since drug makers will eventually be able to market their medications for indications that were not approved by the FDA. Such marketing could not only increase revenue but reduce costs because there would be a less rigorous review before the FDA.
Further haggling is likely over which activities, literature, and statements constitute false or misleading information. “I do think we’ll see more of that if this becomes established law over time,” says Landmon. “These studies are often complicated and have intricate statistics, so you will have an increased argument over whether something is false and misleading.”
Cite this as: BMJ 2013;346:f320
Competing interests: I have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare.
Provenance and peer review: Commissioned; externally peer reviewed.