Pharmaceutical companies and their sales reps can distribute information, such as medical journal articles, about unapproved (“off-label“) uses of their drugs as long as they adhere to FDA guidelines. However, the FDA takes the position that this information must be distributed separately from information that is “promotional in nature,” i.e., for marketing purposes, a position that is now open to question.
Off-label promotion of a drug for a use that has not been approved by the FDA is, in the FDA’s view, a violation of the federal Food, Drug & Cosmetic Act (FDC Act). It is subject to criminal prosecution, because promoting a drug for new, unapproved uses is evidence of an intent that the drug be used before it has gone through the extensive process of clinical trials and a review of the evidence of safety and efficacy by a panel of experts, as required by law before a drug can be marketed. Thus, off-label promotion is seen as an end-run around the approval process that perverts the purpose of the FDC Act, which is to protect the public from ineffective and unsafe drugs.
Studies show that personal sales visits to physicians by pharmaceutical reps (called “detailing”) drives prescriptions in favor of the drugs being promoted. This is true even though physicians’ view of detailing ranges from neutral to highly negative, a “necessary evil,” and physicians are aware of potential conflicts of interest these visits precipitate.
While there are restrictions on off-label promotion, off-label prescribing by a physician is not illegal. Physician practice is regulated by the states and not within the jurisdiction of the FDA. In fact, off-label prescribing is considered both ethical and within the standard of care in appropriate circumstances. (I am currently taking a drug for an off-label use, and was informed of this, plus the risks and benefits, by my physician prior to his prescribing it.) It is also common, according to an article by law professors Ryan Abbot and Ian Ayers in the Duke Law Journal, which is well worth reading:
for the 3 leading drugs in each of the 15 leading drug classes, off-label use accounts for approximately 21% of prescriptions. Moreover, off-label uses may be the norm in some areas of practice, such as oncology, pain management, and palliative care, and in some patient populations, such as children, the elderly, and the severely ill. For example, about 80 percent of all drug prescriptions for children are off-label, and between 80 and 90 percent of all drug prescriptions for rare diseases are off-label. [Footnotes omitted.]
As Abbott and Ayers explain, and as one might expect, evidence of safety and efficacy for off-label use is sometimes lacking. One estimate is that about 15% of all off-label drug uses lack scientific support for efficacy and over 70% lack significant scientific support. A 2008 study estimated that 67% of children treated with antipsychotic drugs were prescribed off-label treatments with an “uncertain” evidence base.
Patients do not seem to be aware of these facts. In a 2006 poll of the American public, about half of the respondents believed doctors were allowed to prescribe only for approved uses, and about half believed doctors should be prohibited from off-label prescribing.
In particular cases, an off-label drug may be the patient’s only option. Some drugs have a long history of safe and effective use and are supported by good evidence, including controlled clinical trials. And there are resources available to physicians that evaluate and disseminate evidence supporting off-label use, such as the American Hospital Formulary Service Drug Information. However, one review of compendia governing off-label oncological uses concluded that they were “lacking in consistency, quality, transparency and timeliness.”
In sum, FDA prohibitions on off-label promotion attempt to preserve the original purpose of the FDC Act, which is to protect the public health by requiring good evidence of safety and efficacy before a drug can be marketed for a particular use. Distribution of journal articles and like information to physicians by pharmaceutical companies is permitted, with the realization that off-label prescribing can be beneficial to patients, as long as the companies refrain from actively selling the physician on an off-label use.
The Caronia case
Into this somewhat delicate balance, the U.S. Court of Appeals for the Second Circuit dropped a bombshell of a decision that threatens to undermine the entire drug regulatory scheme, United States v. Caronia. Or maybe not so much, depending upon whom you ask. What is certain is that the effect of the decision is still being sorted out, with the FDA yet to issue new guidance on off-label promotion. The decision is also an exemplar of the expanding First Amendment protection of commercial speech by the federal courts.
Orphan Medical sales representative Alfred Caronia promoted the brand-name drug Xyrem to physicians. Xyrem is sodium oxybate. The active ingredient is gamma hydrooxybutyrate (GHB), also known as the “date rape” recreational drug. Xyrem was approved by the FDA in 2002 for use in narcolepsy with severe cataplexy, a rare clinical condition.
Another Orphan sales rep told the government that the company decided to start promoting Xyrem off-label to increase revenue and encouraged reps to market off-label uses to physicians, including those who were unlikely to see patients with narcolepsy. The U.S. Department of Justice began an investigation. A physician cooperating in the investigation wore a wire and recorded Caronia suggesting, without any prompting, that Xyrem was effective for a range of conditions, including insomnia, fibromyalgia, restless leg syndrome, chronic pain, Parkinson’s disease, and MS. Caronia also told the physician that the drug could safely be used in elderly and pediatric patients, although the FDA-approved labeling stated the drug had not been tested in these patients.
Caronia, Orphan Medical and a psychiatrist, who was assisting the company in this scheme, were prosecuted for conspiracy to introduce a misbranded drug into interstate commerce. The company pled guilty and paid civil and criminal fines of about $27 million. Caronia, however, did not enter a plea, went to trial, and was convicted.
Drug promotion is protected “commercial speech” under the First Amendment, as interpreted by the Supreme Court. (More on this later.) Thus, the implications of convicting Caronia for what was assumed to be truthful speech (more on that later also) were considered by the trial judge and rejected. The judge reasoned that
constraining the marketing options of manufacturers is one of the ‘few mechanisms available’ to the FDA to ensure that manufacturers will not seek approval for only certain limited uses of drugs, then promote that same drug for off-label uses, effectively circumventing the FDA’s new drug requirements. [citation omitted.]
The court looked at whether the FDA could employ non-speech restrictions that would serve the same purpose of ensuring the integrity of the new drug process and found that no such alternatives could be identified.
On appeal, Caronia argued that the government could not criminalize his speech, as long as his promotion of Xyrem was truthful and non-misleading. The U.S. Court of Appeals for the Second Circuit agreed, in a 2-1 decision. The government argued that it wasn’t prosecuting Caronia for his speech at all, rather it was merely using his speech as evidence of his intent to commit a crime, but that view was rejected by the appellate court.
At this point, some high-priced legal talent stepped in to assist Caronia’s criminal defense attorney on appeal. The Medical Information Working Group, a coalition of drug manufacturers represented by both Ropes & Gray and Sidley Austin, filed an amicus brief on behalf of Coronia. The Washington Legal Foundation, founded, in part, to “fight activist lawyers, regulators, and intrusive government agencies at the federal and state levels, in the courts and regulatory agencies across the country” also filed an amicus brief, represented by Jones Day. Obviously, it would be worth a great deal to the pharmaceutical industry to be rid of the prohibition on off-label promotion.
As mentioned, Albert Caronia’s speech (that is, his sales pitch) was protected by the First Amendment as “commercial speech,” an interesting concept. For about 200 years of First Amendment jurisprudence, commercial speech, such as advertising and sales promotion, was not considered protected at all. It was not until the 1970s that the Supreme Court decided commercial speech deserved some level of First Amendment protection, although not at the same level as political or social speech. In a 1980 case, Central Hudson, the Supreme Court developed a framework for evaluating commercial speech restrictions under the First Amendment. This framework is succinctly explained in an excellent article discussing Caronia authored by Aaron S. Kesselheim, M.D., J.D., M.P.H., and Michelle M. Mello, J.D., Ph.D., appearing in the North Carolina Law Review.
First, was the speech false or misleading, or did it concern unlawful activity? If so, the speech deserves no protection. Second, is the government’s interest in regulating the speech substantial? Third, does the regulation directly and materially advance the government’s interest? Finally, is the regulation narrowly tailored, meaning, no more extensive than necessary to serve that interest?
Unfortunately, because the government was using Caronia’s speech only as evidence of intent (even though the court said it wasn’t), it had no incentive to put on any evidence regarding the truthfulness of his speech at trial. (Although I have not researched the issue, I tend to doubt there is good evidence that Xyrem is safe and effective for all of the uses and all of the patient populations he claimed during his recorded conversation with the physician.)
Thus, on appeal, the court assumed the information was truthful. However, it noted, correctly, that the First Amendment protects only truthful and non-misleading speech, leaving open the possibility that, in future cases, the government could, in the court’s view, constitutionally prosecute a sales rep’s off-label promotion if it could show that the information given the physician was untruthful or misleading. A remaining question is whether off-label promotion is per se illegal anymore, even if the government makes it absolutely clear at trial that the rep’s speech is only being used as evidence of intent. We’ll return to that question at the end of this post.
The court recognized that the FDA certainly had a substantial interest in preventing off-label promotion: “preserving the efficacy and integrity of the FDA’s drug approval process and reducing patient exposure to unsafe and ineffective drugs.” The court then turned to the third and fourth prongs of the Central Hudson test and found that the FDA failed on both. It is here that the ruling is most disturbing.
The court decided that, far from advancing the FDA’s interest in public protection, the FDA was “paternalistically” interfering with information being given to physicians, a skilled and sophisticated audience, in the court’s view, who could more than adequately determine the usefulness of the sales rep’s information. With this information in hand, the court opined, physicians could actually serve the public interest by making sure “that decisions about the use of prescription drugs, including off-label usage, are intelligent and well-informed.”
As to the fourth Central Hudson prong, the court determined that restricting off-label promotion was overly broad because other means could achieve the same goal without interfering with protected speech. How? By educating physicians and patients to distinguish between “misleading and false promotion, exaggerations and embellishments, and truthful or non-misleading information,” require off-label use disclaimers, limit the number of off-label prescriptions, and warn physicians about tort liability from adverse outcomes due to off-label uses.
The government did not ask for a rehearing in front of the full Second Circuit Court of Appeals, nor did it petition the U.S. Supreme Court to hear the case, perhaps because it wanted to contain the damage and not risk, in the case of an adverse Supreme Court decision, nationwide impact.
One of the cases the court relied on in reaching its decision was Thompson v. Western States Medical Center, a case that should serve as a cautionary tale for courts looking to second guess the FDA’s regulatory scheme. In 2002, in Western States, the Supreme Court struck down a prohibition on advertising by compounding pharmacies. The FDA viewed the prohibition as recognition of the useful services compounding pharmacies could provide in local communities, regulated by the states and without federal oversight. At the same time, by prohibiting advertising, these pharmacies would be restrained from growing too big and essentially turning themselves into unregulated large-scale drug manufacturers.
With FDA regulation out of the way, that is exactly what happened. Many compounding pharmacies scaled up. One of these was a Massachusetts compounding pharmacy that manufactured, and extensively advertised, steroid injections. A decade after the Western States decision, these injections ended up sickening hundreds and killing dozens of people from fungal infections due to unsafe compounding practices.
Criticism of Caronia
The Caronia decision has garnered a good deal of criticism, according to an essay by law professor Christopher Robertson, J.D., Ph.D.:
Opinion leaders and scientific journal editors have expressed concern about the Caronia decision and the trend that it extends, as the latest in a wave of litigation and scholarship calling into question the constitutionality of FDA’s regulatory regime. The head of the Cleveland Clinic called the legitimation of off-label promotion ‘a potential catastrophe for patients.’ . . . Scholars are already predicting that, if it gets such a case, ‘the Supreme Court will find the FDA’s current regulatory scheme unconstitutional.’
This criticism starts in the case itself, in the dissent of one member of the three-judge panel, Judge Debra Ann Livingston. She viewed the majority’s opinion as “call[ing] into question the very foundations of our century-old system of drug regulation.” The majority, she said, would allow “any substance that may be legally sold for some purpose [to] be promoted by its manufacturer for any purpose – so long as the manufacturer’s statements are merely unsubstantiated, rather than demonstrably false or misleading.”
Kesselheim and Mello echo this criticism:
The decision appears to pave the way for medical product companies to conduct poor-quality studies for the purpose of showing products’ utility for unapproved indications. There is no need for companies to design these studies to meet the FDA’s standards for methodological rigor if the companies have no intention of submitting an application for approval of the new use but rather intend to use the study findings only in marketing communications. Companies can design studies in ways that maximize the chances of obtaining a desired result and select which studies to emphasize in promotional communications, ignoring others that do not support their promotional message.
Indeed, pharmaceutical companies would do well to borrow from the CAM playbook in constructing and interpreting studies. Here at SBM, we’ve documented the numerous ways one can play with the evidence to produce a desired result. For example, one can bury the damning results in a lot of noise. The study can be spun to suit one’s purposes. One can twist a negative study into a positive one by moving the goalposts on the study’s objectives and using fetching charts calibrated to make the results look good. Or, just do bad studies, as has been demonstrated time and again with acupuncture. And, as a last resort, there is always outright fraud, Andrew Wakefield-style.
With all due respect, I wouldn’t be so sanguine about physicians’ abilities to sort out all the evidence and come to the right conclusion. First, who has the time? Second, again turning to CAM as an example, the embrace of “integrative medicine” leaves one wondering if evaluating the evidence is within the skill set of a certain number of physicians. Although for entirely different reasons, Kesselheim and Mello are with me on this one: “courts have had greater confidence than is warranted in physicians’ ability to evaluate claims about off-label uses.”
Finally, in light of our experience with dietary supplements, it is wishful thinking to assume that educating physicians and patients to distinguish between “misleading and false promotion, exaggerations and embellishments, and truthful or non-misleading information,” is an achievable goal, or that disclaimers will protect the public.
The FDA has not officially changed its position that off-label promotion is a violation of the FDC Act, although the pharmaceutical industry is trying mightily to push it in that direction. The government is still prosecuting off-label promotion cases. Perhaps the FDA does not agree with critics of the Caronia decision that its ability to regulate drugs has been seriously undermined. At least one law firm representing drug companies warns against a hasty interpretation that Caronia is a get-out-of-jail-free card. It will likely take several years to sort all of this out.
In the meantime, patients should be aware that off-label prescribing is not unusual and that it is sometimes based on insufficient evidence, a problem that some experts think could be exacerbated by more liberal sales promotion practices. Patients have every right to ask their physicians the circumstances of his or her prescribing a drug and the evidence for doing so.