The ability of physicians to prescribe approved medicines for purposes not sanctioned by the Food and Drug Administration (FDA) is one of the most important elements of medical care in the United States. These "off-label" uses are perfectly legal, and doctors rely on them extensively. But the agency views off-label prescribing as an attempt to circumvent its control over the nation's pharmaceutical supply, so a number of regulations make it difficult for doctors to learn about and prescribe drugs off-label.
The most prominent rule entirely forbids drug manufacturers from promoting off-label uses. That might change soon, however, because two different federal courts are now considering lawsuits challenging the constitutionality of the off-label promotion ban. And given a string of recent Supreme Court cases affirming commercial free speech rights, one of those cases may at least partially invalidate the FDA's restrictions.
Before a drug can be sold in the United States, it must be certified by the FDA as safe and effective for a specific, or "on-label," use. However, once a drug is approved, physicians may legally prescribe it for any other purpose. And because medical research regularly discovers new treatment options years before the FDA can approve them, off-label prescribing enables patients to benefit from the most up-to-date knowledge.
The practice is ubiquitous in cancer treatment, cardiology, and neurology, and by some estimates, at least 20 percent of all prescriptions written are off-label. The American Medical Association says that many off-label uses are considered "reasonable and necessary medical care, irrespective of labeling." In fact, doctors can be subject to malpractice liability if they do not use drugs for off-label indications when doing so constitutes the standard of care. That's one reason most private health insurance plans with prescription drug benefits cover various off-label uses, as do Medicare and Medicaid.
The FDA acknowledges this in theory. According to the agency's website, "Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment." But the FDA doesn't make it easy for doctors or patients to learn about new off-label uses.
Doctors learn about some off-label uses in medical school, and later by reading medical journals articles or hearing about them from colleagues or at conferences. But the FDA uses its authority over drug labeling and "promotion" (which includes not just advertising but virtually any communication with health professionals or patients) to prevent manufacturers from disseminating information about off-label uses, even to doctors.
Drug makers may engage in a limited range of so-called educational activities, such as speaking about research on off-label uses at medical conferences. And in some circumstances, they may send peer-reviewed medical journal articles and excerpts from medical textbooks to physicians – but not if the firm has any financial ties to the underlying research. Almost everything else is forbidden, though the regulations are so unclear that even experts cannot always tell what is permitted.
National surveys commissioned by the Competitive Enterprise Institute found that a large majority of physician specialists believe the FDA's policies have made it more difficult for them to learn about new uses, and that the agency should not restrict information about off-label use. Nevertheless, the FDA and federal prosecutors regularly hit violators with both civil and criminal sanctions. Just last month, drug maker GlaxoSmithKline pled guilty and paid a record $3 billion to settle allegations that it illegally promoted several of its products for off-label uses. Similarly, Merck agreed to pay $950 million to settle claims that it illegally promoted Vioxx off-label.
But it isn't just big manufacturers that have been targeted. In January 2010, the FDA threatened to prosecute a Florida dermatologist for mentioning in interviews with Elle and Allure magazines and on NBC's Today show that an anti-wrinkle drug she was testing had shown positive results and that "early data shows it may last longer and kick in faster than Botox."
The FDA's aggressive enforcement has attracted the attention of constitutional scholars who argue that restrictions on truthful and non-misleading speech violate the First Amendment. Well-established case law holds that government may not categorically bar truthful and non-misleading speech simply because its purpose is to promote a commercial transaction. Instead, the government must have a substantial interest in regulating the speech in question, and the regulation must directly advance that governmental interest and be no more extensive than necessary.
The agency and its supporters say the ban prevents snake oil salesmen from peddling unproven fixes, and the courts agree that preventing false or fraudulent speech is a substantial governmental interest. But the rules do not merely forbid false or misleading claims; they ban all promotion of off-label uses, even if they have been proven to be safe and effective in clinical trials.
Over the past decade, a handful of challenges have been brought in federal courts, with limited success. But none has resulted in an unambiguous ruling that the restrictions are unconstitutional.
Prior to 1999, for example, FDA regulations prohibited even the distribution of peer-reviewed medical studies unless the manufacturer had already submitted a supplemental application for approval of the off-label use in question. But in a case brought by the nonprofit Washington Legal Foundation, a federal district court held that a ban on disseminating truthful and non-misleading information contained in medical journal articles was unconstitutional.
On appeal, the FDA tweaked its interpretation of the law and claimed the rules governing journal articles merely established a "safe harbor" under which manufacturers would be automatically deemed in compliance. The regulations did not prevent all off-label promotion, according to agency lawyers. And they conceded that drug manufacturers do have some First Amendment rights, including the right to distribute journal reprints. That rendered the constitutional question moot. But in the intervening years, the FDA has declined to say what else is permitted.
The U.S. 2nd Circuit Court of Appeals in New York and the U.S. District Court for Washington, D.C. will each have an opportunity to shed some light on the matter in the coming months.
In January 2011, the 2nd Circuit heard the appeal of a drug salesman named Alfred Caronia who was convicted of conspiracy to misbrand his company's narcolepsy drug Xyrem. Caronia arranged a meeting between a paid medical consultant named Peter Gleason and another physician who was later revealed to be a confidential government informant. At that meeting, the informant asked Gleason about using Xyrem off-label to treat other forms of drowsiness and chronic fatigue. When Gleason answered the questions—providing truthful information about the drug's safe and effective but unapproved uses—both he and Caronia became criminals in the FDA's eyes.
Caronia choose to have his day in court, while Gleason pled guilty to a misdemeanor charge, and Orphan Medical agreed to a $20 million criminal and civil settlement. Gleason's medical licenses were suspended, and his life fell apart. He committed suicide in February of this year. Ironically, the FDA has since approved the off-label uses in question, indirectly validating Gleason's claims.
During oral arguments in January, the 2nd Circuit seemed inclined to agree that the FDA rules are unclear, ambiguous, and overbroad. At one point, Justice Department attorney Douglas Letter tried to explain that off-label promotion "is not a crime" per se, but is merely evidence of Caronia's and Gleason's intent to "introduce a misbranded drug into commerce," which is illegal. But the only way the drug was "misbranded" was Gleason's claim that it was safe and effective for off-label uses. The judges had difficulty following Letter's argument and questioned why such speech should be considered illegal.
The other ongoing challenge, in the D.C. District Court, is even more bizarre. New Jersey-based drug maker Par Pharmaceutical argues that off-label promotion regulations could subject manufacturers to prosecution for wholly lawful on-label promotion.
Par manufactures an appetite stimulant called Megace, approved for treating anorexia, severe malnutrition, and sudden weight loss in AIDS patients. It is also widely recommended by major treatment guidelines for off-label use to stimulate the appetite of geriatric and cancer patients.
Par's most potent argument is that the prohibition of off-label promotion of Megace also precludes a substantial amount of on-label promotion. The facilities that commonly treat patients suffering from anorexia and late-stage AIDS also tend to treat geriatric and cancer patients. Unfortunately for Par, the FDA prohibits drug makers from promoting fully-approved on-label uses in environments where off-label prescribing is likely to occur. In filings with the district court, Par provides examples of similarly-situated drug companies having been prosecuted for what otherwise appeared to be fully legal speech.
Surely the U.S. Constitution must preclude criminal prosecution for engaging in explicitly lawful conduct, Par asks? The fact that the FDA's rules cast even this in doubt shows just how confusing the regulations have become.
The U.S. Supreme Court has held on several occasions, most recently in June of this year, that truthful speech used in pharmaceutical marketing is entitled to the same level of First Amendment protection as other commercial speech. And a recent decision on a related issue by the 7th Circuit Court suggested in non-binding dicta that the FDA's off-label speech restrictions are likely to be "unconstitutional in at least some applications ." There is good reason, therefore, to believe that the 2nd Circuit or the D.C. District Court will strike down the off-label promotion ban, at least in part.
Few would argue that the government may not regulate commercial speech to ensure it is truthful and not fraudulent. But the First Amendment would mean little if it did not protect the right to say and hear truthful information. As the Supreme Court concluded in a landmark 1996 case involving advertising by pharmacists, the "First Amendment directs us to be especially skeptical of regulations that seek to keep people in the dark for what the government perceives to be their own good."
Gregory Conko is a senior fellow at the Competitive Enterprise Institute in Washington, D.C. Henry I. Miller, a physician and former FDA official, is the Robert Wesson Fellow of Scientific Philosophy and Public Policy at Stanford University's Hoover institution.
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