One of the most important elements of medicine is also among the least well known: the ability of physicians to prescribe approved medicines for purposes not sanctioned by the Food and Drug Administration. These so called “off-label” uses are perfectly legal, and doctors rely on them extensively. But in a number of ways, regulators make it difficult for doctors to learn about and prescribe drugs off-label; one such way is a rule that forbids manufacturers from promoting such uses. That might change soon. Two federal courts are now considering lawsuits that challenge the constitutionality of the off-label promotion ban.
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—to treat high blood pressure or a certain kind of leukemia, for example. However, once a drug has been approved, physicians may legally prescribe it for any other purpose. And because medical research reveals treatment successes long before a new use can work its way through the lengthy FDA approval process, off-label prescribing enables patients to benefit from the most up-to-date medical knowledge.
The practice is ubiquitous in a number of medical specialties and, by some estimates, at least 20 percent of all prescriptions written are off-label. Naturally, off-label prescribing must be done judiciously because “guesses” about possible uses of drugs may have deleterious results, as illustrated by a recent safety review of the heart drug Multaq (also known as dronedarone). According to a December 2011 announcement by the FDA, although the drug reduces the likelihood of hospitalization in patients who have had transient atrial fibrillation (an abnormal heart rhythm)—which is the approved, on-label, use—the drug increases the risk of serious cardiovascular events, including death, when used by patients in permanent atrial fibrillation. That means doctors must continuously gather information about the risks and benefits of all the medicines they prescribe, for both on- and off-label uses.
The FDA has acknowledged, “off-label uses or treatment regimens may be important and may even constitute a medically recognized standard of care.” Nevertheless, regulators aggressively exercise their authority over drug labeling and “promotion”—which is construed to encompass not just advertising but virtually any communication with health professionals or patients about the drug—to prevent manufacturers from disseminating information about off-label uses, even to doctors.
A drug firm may only engage in a severely limited range of so-called “educational” activities, such as speaking about research projects at medical conferences. Scientists, but not sales representatives, working for drug firms may answer questions about off-label uses posed directly to them by doctors. And in some circumstances, they may also 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.
Since most clinical research on medicines is funded, at least in part, by drug firms, this restriction cordons off a huge fraction of published research from manufacturers’ dissemination. And almost everything else appears to be prohibited, although the FDA’s regulations are so unclear that even legal and regulatory experts often cannot decipher what is permitted and what is not.
An Unconstitutional Restriction of Speech?
Constitutional scholars have argued that restrictions on truthful and non-misleading speech violate the First Amendment to the Constitution. 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 to do so.
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 had 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 the ban on disseminating truthful and non-misleading information contained in medical journal articles was an unconstitutional restriction of commercial speech.
On appeal, the FDA tweaked its interpretation of the law and claimed that the rules governing journal articles merely established a “safe harbor” under which manufacturers would be automatically deemed to be in compliance. The regulations did not prevent all off-label promotion, according to agency lawyers, who conceded that drug manufacturers do have some First Amendment rights, including the right to distribute journal reprints. That made the specific constitutional question moot, but in the intervening years, the FDA has declined to say definitively what else is permitted.
Within the next few months, however, the U.S. Court of Appeals for the Second Circuit in New York and the U.S. District Court of D.C. will both have an opportunity to opine on and clarify the issue.
In January 2011, the Second 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 had arranged a meeting between a paid medical consultant named Peter Gleason and another physician who was later revealed to be a government informant.
At that meeting, the informant asked Dr. 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 eyes of the FDA.
Caronia chose to have his day in court, but 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, his life fell apart, and he committed suicide in February 2011. Ironically, the FDA has since approved one of the off-label uses in question.
Unclear, Ambiguous, and Overbroad Rules
During oral arguments in January 2011, the Second Circuit’s three-judge panel seemed inclined to agree that the FDA rules are unclear, ambiguous, and overbroad. At one point, Department of Justice 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 a crime.
But the government’s reasoning was circular, because the only way in which the drug was “misbranded” was Gleason’s claim that the drug was safe and effective for off-label uses. Not surprisingly, the judges had difficulty following the government’s argument and seemed sympathetic to Caronia’s position.
The DC District Court challenge is even more bizarre. New Jersey-based drug maker Par Pharmaceutical argued that the off-label promotion regulations could subject manufacturers to prosecution for wholly lawful on-label promotion.
Par Pharmaceutical manufactures an appetite stimulant called Megace, which has been approved for treating anorexia, severe malnutrition, and sudden weight loss in AIDS patients. It is also widely recommended by major treatment guidelines for the off-label use to stimulate the appetite of geriatric and cancer patients. Megace and similar drugs are so widely accepted as the standard of care for those conditions that it would arguably be unethical to conduct placebo-controlled trials in order to add the new indications to the label.
Par’s most potent argument is that the prohibition of off-label promotion of Megace also precludes the promotion of a substantial number of obviously legitimate on-label uses. The hospitals and long-term care facilities that commonly treat patients who suffer from anorexia and late-stage AIDS also tend to treat geriatric and cancer patients. Here’s the rub: The FDA prohibits drug makers from promoting fully-approved on-label uses in environments where a substantial amount of off-label prescribing is likely to occur. In filings with the District Court, Par provides examples of other drug companies in a similar Catch-22 that have been prosecuted for what otherwise appeared to be fully legal speech.
The U.S. Supreme Court has held on several occasions, most recently in the June 2011 case Sorrell v. IMS Health, that truthful speech used in pharmaceutical marketing is entitled to the same level of First Amendment protection as other forms of commercial speech. And the U.S. Court of Appeals for the Seventh Circuit decision in United States v. Caputo (2008) concluded 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 Second Circuit or the D.C. District Court will strike down at least part of the off-label promotion ban.
The government should be able to regulate commercial speech to ensure it is truthful and not fraudulent, but the First Amendment’s guarantees would be weak, indeed, if they did not protect the right to utter, hear, and promulgate truthful, non-misleading information. As the Supreme Court concluded in the landmark case Thompson v. Western States Medical Center (2002) 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.” That is a supremely good rule, one that leads to the conclusion that some types of off-label promotion are protected speech.