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If you use a beta-blocker called Corgard to prevent migraine headaches, you are taking advantage of an important if obscure element of modern medicine: physicians' ability to prescribe approved medicines for purposes not explicitly sanctioned by the Food and Drug Administration (FDA). Corgard is approved for angina and high blood pressure only, yet migraine sufferers and their physicians know that it has other useful properties as well. These so-called "off-label" uses of drugs are perfectly legal, yet regulators make it all but impossible for manufacturers to inform doctors about such uses. No law or regulation explicitly forbids it, but the FDA treats it as misbranding or fraud. The government has prosecuted numerous drug makers for off-label promotion, with penalties and settlements in the billions of dollars.
But that could change soon. In the last few years, the agency has lost several cases in which federal courts have held that giving doctors truthful information about off-label uses is protected by the U.S. Constitution's First Amendment. And while prosecutors have continued to drag drug makers to court, new leadership at the FDA has finally signaled some willingness to obey the Constitution. In the waning days of President Barack Obama's administration, the agency issued a rule that reinforced its speech restrictions, but regulators are now reconsidering that position.
Before a drug can be sold in the United States, it must be certified by the FDA as safe and effective for a specific "on-label" use—to treat high blood pressure or a certain kind of leukemia, for example. But once a drug has been approved, physicians may legally prescribe it for any other purpose. There is typically a long lag between clinical research findings and FDA approval of a new use; journal articles and presentations at scientific conferences far outpace the agency's process. So off-label prescribing makes it possible for patients to benefit from the most up-to-date medical knowledge.
Off-label prescribing is ubiquitous in a number of medical specialties and, by some estimates, at least 20 percent of all prescriptions are written for off-label uses. A 2013 study, for example, found that about 30 percent of the prescriptions for oncology drugs were for off-label uses.
Needless to say, off-label prescribing must be done judiciously. "Guesses" about possible uses of drugs may have deleterious results, as illustrated by a 2011 safety review of the heart drug Multaq. The approved, on-label use of the drug is to treat people with transient atrial fibrillation (an abnormal heart rhythm). However, according to the FDA, the drug increases the risk of serious cardiovascular events, including death, when used by patients with permanent atrial fibrillation. Prescribing Multaq for the latter condition because it is safe and effective for the former would put patients at grave risk.
So doctors know they must continuously educate themselves about the risks and benefits of all the medicines they prescribe, for both on- and off-label uses. And drug manufacturers have a legal obligation to monitor the safety of their products long after they've been approved; whether they're promoting approved uses or off-label ones, the FDA has the authority to prosecute companies when they distribute false or misleading information. Similarly, drug companies can (and routinely are) sued by patients who believe some aspect of information is incorrect or misleading. Those are compelling reasons for manufacturers to continue to test their drugs long after approval, despite this rhetorical question posed by a former FDA official in the Washington Post, "If your drug is approved for X, why would you ever commit millions [of dollars] in additional testing to get approved for Y, when it's already legal to use it for Y?"
If the threat of agency action or private litigation weren't enough, there is yet another reason why drug companies continue to test the safety and effectiveness of their products for both on- and off-label uses. The overwhelming majority of drug sales in the United States are paid for by insurance companies and government health care programs, and they demand evidence that drugs are safe and effective before they agree to pay for new uses.
Medical professional societies, the FDA, or perhaps the National Institutes of Health or another agency could do more to keep track of and distribute scientific evidence about off-label uses. But drug makers will inevitably have the most comprehensive and up-to-date information about their products.
The FDA itself acknowledges that "off-label uses or treatment regimens may be important and may even constitute a medically recognized standard of care" and insists that drug companies are in the best position to understand the risks and benefits of their products. Nevertheless, regulators have aggressively exercised 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.
Until recent federal court decisions, drug firms were permitted only to engage in a severely limited range of so-called "educational" activities, such as speaking about research projects at medical conferences. Scientists working for drug firms, but not sales representatives, could answer questions about off-label uses posed directly to them by doctors. In some circumstances they were able to send peer-reviewed medical journal articles and excerpts from medical textbooks to physicians—but not if the firm had any financial ties to the underlying research.
Since most clinical research on medicines is funded, at least in part, by drug firms, this restriction cordoned off a huge fraction of published research from dissemination by manufacturers. And almost everything else appeared to be prohibited, although the FDA's regulations are so unclear that even legal and regulatory experts often had difficulty deciphering what was permitted and what was not.
When pressed, FDA officials have occasionally acknowledged that truthful speech is protected by the First Amendment. But they have continued to prosecute manufacturers, even when company employees merely informed doctors about off-label uses the agency eventually approved. The agency's attitude, according to federal judge Royce Lamberth, was that scientific evidence about off-label uses should be considered false until the FDA says it is true. According to Lamberth, "the FDA exaggerates its overall place in the universe," inasmuch as the "First Amendment is premised upon the idea that people do not need the government's permission to engage in truthful, non-misleading speech about lawful activity."
The agency has gone to baffling lengths to defend its position. For example, prosecutors (from the Department of Justice, acting on behalf of FDA) have argued that the FDA policies do not prohibit constitutionally protected speech but merely unprotected conduct—that is, mislabeling a drug. Under the Food, Drug and Cosmetic Act, a drug's FDA-approved label must include safety information for the manufacturer's "intended use" of the product. The agency's theory is that off-label promotion renders a drug mislabeled because the promotion is evidence of another intended use not described on the product's label. Most courts have seen through this circular logic and have therefore concluded that that the FDA policies are unconstitutional.
In a 1999 case brought by the nonprofit Washington Legal Foundation, a federal district court held that the FDA's policy of restricting the dissemination of medical journal articles describing off-label uses was an unconstitutional restriction of commercial speech. On appeal, the FDA tweaked its argument and 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. That lack of transparency is unfair both to industry and to patients.
Another legal milestone was the 2012 case U.S. v. Caronia, in which the federal Second Circuit Court of Appeals overturned the conviction of a pharmaceutical sales representative who told a doctor about off-label uses of Xyrem, a prescription drug manufactured by Orphan Medical, Inc. The court held that "the government cannot prosecute pharmaceutical manufacturers and their representatives under the [Food, Drug and Cosmetic Act] for speech promoting the lawful, off-label use of an FDA-approved drug." Conviction for off-label marketing that was not untruthful or misleading would infringe the defendant's First Amendment rights, the court found, although "of course, off-label promotion that is false or misleading is not entitled to First Amendment protection." The FDA opted not to appeal the decision to the Supreme Court, but said that the Caronia decision would not significantly affect its enforcement.
In 2015 a U.S. district court judge in New York handed the FDA another significant defeat, ruling again that the agency cannot bar truthful, off-label marketing without violating freedom of speech. That led to an agreement between the FDA and the plaintiff, Amarin, that the drug maker may promote one specific off-label use of Vascepa, a drug approved for lowering triglycerides, so long as the company uses "truthful and non-misleading" speech.
Those decisions by lower courts comport with U.S. Supreme Court rulings, which have held on several occasions, most recently in the 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.
Nevertheless, in 2016 the FDA secured a guilty verdict in a case, U.S. v. Facteau, against two medical device company executives, even though the judge informed the jury that off-label promotion "is not itself a crime." The judge bought the government's bogus argument that it was prosecuting the defendants not for their speech but for the "act" of mislabeling a medical device. That verdict may, of course, be overturned on appeal, but it suggests the FDA has not been chastened by the growing number of court decisions against it.
Of course, even if the courts do eventually establish a clear and unambiguous precedent holding off-label promotion to be constitutionally protected, that need not keep the FDA and federal prosecutors from hounding drug makers. The feds know that under federal anti-fraud laws, even charging a drug firm with mislabeling is enough to disqualify the company from selling any products at all to federal health programs, such as Medicare and the Veterans Health Administration. Even if the charge is later dismissed due to its unconstitutionality, an indictment alone could cost the firms billions of dollars in lost sales while the case is being litigated.
When faced with a threat of prosecution and the likely loss of billions in revenue, most companies capitulate and agree to pay a hefty fine and to refrain from the perfectly legal and constitutionally protected activity of off-label promotion. There have been dozens of examples, including Allergan, which agreed in 2010 to a $600 million settlement to resolve a case involving the promotion of its drug Botox for treatment of chronic migraines before FDA review or approval of the drug for that indication; and Endo Pharmaceuticals' agreeing in 2014 to pay $171.9 million to resolve liability for off-label promotion of topical anesthetic Lidoderm.
Businesses that might have gone to court to clear their names and defend their First Amendment rights have chosen not to do so in order to avoid a criminal indictment that could cost their shareholders billions. That is, in effect, legalized extortion by the government.
Fortunately, a new head of the FDA, Dr. Scott Gottlieb, appears to have brought with him a new attitude about the legality of off-label promotion. In early January 2017, during the Obama administration's final few days, the FDA issued a rule on "intended uses" that reiterated its view that off-label promotion renders a drug or medical device criminally mislabeled. The incoming Trump administration put a hold on that and all other new regulations, choosing to implement some and reverse many others. The FDA's intended-use rule was among those chosen for additional review, suggesting that the new administration may not let it go forward—and may, in fact, rewrite the document to clarify what kinds of off-label promotion will be considered legal. A final decision is expected sometime this month, and many observers are optimistic that the agency will finally acknowledge that the FDA is not immune to the First Amendment.
The government should be able to regulate commercial speech to ensure it is not misleading or 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 2002 case Thompson v. Western States Medical Center, which involved 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 excellent rule surely suggests that some types of off-label promotion are protected speech.
Henry I. Miller, a physician and molecular biologist, is the Robert Wesson fellow in scientific philosophy and public policy at Stanford University's Hoover Institution. Gregory Conko is deputy director of the George Mason University Law & Economics Center.
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