The law has long been of two minds about the power of the Food and Drug Administration (FDA) to regulate the off-label use of drugs that it approves for sale. Today the FDA has the unquestioned power to limit the uses for which a drug may be sold to those uses approved by the FDA after a rigorous and costly review process. By the same token, the FDA is prohibited by statute from interfering with the practice of medicine. Doctors, therefore, may exercise their professional judgment and prescribe any FDA-approved drug for unapproved or “off-label” use.
This dual regime makes little sense. If FDA approval is so important, why allow physicians to prescribe a drug for an unapproved use, ever? Alternatively, if physicians may prescribe drugs for conditions that have not been reviewed by the FDA, why allow the FDA to block drugs from physician-prescribed use in the first place?
Illustration by Barbara Kelley
The current law ducks this tension with an inelegant compromise. Physicians may go their own way in prescribing drugs for off-label uses; indeed, the appropriate standard of care in medical malpractice cases may require the off-label use of an approved drug. Yet, drug companies and their sales agents are not allowed to promote the drugs for off-label uses. If they do, the FDA imposes heavy criminal sanctions on them.
The Case of Alfred Caronia
The current situation may now change in light of a recent decision of the Court of Appeals for the Second Circuit in United States v. Caronia. In 2005, the government launched a routine criminal prosecution of Alfred Caronia for his illegal off-label promotion of the drug Xyrem. Xyrem had received FDA approval for narcolepsy (sleep disorder) and cataplexy (weak muscles). As a matter of law, the FDA is supposed to approve only drugs that are “safe and effective for use under the conditions, prescribed, recommended, or suggested in the labeling thereof.” In practice, that standard conceals a messier truth, for the FDA approves drugs with horrific side effects, because there is no better alternative.
For example, when Xyrem is properly used, it can lead to “difficulty breathing while asleep, confusion, abnormal thinking, depression, nausea, vomiting, dizziness, headache, bedwetting, and sleepwalking.” If anyone abuses the drug, the list of adverse effects extends to “seizures, dependence, severe withdrawal, coma, and death.” The FDA requires all of these symptoms to be listed in the black box warning required for the most dangerous medicines.
Caronia got into trouble when he admitted to a physician-turned-government-informant that Xyrem had also been used to treat insomnia, periodic leg movement, and a host of other conditions. He also noted that some physicians had prescribed it to patients under the age 16, for which it had not received FDA approval.
The Why and How of Off-Label Uses
On high principle, the FDA has long insisted that any drug company promotion of off-label uses undermines the integrity of its preapproval system. But even as the FDA criminally prosecutes drug companies for such promotion, information about the off-label uses still gets around. Thus, between 25 and 60 percent of drugs are prescribed for off-label uses. For cancer patients, that number may be as high as 65 percent; patients on dialysis or those with AIDS are also high consumers of off-label products.
Given that widespread use, the FDA’s position has at least two serious downsides. The first is this: if the off-label uses are indeed beneficial, anything that slows down their dissemination could mean the difference between disease or recovery—life or death—in thousands of sick individuals. The second is that the prohibition against promotion cuts so deeply that drug companies are not allowed even to warn doctors about the bad side-effects from unauthorized uses, lest that warning be construed as an implicit approval for an off-label use.
Fortunately, there are many physician-operated intermediaries that do supply accurate and up-to-date information about these off-label uses. Those warnings are more valuable than anything that the FDA recommends because they have four systematic advantages: (1) they are updated to take into account recent evidence, (b) they look at foreign as well as domestic use patterns, (3) they deal with the critical issues of drug interaction, which addresses how drugs should, or should not, be used in combination, and (4) they prioritize drug uses so that more effective and less toxic drugs are tried first.
Allowing drug companies to disseminate this third-party generated information is stoutly resisted by the FDA—more, one fears, for its own bureaucratic imperatives than for the welfare of the patient population. Indeed, no one to date has made a credible claim that these widespread off–label uses are more dangerous than the FDA-approved uses.
Enter the First Amendment
It is encouraging, if somewhat surprising, that the Second Circuit set aside Caronia’s conviction; promoting the drug, the court reasoned, violated his right to freedom of speech under the First Amendment. The logic behind that conclusion is simply this: when physicians and patient groups communicate about that same information, their dealings lie outside the reach of the criminal law. Could Congress also silence these parties? Of course not. So why can’t drug company representatives do the same exact thing?
For many years, this First Amendment claim might have been barred by the now discarded Supreme Court rule that commercial speech lies outside the protection of the First Amendment. That position does not have much traction today; consider the advertisement of commercial products. The modern law on this issue is crystallized in the well-rehearsed test of Central Hudson Gas & Electric Co. v. Public Service Commission (1980), which was used to strike down a state law that forbade all advertisements by a public utility.
Under Central Hudson, for the regulation against speech to be valid, it must target speech that is either false or misleading—neither of which occurs in the truthful promotion of off-label uses. If the speech is determined to be neither false nor misleading, the burden shifts to the government to show that its regulation is narrowly tailored to advance an important state interest.
At this juncture, everything turns on the strength of the FDA’s power to safeguard health and safety, which fall within the heart of Congress’s power to regulate. On this issue, the Supreme Court took a very expansive view of the power of Congress to keep drugs from the market in United States v. Rutherford (1979). But more recently, in the context of speech, the Court has been far more suspicious of government. The 2011 Supreme Court case of Sorrell v. IMS Health, for instance, struck down on First Amendment grounds a Vermont law that limited the sale, transmission, or use of prescriber-identifiable data.
The acid test is therefore about how broadly one conceives the legitimate ends of state regulation. Once it is conceded that these cases of speech do not involve fraud or misleading statements, it is hard to come up with a compelling rationale that allows the government to prevent truthful information from reaching those people who are in desperate need of it.
These points are controversial. The dissent of Judge Debra Ann Livingston in the Second Circuit case adhered the traditional view that Caronia was part of a general scheme of economic regulation, to which the standard of extreme deference applied. She is surely correct to write that, even if there is no law forbidding the consumption of arsenic, “this would not endow Abby and Martha with a First Amendment right to offer arsenic-laced wine to lonely old bachelors with the intent that they drink it.” But note the key difference. Abby and Martha wanted to kill people, not to save lives. Even the most robust interpretation of the First Amendment does nothing to prevent the state from using speech acts to secure a conviction for murder, rape, or grand theft auto.
Murder, rape, and theft have always been classified as malum in se—bad in themselves—precisely because they violate the fundamental libertarian prohibition against the use of force or fraud. But Caronia did nothing that offends that fundamental social norm. The FDA prohibition against the promotion of off-label uses of drugs has, as its sole objective, the protection of the FDA’s undeserved monopoly over information.
The supposed conspiracy for which Caronia was convicted has a better name: productive cooperation, which deserves protection in economic and non-economic ventures alike. Most people rate their ability to gain access to information about life-saving drugs as far more valuable than their ability to participate in political elections. The First Amendment should be read to follow that intuition.
Caronia is a step in the right direction. If it stands up, it will open up the information market for pharmaceutical products. But other federal courts have yet to weigh in, and the issue faces an uncertain future before a Supreme Court that is torn between its extreme deference to legislation on economic and commercial issues and its more suspicious attitude toward the regulation of commercial speech.
Some years ago, the Circuit Court for the District of Columbia in Abigail Alliance v. von Eschenbach held, following Rutherford, that people do not have a constitutional right to use experimental drugs without FDA permission, no matter how sound their medical advice, how dire their condition, or how useless their available alternatives. The decision is deeply ironic because it is well established that autonomous people cannot be forced to take drugs against their will, no matter how beneficial. Yet the FDA can deny these same individuals the autonomous right to choose a beneficial drug of their choice.
Cases like Rutherford and Abigail Alliance hold out the dreadful prospect that Congress could ban all off-label uses of drugs on the ground that the prohibition does not implicate any interest in free speech. It is doubtful that an enraged public would stand for a decision that chokes off most of the available treatments for life-threatening conditions.
The key point here is that the Supreme Court should take stock of the situation and ask if Congress should ever be able to block the sale of a drug that is not tainted by false or misleading information. The unbounded power of the FDA to block the use of such drugs does not square with any defensible conception of individual autonomy or freedom of speech. The FDA is vulnerable. The Supreme Court should cut it down to size.