The Off-Label Drug War of Words

If knowledge is power and ignorance is bliss, what is power used to prevent knowledge from eliminating ignorance?

I don’t know; ask the FDA (U.S. Food and Drug Administration).

The practice of prescribing a drug “off label” to treat an illness other than that for which it was originally intended predates not only the FDA, but Western Civilization itself. The trial and error process by which medicine has advanced-and continues to advance-has certainly been made more scientific by the clinical trial processes required before the FDA approves a drug for a new use. Thankfully for the cause of progress, this is not the only place where trial and error occurs.

Once a new drug has been deemed safe by regulators and is released to the market, it is still lawful for scientists and physicians to use their judgment and experience, as well as that of their peers, to advance the clinical frontier. Nowhere is this more important than in treating deadly diseases like cancer, where the stakes of waiting for new drug approvals are extremely high, and so-called orphan diseases, where the financial motivation to develop new treatments is low.

Many of these off-label uses have proven so successful that they have gone on to become “standard of care” treatments. Other off-label uses, particularly for treating allergies or psychiatric ailments, are widespread despite the fact that 75 percent of off-label treatment lacks scientific evidence demonstrating improved efficacy compared to a placebo. A few off-label uses, like the notorious Fen-Phen combination once prescribed for weight loss, proved to have disastrous side effects. Yet such risk of error is inherent to the trial-and-error process.

The most commonly quoted estimate is that 21% of all prescriptions are written for off-label use. This generates valuable clinical experience and knowledge that is formally disseminated through peer-reviewed journal articles, medical conferences, and manufacturer sponsored educational outreach programs. It is also informally disseminated through doctor-to-doctor, doctor-to-patient, patient-to-patient, and patient-to-doctor conversations, increasingly mediated by online social networks.

Some of this dissemination-even if it is proven to be 100% truthful, such as distribution of a peer reviewed paper-can land you to jail. Even more strangely, one person can be sent to jail, or a corporation fined millions of dollars, for disseminating the same information which it would be perfectly legal for another person or corporation to distribute. The fact that the information is both truthful and beneficial to doctor and patient is no defense.

How is this possible in the USA?

I don’t know; ask the FDA.

Despite acknowledging the importance and even necessity of off-label prescribing, the FDA has been waging war on it for years. The regulatory logic behind the agency’s position is that no one would submit to the enormous expense of additional clinical trials of already approved drugs for new uses if those new uses enjoyed a level playing field in the marketplace despite lack of FDA approval. The FDA cannot directly control the actual practice of medicine (at least not yet), and the First Amendment unambiguously protects free speech if it is truthful and non-commercial. So the only club the agency has left in an effort to encumber the off-label market is to go after commercial speech, which enjoys a lower level of constitutional protection.

The FDA has waged much of this war through enforcement activities, including the use of undercover agents posing as doctors. This has led to multi-million dollar settlements, jail terms, and in at least once case the suicide of a doctor after his life was ruined. Most of those caught in the FDA’s snare were never accused of disseminating untruthful information. Rather, they were accused of having a financial interest in the dissemination of truthful information in contravention to FDA regulations. This rendered their activities commercial speech, whose First Amendment protection-attenuated as it already is-has been under assault for over a century.

The FDA has gotten away with this despite the fact that its regulations are muddled and subject to capricious enforcement. In response, manufacturers have been begging both the FDA and the courts to make the rules clear and unambiguous, in order to create a bright red line between permitted and banned activities. Patient groups also have petitioned the FDA to get its act together. Lawsuits abound. A comprehensive review of the courtroom battles trying to clear up this mess can be found in an August 2011 article in Health Matrix: The Journal of Law & Medicine, titled, “Hidden Truth: The Perils and Protection of Off-Label Drug and Medical Device Promotion.”

But don’t hold your breath. Capriciousness, unpredictability, obfuscation, and delay are central to the FDA’s regulatory campaign to sabotage off-label prescribing. Meanwhile, offering inducements, such as patent extensions or tax advantages, to convince manufacturers to submit approved drugs to additional clinical trials for new uses seem not to have occurred to the FDA.

The chilling effect of this regulatory overreach on innovation is devastating. But innovation isn’t the only victim. The damage to the rule of law is profound as well.