Off-Label Drug Use – Are You Informed?

Last October, we highlighted the Huffington Post’s series regarding Johnson & Johnson's drug Risperdal and the billions of dollars the company made whilst failing to warn prospective patients, particularly young males, about the risk of developing breasts. .  In that article, we touched upon the concept of “off-label” drug use, a hot topic recently addressed by the Wall Street Journal, in an article entitled, “Risk of Off-Label Uses for Prescription Drugs.”

The timing of the article could not have been better as the United States District Court for the Eastern District of California is prepared to hear arguments in U.S. ex rel. Solis v. Millennium Pharmaceuticals, Inc. as to whether the US Food & Drug Administration (FDA) has the authority to limit the pharmaceutical industry’s right to free speech in “truthfully” marketing its products.  Recall that a pharmaceutical company is not permitted to market its product off-label, an unlawful activity that has cost some pharmaceutical manufacturers hundreds of millions, if not billions of dollars.

The Wall Street Journal’s article was premised upon a recent study spearheaded by the United States Department of Veterans Affairs, the University of Pittsburgh School of Medicine and the University of Pittsburgh School of Pharmacy, and published in the Journal of the American Medical Association Internal Medicine (JAMA), entitled “Off-Label Drug Use and Adverse Drug Events Turning up the Heat on Off-Label Prescribing.” 

The study was done, in part, because of concerns regarding adverse drug events (ADEs), and that no systematic investigation of the effects of off-label drug use in adult population had been performed to date.   This is quite remarkable considering the fact that, according to the study, a significant proportion of drugs doctors prescribe (approximately 12 percent) are for uses other than those approved by the FDA.

In order to fully appreciate the magnitude of the study, on must understand the concept of off-label drug use, which is the practice of prescribing medications for indications, or using a dosage or dosage form, that have not been approved by the US Food and Drug Administration. Surprisingly, FDA has no specific regulation addressing off-label drug use, but it did issue a notice of proposed rule-making in 1972 that provides insight into the agency’s analysis:

Once [an approved] new drug is in a local pharmacy after interstate shipment, the physician may, as part of the practice of medicine, lawfully prescribe a different dosage for his patient, or may otherwise vary the conditions of use from those approved in the package insert, without informing or obtaining the approval of the Food and Drug Administration.  This interpretation of the Act is consistent with Congressional intent as indicated in the legislative history of the 1938 Act and the drug amendments of 1962. Throughout the debate leading to the enactment, there were repeated statements that Congress did not intend the Food and Drug Administration to interfere with medical practice and references to the understanding that the bill did not purport to regulate the practice of medicine as between the physician and the patient. Congress recognized a patient's right to seek civil damages in the courts if there should be evidence of malpractice, and declined to provide any legislative restrictions upon the medical profession.  [37 Fed.Reg. 16503 (1972)]

In 1981, the above proposed rule was cited by the US Court of Appeals for the Fifth Circuit in the case of The United States v. H. Ray Evers, M.D.  In that case, the FDA sued Dr. Evans for “misbranding” a drug in violation of the Federal Food, Drug and Cosmetic Act (“Act”).  More specifically, Dr. Evers had been utilizing “chelation” drugs, which were FDA approved for the treatment of heavy metal poisoning, to treat circulatory disorders.  Interestingly, prior to bringing suit, the FDA explicitly informed Dr. Evers that he could legally prescribe chelating drugs for the treatment of circulatory disorders.  Moreover, during litigation, the United States agreed with Dr. Evers that the provisions of the Act and the FDA regulations did not prevent him from prescribing chelation drugs off-label.  Instead, the United States took issue with Dr. Evers promotional activities associated with his off-label drug use.  Ultimately, the US Court of Appeals found in favor of Dr. Evers because he was not promoting the use of chelation drugs to other physicians, but only to his patients.

In many cases, off-label drug use can be beneficial.  For instance, if a doctor has a patient with a diagnosis of major depression disorder with psychotic features, then in that instance, a doctor may have a reasonable basis to treat his/her patient with an "off-label" medication such as Risperdal, which is only FDA approved to treat schizophrenia or bi-polar disease.  While the patient does not have the diagnosis of schizophrenia or bi-polar disease, the patient does suffer from psychosis, for which there are no FDA approved drugs on the market to treat.  Thus, a physician may be justified in prescribing the drug off label, provided that the patient has been fully informed about the risks of that medication.  However, should the patient begin to suffer from an adverse effect associated with the drug, the risk-benefit profile for that patient should be reassessed.

This philosophy is supported by the JAMA article/study cited above, which has demonstrated that off-label use that lacked strong scientific evidence had a higher ADE rate (21.7 per 10,000 person-months) compared with on-label use and off-label use with strong scientific evidence (13.2 per 10,000 person-months) had about the same risk for ADEs as on-label use.  Furthermore, the risk for ADEs grew as the number of prescription drugs the patient used increased.  For example, patients using eight or more drugs had more than a five-fold increased risk for ADEs compared with patients who used one to two drugs.  The authors of the study concluded that "Off-label drug use, and particularly off-label use without strong scientific evidence, is a risk factor for adverse drug events (ADEs). Hence, physicians and physician organizations should recognize the enormity of the problem and be active participants in the promotion of cautious prescribing of drugs for off-label uses lacking strong scientific evidence.  Future electronic health records (EHRs) should be designed to enable post-marketing surveillance of treatment indications and treatment outcomes to monitor the safety of on- and off-label uses of drugs."  In a related commentary, Chester B. Good, M.D., M.P.H., and Walid F. Gellad, M.D., M.P.H., of the Veterans Affairs Pittsburgh Healthcare System, write: "Egulae and colleagues have provided compelling evidence that off-label prescribing is frequently inappropriate and that prescribing in these circumstances increases the risk for an adverse event substantially. The FDA and the courts must carefully consider these findings as they contemplate guidance that would relax regulations to permit promotion of drugs beyond their labeled indications."

Consumers beware – many drugs being prescribed off-label today carry significant FDA warnings, some of which caution the user that the drug may substantially increase the risk of death and/or serious bodily injury in some patient sub-populations.  Therefore, before taking a medication, one should consider investigating the medication in detail to determine if the benefit outweighs the risk.    At a minimum, your research should identify the signs and symptoms of adverse reactions associated with the medication, in order to timely trigger reassessment of the need for the drug.