Informed Consent and Shared Decision-Making: A Requirement to Disclose to Patients Off-Label Prescriptions
Authors: Michael Wilkes, Margaret Johns
Journal: PLoS Medicine (2008)

A 9-year-old with cerebral palsy received an injection of the neurotoxin “Botox” to relieve muscle spasms. This off-label use was legal but not approved by the US Food and Drug Administration (FDA) for this indication. People with headaches have also received Botox injections as a legal, but unapproved, treatment—in this case the FDA is investigating whether the manufacturer actually promoted the drug for this indication. In fact, the drug has some significant dangers leading to hospitalizations and deaths [1].

A more familiar instance of off-label drug use would be the example of a 47-year-old male presenting to his doctor with lower back pain. The doctor, having previously suggested over-the-counter medications, prescribes a drug to ease the pain. The doctor tells the patient to take the drug three times a day, but provides no other information. In this case, a reasonable person might wish to be told: (1) that the prescribed drug gabapentin was approved by the FDA only to treat seizures in epilepsy—not for back pain; and (2) that no reliable research supports using the drug for back pain.

These examples are not uncommon, yet current practice does not require or even suggest that doctors disclose any of these facts to their patients. This article argues that as an extension of the legal doctrine of informed consent and the ethical duty of shared decision-making (SDM), patients should be told when a drug is being prescribed “off-label;” that is, it has not been approved for the indication and is being used experimentally.


Summary Points


Off-label prescriptions are those that do not comply with the FDA-approved use for the drug. While they are legal and account for roughly half of all prescriptions written today, often they are not supported by sound scientific evidence.


In addition, they have the potential to drive up the cost of health care and expose patients to unnecessary risks and uncertain outcomes. Legal and ethical principles require physicians to inform patients about risks of medical treatments.


We propose that the doctrine of informed consent be rigorously applied to require doctors to disclose to patients when they are prescribing a drug off-label.


Providing full disclosure to patients and encouraging them to share in decision-making in situations of medical uncertainty is vital to respecting their autonomy.





Off-Label Prescribing
Because a basic premise of the US Federal Food, Drug, and Cosmetic Act is that manufacturers are prohibited from marketing drugs or devices without FDA approval, the public commonly assumes that all uses of prescription drugs have been approved by the FDA. However, after a drug is approved for one set of indications, researchers and doctors often discover new applications for it. Even when the FDA approves a drug for a single, specific use, doctors may legally prescribe the drug to any patient for any use. Physicians are not restricted to prescriptions that comply with the FDA approval. The FDA considers such treatments “off-label” because substantial evidence regarding their safety and efficacy has not been presented or evaluated. But such uses are perfectly legal. In fact, FDA policy explicitly states that “once a [pharmaceutical] product has been approved for marketing, a physician may prescribe it for uses in treatment regimes of patient populations that are not included in the approved labeling” [2]. Indeed, as the Supreme Court has recognized, off-label prescribing “is an accepted and necessary corollary of the FDA's mission to regulate in this area without directly interfering with the practice of medicine” [3].

There are many examples of responsible, off-label prescribing. Specifically, pediatric prescriptions are frequently off-label because many drugs have not been tested on children. Aspirin was widely prescribed to reduce the risk of heart attack long before it was FDA-approved for this purpose. Off-label uses are widespread in oncology, and off-label, antiretroviral combination therapies have saved many AIDS patients. In short, off-label drug prescribing is a significant part of mainstream medicine [4].

While off-label prescriptions are common and sometimes necessary, they also present significant risks. Often, the drug has not been proven safe or effective for treating the patient's condition [5,6], and off-label prescribing usually “occurs without scientific support” [6]. FDA panels have found that off-label uses can be dangerous [7,8]. For example, doctors wrote 18 million prescriptions for the off-label use of fenfluramine for weight loss before it was discovered that thousands of people suffered heart valve damage from it [7].

Off-label prescribing has potential consequences for both the individual patient and for our health care system. First, an off-label prescription may be ineffective or downright detrimental in treating the medical condition. By definition, no governmental body has evaluated the effectiveness or safety for the off-label indication, and often there is no rigorous evidence base to properly evaluate the drug. Second, accepting poorly studied therapies heightens the risk of overmedication and drug interactions. And finally, the drugs prescribed off-label are often more expensive than an off-patent or generic medicine.

Furthermore, there is the potential for an escalating financial burden on our health care system. According to a report by the National Association of Attorneys General, the single biggest factor driving the increase in health care costs is the price of prescription drugs [9,10]. It is likely that a significant part of prescription drug cost is due to increased off-label prescribing of on-patent drugs [11,12]. Prescription drugs are the fastest growing part of our health care costs [9,10], with spending increasing at double-digit rates annually from 1997 to 2005 [9]. Between 1990 and 2002, the amount spent on prescription drugs in the United States increased 4-fold from US$40.6 billion to US$162 billion [9].

In practice, the FDA exercises little oversight on off-label promotion. Making matters worse, pharmaceutical companies often publish questionable research using medical education and communication companies (MECCs) [10]. These MECCs conduct flimsy research and present continuing medical education courses on off-label uses [10]. Often research is written by company-paid ghost writers but bears the name of a medical school faculty member paid generously for the use of their name [13,14]. These “articles” are then presented to doctors at free “educational” programs [10,15]. This strategy is often used to promote off-label, on-patent uses. Not surprisingly, these studies are heavily biased in favor of the company's product and aggressively disseminated to practicing physicians using the army of pharmaceutical sales representatives. Unfortunately, lax regulation has sometimes led to illegal over-promotion of off-label therapies.