The Curious Case of Off-Label Use

In the United States, new drugs and devices cannot be marketed until the Food and Drug Administration finds that they are safe and effective for their intended use. To obtain FDA approval, pharmaceutical and device manufacturers must submit extensive animal, in vitro, and human study data demonstrating safety and effectiveness. Agency staff members-often joined by an external interdisciplinary advisory committee-review the research reports to evaluate the quality of the data and make the essential risk-benefit judgments that determine whether a medical product is safe and effective.

Drug and device companies spend many years and millions of dollars preparing the data required for FDA approval. Although the agency review process is imperfect, it does ensure that a company's claims about its product are closely scrutinized by independent scientists, physicians, and patient representatives. Safety is evaluated in light of the product's specific purpose: Are the therapeutic benefits valuable enough and likely enough to justify the known risks posed by the product? Effectiveness, too, is determined in light of the product's specific purpose: Does it have the desired impact on enough people with the condition at which it is aimed? When the FDA approves a product, officials approve a specific label for the product, too. That label must contain detailed scientific information about the product, including the approved indications, dosage and method of administration, and use in specific populations.

This rigorous and fine-grained regulatory approach to product evaluation is circumscribed, however. When Congress created the FDA, members said that they did not intend for the agency to regulate the practice of medicine. Thus, the FDA oversees only product manufacturers and commercial activities. This general regulatory stance explains the curious case of off-label use. After the FDA approves a drug or device for its intended use, physicians and other authorized practitioners may prescribe the product for uses not covered by the approved label. The FDA severely restricts manufacturers' freedom to promote products for unapproved uses. Companies that want to expand the formally approved uses for their products must submit safety and effectiveness data and secure FDA approval for the new uses. But the FDA takes a hands-off approach to clinicians prescribing products for unapproved uses.

As a result, drugs and devices are prescribed in circumstances not covered by the initial product evaluation. Off-label prescribing occurs not just when clinicians give products to people with conditions not listed on the approved label, but when they depart from the approved drug dosage, method of administration, or patient population. Unapproved product combinations, such as using two different drugs to treat a single condition, are another form of off-label prescribing.

Surveys show that off-label prescribing occurs routinely. For example, a study published last year examined prescribing practices for 169 commonly used drugs. Researchers found that about 21 percent were prescribed to patients with diagnoses other than those included on the label. Off-label prescriptions were relatively common for cardiac drugs (46 percent), anticonvulsant drugs (46 percent), and asthma medications (42 percent). Researchers also found that about 15 percent of all drugs were prescribed for off-label uses with little or no scientific support. For some types of drugs, the figures were unusually high. For example, 96 percent of off-label prescriptions for psychiatric drugs and 89 percent of those for allergy drugs were based on limited or no scientific evidence.¹

The Debate over Current Policy

The FDA's hands-off approach to off-label prescribing has many supporters. One is the American Medical Association, which says the approach respects "the autonomous clinical decision-making of a physician." Off-label use is defensible, according to the AMA, "when such use is based upon sound scientific evidence and sound medical opinion."² This organization and others supporting the current FDA approach stress its benefits to patients. For some practitioners, such as pediatricians, oncologists, and HIV/AIDS specialists, off-label drugs are essential to their work. If any deviation from the product label had to await specific FDA approval, clinicians say, patients would lose the opportunity to benefit from innovations that develop as the product is used in...