Off-label use
Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration.[1] Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although most studies of off-label use focus on prescription drugs.
Off-label use is very common and generally legal unless it violates ethical guidelines or safety regulations. The ability to prescribe drugs for uses beyond the officially approved indications is commonly used to good effect by healthcare providers. For example, methotrexate is commonly used off-label because its immunomodulatory effects relieve various disorders.[2] However, off-label use can entail health risks and differences in legal liability. Marketing of pharmaceuticals for off-label use is usually prohibited.
Frequency of off-label use[edit]
Off-label use is very common. Generic drugs generally have no sponsor as their indications and use expands, and incentives are limited to initiate new clinical trials to generate additional data for approval agencies to expand indications of proprietary drugs.[1] Up to one-fifth of all drugs are prescribed off-label and amongst psychiatric drugs, off-label use rises to 31%.[3]
Among use of antipsychotic medications in the United States, a shift occurred from typical agents in 1995 (84% of all antipsychotic visits) to atypical agents by 2008 (93%). Atypical use has grown far beyond substitution for the now infrequently used typical agents.[4]
A 2009 study found that 62% of U.S. pediatric office visits from 2001 to 2004 included off-label prescribing, with younger children having a higher chance of receiving off-label prescriptions. Specialist physicians also prescribed off-label more frequently than general pediatricians.[5] In 2003, passage of the Pediatric Research Equity Act gave the FDA power to require pharmaceutical companies to perform clinical trials in all age groups in which clinical use is reasonably foreseeable. By some estimates, the number of clinical trials performed in children from 2002 to 2012 exceeded that in the prior 50 years.[6]
In 2014, the American Academy of Pediatrics released a statement regarding off-label use of pharmaceuticals in children. The article recommends to pediatricians that "Off-label use is neither incorrect nor investigational if based on sound scientific evidence, expert medical judgment, or published literature" and that "Evidence, not label indication, remains the gold standard from which practitioners should draw when making therapeutic decisions for their patients." The statement further advocates additional support and additional incentives for clinical testing of drugs in children, and publication of all results irrespective of positive outcome.[7]
A study published in 2006 found that off-label use was the most common in anticonvulsants. The study also found that 73% of off-label use had little or no scientific support.[3]
By default, use of non-approved drugs is common in obstetrics. By 2010, during almost five decades of activity, the Food and Drug Administration (FDA) had approved only two drugs for obstetrical indications, namely oxytocin and dinoprostone.[8] A small market and the high risk of medicolegal action, as exemplified by the Bendectin case, may explain the reluctance to develop drugs for approval.[8]
Some drugs are used more frequently off-label than for their original, approved indications. A 1991 study by the U.S. General Accounting Office found that one-third of all drug administrations to cancer patients were off-label, and more than half of cancer patients received at least one drug for an off-label indication. A 1997 survey of 200 cancer physicians by the American Enterprise Institute and the American Cancer Society found that 60% of them prescribed drugs off-label.[9][10] In some cases, patients may perceive the efficacy of treatments for off-label purposes to be higher than for their indicated purpose.[11] Frequently, the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs. An example is the use of tricyclic antidepressants to treat neuropathic pain. This old class of antidepressants is now rarely used for clinical depression due to side effects, but the tricyclics are often effective for treating pain (e.g. neuropathy),[12] as well as attention deficit/hyperactivity disorder (ADHD) particularly in adults.[13][14][15]
Veterinary medicines[edit]
The veterinarian has a much smaller pharmacopeia available than does the human practitioner. Therefore, drugs are more likely to be used "off-label" – typically, this involves the use of a human medication in an animal, where there is no corresponding medication licensed for that species. This problem is compounded in "exotic" species (such as reptiles and rodents) where there are very few, if any licensed medications. In addition, especially in Europe, equine veterinarians are forced to use many drugs off-label, as the horse is classified as a "food-producing animal" and many veterinary drugs are labeled specifically not for use in animals intended for human consumption.
In the United States, this practice is permitted by the Animal Medicinal Drug Use Clarification Act of 1994 (P.L. 103-396). The FDA specifically prohibits extralabel use of a number of antibiotics, anti-inflammatory drugs and hormones in food producing animals. FDA also tightly controls the use of certain veterinary-prescribed drugs when administered in the feed of food-producing animals.[33]