|Regulation of therapeutic goods in the United States|
Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, unapproved dosage, or unapproved form of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although most study of off-label use centers on prescription drugs. Off-label use is generally legal unless it violates specific ethical guidelines or safety regulations, but it does carry health risks and differences in legal liability.
A leading example of how regulatory agencies approach off-label use is provided by the United States Food and Drug Administration (FDA)'s Center for Drug Evaluation and Research, which reviews a company's New Drug Application (NDA) for clinical trial data to see if the results support the drug for a specific use or indication. If satisfied that the drug is safe and effective, the drug's manufacturer and the FDA agree on specific language describing dosage, route of administration, and other information to be included on the drug's label. More detail is included in the drug's package insert.
The FDA approves a drug for prescription use, and continues to regulate the pharmaceutical industry's promotional practices for that drug through the work of the Office of Prescription Drug Promotion (OPDP, formerly the Division for Drug Marketing, Advertisement and Communication (DDMAC). The FDA does not have the legal authority to regulate the practice of the medicine, and the physician may prescribe a drug off-label. Contrary to popular notion, it is legal in the United States and in many other countries to use drugs off-label, including controlled substances such as opiates. Actiq, for example, is commonly prescribed off-label even though it is a Schedule II controlled substance. While it would be legal for a physician to independently decide to prescribe a drug such as Actiq off-label, it is illegal for the company to promote off-label uses to prescribers. In fact, Cephalon, the maker of Actiq, was fined for illegal promotion of the drug in September 2008. Under the Food, Drug, and Cosmetic Act (FDCA) at U.S.C. 21 §§301-97, manufacturers are prohibited from directly marketing a drug for a use other than the FDA-approved indication. However, in December of 2012, the United States Second Circuit Court found that promotion of off-label uses by a company sales representative was considered to be protected speech per the First Amendment. In addition, The Food and Drug Administration Modernization Act of 1997 created an exception to the prohibition of off-label marketing, allowing manufacturers to provide medical practitioners with publications on off-label uses of a drug, in response to an unsolicited request. In 2004, the federal government and whistleblower David Franklin reached a $430 million settlement in Franklin v. Parke-Davis to resolve claims that Warner-Lambert engaged in off-label promotion of Neurontin in violation of the FDCA and the False Claims Act. At the time, the settlement was one of the largest recoveries against a pharmaceutical company in U.S. history, and the first off-label promotion settlement in U.S. history.
Frequency of off-label use
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. Up to one-fifth of all drugs are prescribed off-label and amongst psychiatric drugs, off-label use rises to 31%. 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. New drugs are often not tested for safety and efficacy specifically in children and even when they are tested, the results of these trials may not be disseminated to practicing physicians. A 2009 study found that 62% of U.S. pediatric office visits included off-label prescribing, with younger children at higher risk of receiving off-label prescriptions. Specialist physicians also prescribed off-label more frequently than general pediatricians.
A study published in 2006 found that off-label use was the most common in cardiac medications and anticonvulsants. This study also found that 73% of off-label use had little or no scientific support.
By default use of non-approved drugs is common in obstetrics as, by 2010, during almost five decades of activity the FDA had approved only two drugs for obstetrical indications, namely oxytocin and dinoprostone. 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.
Some drugs are used more frequently off-label than for their original, FDA-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 doctors by the American Enterprise Institute and the American Cancer Society found that 60% of them prescribed drugs off-label. In some cases, patients may perceive the efficacy of treatments for off-label purposes to be higher than for their indicated purpose. 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.
Regulations of off-label use in various countries
In the United States, no law prohibits a physician or other healthcare practitioner from prescribing an approved medication for other uses than their specific FDA-approved indications. Pharmaceutical companies are not allowed to promote a drug for any other purpose without formal FDA approval. Marketing information for the drug will list one or more indications, that is, illnesses or medical conditions for which the drug has been shown to be both safe and effective.
However, once a drug has been approved for sale for one purpose, physicians are free to prescribe it for any other purpose that in their professional judgment is both safe and effective, and are not limited to official, FDA-approved indications. This off-label prescribing is most commonly done with older, generic medications that have found new uses but have not had the formal (and often costly) applications and studies required by the FDA to formally approve the drug for these new indications. However, there is often extensive medical literature to support the off-label use.
In 1993, the FDA approved gabapentin, marketed by Pfizer under the name "Neurontin", only for treatment of seizures. Pfizer subsidiary Warner-Lambert illegally used scientific activities, including continuing medical education and research, to commercially promote gabapentin, so that within five years the drug was being widely used for the off-label treatment of pain and psychiatric conditions—conditions that had not been approved by FDA. In 2004, Warner-Lambert admitted to charges that it violated FDA regulations by promoting the drug for these off label uses: pain, psychiatric conditions, migraine, and other unapproved uses. The company paid $430 million to the federal government to settle the case.
Access to pharmaceutical industry documents has revealed marketing strategies used to promote drugs for off-label use. The United States federal government is aggressively pursuing criminal and civil cases against pharmaceutical companies and their employees for promoting off-label uses of prescription drugs. Between 2003 and 2008, U.S. federal prosecutors and state attorneys general brought more than a dozen cases against drug manufacturers for off-label marketing and won more than $6 billion in criminal and civil settlements. In September 2009, Pfizer paid $1.3 billion, the largest criminal fine ever imposed in the United States, for the off-label marketing of Bextra and three other drugs. Pfizer paid an additional $1 billion in civil penalties resulting from the same illegal activities.
Physicians in the United Kingdom can prescribe medications off-label. According to the British General Medical Council, off-label prescriptions must better serve patient needs than alternatives and must be supported by evidence or experience to demonstrate safety and efficacy.
- Actiq (oral transmucosal fentanyl citrate), a Schedule II controlled substance, is used off-label to treat moderate to severe chronic, non-malignant pain even though it is FDA-approved solely for breakthrough pain in cancer patients.
- Bevacizumab (Avastin) has been used against wet age-related macular degeneration, as well as macular edema from diseases such as diabetic retinopathy and central retinal vein occlusion.
- Buprenorphine has been shown experimentally (1982–1995) to be effective against severe, refractory depression.
- Bupropion, when sold under the brand name Wellbutrin is indicated for depression. It is also sold as a smoking cessation drug, under the name Zyban. In Ontario, Canada, smoking cessation drugs are not covered by provincial drug plans. Thus, a physician can write a prescription for Wellbutrin to assist with giving up the habit of smoking. It is also given to counter SSRIs' negative effects on the libido, anorgasmia and anhedonia.
- Carbamazepine, or Tegretol, has been used as a mood stabilizer and is accepted treatment for bipolar disorder.
- Dexamethasone and Betamethasone in premature labor, to enhance pulmonary maturation of the fetus.
- Doxepin has been used to treat Angiodema and severe allergic reactions due to its strong antihistamine properties.
- Gabapentin, approved for treatment of seizures and postherpetic neuralgia in adults, is used off-label for a variety of conditions including bipolar disorder, essential tremor, hot flashes, migraine prophylaxis, neuropathic pain syndromes, phantom limb syndrome, and restless leg syndrome.
- Magnesium sulfate is used in obstetrics for premature labor and preeclampsia.
- Methotrexate (MTX), approved for the treatment of choriocarcinoma, is frequently used for the medical treatment of an unruptured ectopic pregnancy. There is no FDA-approved drug for this purpose and there is little incentive to sponsor an unpatented drug such as MTX for FDA-approval.
- Retigabine (INN) is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. Right now is being tested its effects to treat Tinnitus.
- The SSRI medication sertraline (Zoloft) is approved as an anti-depressant but is also commonly prescribed off-label to help men suffering from premature ejaculation.
- Stimulants such as Amphetamine (Adderall) and Methylphenidate (Ritalin) are indicated for childhood attention deficit disorder Benzphetamine (Didrex)(ADD/ADHD), but are often prescribed to treat this condition in adults, as well. Atomoxetine (Strattera), a non-stimulant norepinephrine reuptake inhibitor, is indicated (in the United States) for adult ADD. In Australia dextroamphetamine is indicated for adult ADHD treatment. While Atomoxetine is also indicated for the treatment in Australia, it represents only a minor percentage of the drugs prescribed for the condition, due to its prohibitively high price, and it not being currently subsidised by the Government's Pharmaceutical Benefits Scheme. (By contrast, the stimulant medications methylphenidate and dextroamphetamine are covered under the plan.) Stimulants are also used off-label to treat depression, usually in conjunction with a standard antidepressant drug.
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 licenced for that species. This problem is compounded in "exotic" species (such as reptiles and rodents) where there are very few, if any licenced 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.
This practice is permitted by the Animal Medicinal Drug Use Clarification Act of 1994 (P.L. 103-396). 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.
Research relating to off-label use
According to a national random mail survey of 599 primary care physicians and 600 psychiatrists, there is a strong indication between a physician’s belief that a use is FDA-approved and the known evidence supporting that use, although almost half of physicians believed one off-label use that had little or no supporting evidence. This shows that there is a need for informing physicians about the evidence supporting off-label prescriptions, although the FDA only regulates drug marketing not drug prescribing.
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First Amendment issues
The FDA takes the position that a drug manufacturer may not promote its drug for an unapproved use, and that any such promotion is false and misleading simply because it is not FDA-approved. However, many off-label uses are in fact effective and safe, as is evidenced by subsequent FDA approval of such uses for numerous drug products. The Supreme Court has in recent terms begun to address the boundaries between government regulation of pharmaceuticals and the First Amendment free speech guarantee. Some legal observers have suggested that the trend in the Court's decisions may ultimately reduce the ability of FDA to prevent broader dissemination of off-label information about approved drug products.
A three-judge panel of the United States Court of Appeals for the Second Circuit in Manhattan ruled on December 5, 2012 that a drug sales representative who was criminally prosecuted for making off-label promotional statements about Xyrem had suffered a violation of his First Amendment right to freedom of speech. 
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