Off-label use

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Off-label treatment
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Regulation of therapeutic goods in the United States
Prescription drugs
Over-the-counter drugs
Law
Government agencies
Process
International coordination
Non-governmental organizations

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.

Indications and labeling laws

An

drug regulatory agency
formally agrees that the drug is medically appropriate for the named condition. Indications may depend not only upon the medical condition that is being treated, but also upon other factors, such as dose, the patient's age, size and sex, whether the patient is pregnant or breastfeeding, and other medical conditions. For example, aspirin is generally indicated for a headache, but it is not indicated for headaches in people with an allergic reaction to it.

When the drug's manufacturer has received a

package insert
or "label". Drug manufacturers are not legally permitted to encourage the use of regulated drugs for any indications that have not been formally approved by the country's government, even if significant scientific evidence exists for that unapproved indication, or if another country's drug agency has approved that indication.

However, healthcare providers are not required to limit prescriptions or recommendations to the indications approved by their country's drug regulatory body. In fact, the standard of care for many conditions involves off-label uses, either as first-line therapy or as a subsequent line. In other words, properly understanding why off-label use is common and usually appropriate, rather than rare and usually inappropriate, requires understanding that the distinction between regulatory-agency-approved use versus off-label use is not the same distinction as safe versus unsafe, tested versus untested, or good versus bad; it is a marker of increased certainty about a use being good (safe and effective), as opposed to less certainty—rather than a marker of good as opposed to bad. Regulatory approval for an indication requires a body of evidence that costs money to assemble, and as with evidence-based medicine generally, the desire for a vast, high-quality evidence base is an ideal that real-world practice can only aspire to and further approach, rather than completely match; there may not be enough resources to test every drug for every possible or logical indication to an exhaustive degree. Regulation of therapy freedom thus takes an approach in which anything not explicitly forbidden is allowed rather than an approach in which anything not explicitly allowed is forbidden, and it is accepted that drugs may be used in off-label ways as long as a competent professional prescribes them.

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.[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 2001-2004 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 2002–2012 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

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.

attention deficit/hyperactivity disorder (ADHD) particularly in adults.[13][14][15]

Society and culture

Drug manufacturers market drugs for off-label use in a range of ways. Marketing practices around off-label use have caused various of lawsuits and settlements about inappropriately promoting drugs. Some of those lawsuits have ended granting the largest pharmaceutical settlements in the world.

In the United States in 2017, the government is considering allowing direct-to-consumer advertising to promote off-label drug use.[16] The appointment of Scott Gottlieb to become head of the United States Food and Drug Administration (FDA) furthered discussion, as this person advocates to allow that sort of promotion.[17][18]

Regulation in the United States

In the United States, once a drug has been approved for sale for one purpose, physicians are free to

illnesses
or medical conditions for which the drug has been shown to be both safe and effective.

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.

A leading example of how

clinical trial data to see if the results support the drug for a specific use or indication.[21]
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

one of the largest recoveries against a pharmaceutical company in U.S. history, and the first off-label promotion settlement in U.S. history.[26]

Litigation around the marketing of

First Amendment rights,[29] and in August 2015 a judge ruled that the FDA could not "prohibit the truthful promotion of a drug for unapproved uses because doing so would violate the protection of free speech."[30] The ruling left open the question of what the FDA would allow Amarin to say about E-EPA, and in March 2016 the FDA and Amarin agreed that Amarin would submit specific marketing material to the FDA for the FDA to review, and if the parties disagreed on whether the material was truthful, they would seek a judge to mediate.[31]

Regulation in the United Kingdom

Physicians in the United Kingdom can prescribe medications off-label. According to General Medical Council guidance, the physician must be satisfied that there is sufficient evidence or experience of using the medicine to demonstrate safety and efficacy. Prescribing may be necessary when no suitably licensed medicine is available to meet the patient's need (or when the prescribing is part of approved research).[32]

Veterinary medicines

The

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.[33]

See also

References

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  9. ^ Day to Day (2008-10-22). "Prozac Isn't The Same In A Kid's Body". NPR. Retrieved 2011-11-21.
  10. ^ "Why is off-label use of drugs so common in cancer treatment?". National Cancer Institute. Retrieved 2009-07-12.
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  15. ^ "Nonstimulant Therapy (Strattera) and Other ADHD Drugs - MedicineNet". MedicineNet. Archived from the original on 2016-03-05. Retrieved 2015-02-03.
  16. ^ Carr, Teresa (9 November 2016). "FDA Considers Allowing Drug Ads for Unapproved Treatments". Consumer Reports. Retrieved 3 April 2017.
  17. ^ Brill, Steven (24 January 2017). "It's open season for off-label drug promotion". Axios. Retrieved 24 March 2017.
  18. ^ McGinley, Laurie; Johnson, Carolyn Y. (10 March 2017). "Trump to select Scott Gottlieb, a physician with deep drug-industry ties, to run the FDA". Washington Post. Retrieved 24 March 2017.
  19. ^
    Buckman Co. v. Plaintiffs' Legal Comm., 531 U.S. 341
    (U.S.S.Ct. 2001) ("the FDCA expressly states in part that "[n]othing in this chapter shall be construed to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease within a legitimate health care practitioner-patient relationship." 21 U.S.C. § 396 (1994 ed., Supp. IV).").
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  21. ^ "Development & Approval Process (Drugs)". Fda.gov. 2009-10-27. Retrieved 2011-11-21.
  22. ^ "The Office of Prescription Drug Promotion (OPDP)". Fda.gov. 2008-03-25. Retrieved 2011-11-21.
  23. ^ "Biopharmaceutical Company, Cephalon, to Pay $425 Million & Enter Plea to Resolve Allegations of Off-Label Marketing" (Press release). United States Department of Justice. September 29, 2008. Archived from the original on 2015-07-13.
  24. ^ "Off-Label Use Promotion is Protected Free Speech". blogs.findlaw.com. 2012-12-04. Retrieved 2014-06-26.
  25. ^ 21 U.S.C. §360aaa-6
  26. ^ "Warner-Lambert to Pay $430 Million to Resolve Criminal & Civil Health Care Liability Relating to Off-Label Promotion" (Press release). United States Department of Justice. 2004-05-13. Retrieved 2013-04-30.
  27. ^ VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel. October 2005 National PBM Drug Monograph Omega-3-acid ethyl esters (Lovaza, formerly Omacor)
  28. ^ Herper, Matthew (17 October 2013). "Why The FDA Is Right To Block Amarin's Push To Market Fish Oil To Millions". Forbes.
  29. ^ Thomas, Katie (7 May 2015). "Drugmaker Sues F.D.A. Over Right to Discuss Off-Label Uses". New York Times. Retrieved 17 May 2017.
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  32. ^ General Medical Council (December 2014) [first published February 2013]. "Good Practice in Prescribing and Managing Medicines and Devices" (PDF). General Medical Council (Published guidance). General Medical Council. pp. 10–11. Retrieved 24 May 2018.
  33. ^ CRS Report for Congress: Agriculture: A Glossary of Terms, Programs, and Laws, 2005 Edition - Order Code 97-905 Archived 2013-09-23 at the Wayback Machine

External links

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