Elsevier

Mayo Clinic Proceedings

Volume 87, Issue 10, October 2012, Pages 982-990
Mayo Clinic Proceedings

Special article
Ten Common Questions (and Their Answers) About Off-label Drug Use

https://doi.org/10.1016/j.mayocp.2012.04.017Get rights and content

Abstract

The term off-label drug use (OLDU) is used extensively in the medical literature, continuing medical education exercises, and the media. Yet, we propose that many health care professionals have an underappreciation of its definition, prevalence, and implications. This article introduces and answers 10 questions regarding OLDU in an effort to clarify the practice's meaning, breadth of application, acceptance, and liabilities. Off-label drug use involves prescribing medications for indications, or using a dosage or dosage form, that have not been approved by the US Food and Drug Administration. Since the Food and Drug Administration does not regulate the practice of medicine, OLDU has become common. It occurs in every specialty of medicine, but it may be more common in areas of medicine in which the patient population is less likely to be included in clinical trials (eg, pediatric, pregnant, or psychiatric patients). Pharmaceutical companies are not allowed to promote their medications for an off-label use, which has lead to several large settlements for illegal marketing. To limit liability, physicians should prescribe medications only for indications that they believe are in the best interest of the patient. In addition, health care professionals should educate themselves about OLDU to weigh the risks and benefits and provide the best possible care for their patients.

Section snippets

Question 1: What is the Definition of OLDU?

The most common form of OLDU involves prescribing currently available and marketed medications but for an indication (eg, a disease or a symptom) that has never received Food and Drug Administration (FDA) approval.8, 9 Hence, the specific use is “off-label” (ie, not approved by the FDA and not listed in FDA-required drug-labeling information). The term OLDU can also apply to the use of a marketed medication in a patient population (eg, pediatric), dosage, or dosage form that does not have FDA

Question 2: Is OLDU Common?

Indeed, OLDU is common. Radley et al1 reported in 2006 that in a group of commonly used medications, 21% of prescriptions were for an off-label use. In certain subpopulations of patients, this rate may be even higher. For example, a study by Shah et al11 found that 78.9% of children discharged from pediatric hospitals were taking at least 1 off-label medication. In addition, in a pediatric emergency department, the rate of OLDU was estimated to be 26.2%.2 The off-label use of antidepressant,

Question 3: Can an OLDU for a Given Drug Become a Widely Accepted Practice or Even a Standard of Care?

Off-label drug uses can become widely entrenched in clinical practice and become predominant treatments for a given clinical condition. For example, tricyclic antidepressants do not have FDA approval as a treatment for neuropathic pain, yet this class of drugs is considered a first-line treatment option.15 The use of aspirin provides another interesting example of OLDU. Aspirin was widely used before the introduction of the Food, Drug, and Cosmetic Act of 1938. Therefore, aspirin was

Question 4: What are Some Examples of Widely Practiced OLDUs?

There are examples of widely practiced OLDUs in every specialty of medicine (Table). Since the patient population in pediatrics is often excluded from clinical drug studies, examples of OLDU are especially abundant. For example, morphine has never received an FDA indication for pain treatment in children, but it is extensively used for this indication in hospitalized pediatric patients.11 In another example, researchers discovered in the 1970s that the nonsteroidal anti-inflammatory agent

Question 5: If Efficacious, Why is Government Approval not Obtained to Convert Off-label Uses of Drugs to On-label Uses?

Obtaining a new FDA approval for a medication can be costly and time-consuming. To add additional indications for an already approved medication requires the proprietor to file a supplemental drug application, and, even if eventually approved, revenues for the new indication may not offset the expense and effort of obtaining approval.8 Finally, generic medications may not have the requisite funding foundations needed to pursue FDA-approval studies.8 For these financial reasons, drug proprietors

Question 6: Do Physicians Expose Themselves to Legal Vulnerability for Including OLDUs in Their Clinical Practices, Particularly if the Patient Experiences an Adverse Reaction Related to an OLDU?

Physicians have been involved in legal claims due to an adverse reaction related to a medication prescribed for an off-label use.8, 36 The legal theories used in these lawsuits include unregulated use of a research drug, failure to provide adequate informed consent for an OLDU, and medical negligence.37 In developing legal precedents for off-label therapies, the courts have typically treated drugs and devices as coequals. As such, many of the courts' views on OLDU have evolved from decisions

Question 7: Will Indexed Medical Journals Publish Articles on OLDU?

Reports on OLDU, particularly original observations, are not only tolerated by indexed medical journals but also may actually be encouraged. The most welcomed reports may follow several patterns, the 2 most common of which are described in the following subsections.

Question 8: Can Speakers Discuss OLDU During Accredited CME Courses?

Speakers at accredited CME courses are allowed to discuss OLDU during their presentations. The Accreditation Council for Continuing Medical Education historically required that all discussions of OLDU be disclosed during the CME presentation. However, current Accreditation Council for Continuing Medical Education requirements state that all clinical presentations should be based on “evidence that is accepted within the profession of medicine.”52 If the discussion of OLDU conforms to this

Question 9: Can Drug Companies Promote OLDU?

The 1938 Food, Drug, and Cosmetic Act gave the FDA the power to regulate promotional materials on medications.53 Two provisions from the FDA prohibit most promotion of off-label uses of medications by pharmaceutical manufacturers and marketers. First, the FDA requires approval before distribution into interstate commerce of all medication labeling (including the package insert, print and broadcast advertisements, brochures, and patient education materials).53 Second, the FDA prohibits

Question 10: What is the Difference Between OLDU and Orphan Use of Drugs?

Orphan drugs are medications that are developed and used for rare, or orphan, diseases. Owing to a drug's limited clinical use for an orphan indication, it will typically generate insufficient profitability for the drug's sponsor to seek FDA approval for the narrow indication. As such, practitioners are typically forced to use medications in an off-label manner to treat orphan diseases. Therefore, orphan drugs are often a subtype of OLDU. However, in 1983, the FDA implemented the Orphan Drug

OLDU Summary

Off-label drug use involves prescribing medications for an indication, or using a dosage or dosage form, that has not been approved by the FDA. Since the FDA does not regulate the practice of medicine, OLDU has become common. It occurs in every specialty of medicine, but it may be more common in areas of medicine in which the patient population is less likely to be included in clinical trials (eg, pediatric, pregnant, or psychiatric patients). Pharmaceutical companies are not allowed to promote

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