Special articleTen Common Questions (and Their Answers) About Off-label Drug Use
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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2023, JACC: Basic to Translational ScienceRates of psychotropic medicine prescribing in paediatric populations in Australian general practice from 2000-2016
2022, European NeuropsychopharmacologyCitation Excerpt :In addition, as a result of limited regulatory approvals, psychotropic medicines, including some antidepressants and antipsychotics, are often used off-label in the paediatric population for the management of psychiatric disorders (Schroder et al., 2017a, 2017b). Given that paediatric patients are often excluded from clinical trials, the exposure of this population to psychotropic medicines in routine clinical practice could potentially expose them to unknown adverse events as their characteristics differ from those of the patients included in clinical trial studies (Eguale et al., 2016; McLaren et al., 2018; Wittich et al., 2012). General practitioners (GPs) and specialists (child psychiatrists and paediatricians) generally prescribe psychotropic medicines to paediatric patients.
Boxed Warnings and Off-Label Use of Allergy Medications: Risks, Benefits, and Shared Decision Making
2022, Journal of Allergy and Clinical Immunology: In PracticeCitation Excerpt :The Food and Drug Administration’s (FDA’s) role as a federal consumer protection agency began with the passage of the Pure Food and Drugs Act in 1906.1 The agency was tasked with monitoring medication safety after passage of the federal Food, Drug, and Cosmetic Act of 1938 while the Kefauver-Harris Amendment in 1962 required FDA-approved drugs to show evidence of efficacy for specific indications (ie, “on-label” prescribing).1 As the FDA mandate for confirming safety and efficacy expanded over the years, so too has the institution of boxed warnings.
See editorial comment, page 932