When are off-label (not approved by the Food and Drug Administration (FDA)) treatments used in medical practice?

Off-Label Treatments in Medical Practice

Off-label treatments are commonly used in medical practice when standard FDA-approved therapies have failed, when there is scientific evidence supporting alternative uses, or when treating conditions with limited therapeutic options, particularly in oncology, pediatrics, and rare diseases. 1, 2

Definition and Prevalence

• Off-label use refers to prescribing FDA-approved medications for indications, dosages, patient populations, or routes of administration not included in the FDA-approved labeling 3, 4
• The prevalence of off-label prescribing varies by specialty, with rates up to 40% in adults and as high as 90% in pediatric patients 5
• In oncology specifically, off-label use increased from one-third of cancer drugs in 1991 to between one-half and three-quarters by 2005, with only 27% of these uses supported by strong clinical evidence 1

Appropriate Scenarios for Off-Label Use

Off-label prescribing is generally appropriate in the following circumstances:

• When high-quality evidence supports the use despite lack of FDA approval 5
• When standard FDA-approved therapies have failed and patients have treatment-resistant conditions causing physical or psychological distress 2, 6
• In rare diseases where approved treatment options are limited or nonexistent 7
• In pediatric populations where many medications lack specific FDA approval 5, 7
• In oncology, particularly for advanced-stage cancers where treatment options are limited 1
• When an oral formulation is needed instead of an intravenous equivalent, even though the oral form may not have been formally tested in that specific setting 1

Evidence Requirements and Categories

Off-label use should fall into one of these categories:

• Use justified by high-quality scientific evidence 5
• Use within the context of a formal research proposal 5
• Exceptional use justified by individual clinical circumstances when no alternatives exist 5

Physician Responsibilities

When prescribing off-label medications, physicians should:

• Document thorough informed consent discussing the off-label nature of the prescription, alternative options, specific risks and benefits, and monitoring requirements 2, 6
• Determine whether available evidence justifies specific off-label uses and promote information-gathering when evidence is inadequate 3
• Discuss with patients the uncertainties accompanying off-label uses 3, 6
• Document the reason for off-label use in the patient's record 6
• Specify the intended duration of treatment and establish relevant monitoring protocols 2, 6
• Consider lower doses for off-label indications when appropriate (e.g., 0.3-0.5 mg/kg/day for isotretinoin in moderate acne versus standard dosing for severe acne) 2

Special Considerations by Field

Oncology

• Off-label use is particularly common in advanced-stage cancers 1
• Medicare covers oncology drugs listed in approved compendia, making off-label use more accessible for Medicare enrollees 1
• Oncologists select off-label treatments using FDA labeling, medical literature, published guidelines, drug compendia, and continuing education 1

Pediatrics

• Up to 90% of medications used in children may be off-label due to limited pediatric clinical trials 5, 7
• Special caution is needed as safety profiles may differ from adults 2

Rare Diseases

• Off-label prescribing is often necessary due to the limited number of approved treatments 7
• Post-hoc analysis rather than prospective trials may be more appropriate for evaluating treatments in rare conditions 1

Monitoring and Safety Considerations

• Baseline and ongoing monitoring should be established based on the medication's known adverse effect profile 2
• Patients should be monitored more closely than when medications are used for approved indications 6
• Drug interactions should be carefully evaluated before initiating off-label therapy 2
• Special populations (pediatric, elderly, pregnant women) require additional caution and monitoring 2

Ethical and Legal Implications

• Off-label prescribing is legal but carries ethical responsibilities 3, 4
• The medical community should self-regulate by determining whether available evidence justifies specific off-label uses 3
• Federal authorities should more closely monitor the effects of off-label prescribing 3
• Some countries, including the USA and France, have developed specific regulations regarding off-label use 4

Future Directions

• There is a need for a coordinated approach to evidence development for off-label uses, particularly in oncology 1
• Guidance is needed for trials performed in the post-approval environment to address questions relevant to patients, prescribers, and payers 1
• Australia's national health priority of Quality Use of Medicine and Medicine Safety aims to address off-label medicine use through stakeholder collaboration 6
• Drug repurposing (finding new uses for existing drugs) represents a formalized approach to identifying valuable off-label uses 7