Summary
The FDA regulates the premarket approval of new drugs; however, it does not limit or control how medications are prescribed. Due to a rapidly changing healthcare environment and vigorous research, there may be strong scientific evidence to use an off-label drug.
According to the U.S. Food and Drug Administration (FDA), off-label use is the prescribing of an approved drug for an unapproved use or for use outside of the package insert and label information. Unapproved uses can include indication, dosage, dosage form/route of administration, and duration of therapy. It is also considered off-label to use a drug in a patient population for which it is not approved. The FDA permits a manufacturer to release a drug on the market with an accompanying package insert and label information only after the drug has proved to be safe and effective. Off-label use is not considered investigational use and therefore does not require review by an institutional review board.
While the FDA highly regulates the premarket approval of all new drugs, it does not limit or control how medications are prescribed. Due to the rapidly changing, innovative healthcare environment and vigorous research climate, there may be strong scientific evidence to use an off-label drug. In some situations, off-label use may be the standard of care, and withholding the drug may be a disservice to the patient. For example, the off-label use of drugs in cancer treatment is common. Because chemotherapeutic agents are often prescribed in different combinations for various forms of cancer, it is unfeasible for the FDA to approve all possible combinations.
The prevalence of off-label drugs is also higher in pediatric patient populations. Because of the lack of clinical trials in this population, especially for older drugs, the safety and efficacy required for FDA approval has not been established.
Off-label use without strong scientific evidence is associated with higher rates of adverse drug events (ADEs). Results from a study published in JAMA Internal Medicine showed that patients receiving prescriptions for off-label indications that lacked strong evidence were 54% more likely to experience ADEs significant enough to warrant discontinuation of treatment.
Off-label prescribing is often associated with a lack of practitioner knowledge of approved treatment indications. In these instances, there is a high risk for off-label use without strong scientific evidence, and hence an increased risk for liability.
Lack of informed consent and poor documentation can also result in problems with off-label use.
The Centers for Medicare & Medicaid Services (CMS) and commercial payers may deny reimbursement for off-label drug use. Many payers, however, recognize the benefits of off-label use paired with strong scientific evidence and will therefore provide coverage. For example, CMS will reimburse for off-label anti-cancer chemotherapy regimens if there is a “medically-accepted indication” listed in one of five nationally recognized, authoritative compendia.
While prescription drug advertising is required to be truthful, improper drug promotion has resulted in pharmaceutical companies paying sizeable legal settlements. In response, the FDA designed the Bad Ad Program to help raise healthcare practitioner awareness about misleading drug promotion and provide a way to report violations.
A statement in the FDA’s “Off-Label” and Investigational Use of Marketed Drugs, Biologics, and Medical Devices information sheet sums it up: “Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics, and devices according to their best knowledge and judgement. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects.”
Prevalence of Off-Label Drug Use
While the FDA highly regulates the premarket approval of all new drugs, it does not limit or control how medications are prescribed. Due to the rapidly changing, innovative healthcare environment and vigorous research climate, there may be strong scientific evidence to use an off-label drug. In some situations, off-label use may be the standard of care, and withholding the drug may be a disservice to the patient. For example, the off-label use of drugs in cancer treatment is common. Because chemotherapeutic agents are often prescribed in different combinations for various forms of cancer, it is unfeasible for the FDA to approve all possible combinations.The prevalence of off-label drugs is also higher in pediatric patient populations. Because of the lack of clinical trials in this population, especially for older drugs, the safety and efficacy required for FDA approval has not been established.
Absence of Scientific Evidence for Off-Label Use
Off-label use without strong scientific evidence is associated with higher rates of adverse drug events (ADEs). Results from a study published in JAMA Internal Medicine showed that patients receiving prescriptions for off-label indications that lacked strong evidence were 54% more likely to experience ADEs significant enough to warrant discontinuation of treatment.Off-label prescribing is often associated with a lack of practitioner knowledge of approved treatment indications. In these instances, there is a high risk for off-label use without strong scientific evidence, and hence an increased risk for liability.
Lack of Informed Consent
Lack of informed consent and poor documentation can also result in problems with off-label use.
Creation of Reimbursement Issues
The Centers for Medicare & Medicaid Services (CMS) and commercial payers may deny reimbursement for off-label drug use. Many payers, however, recognize the benefits of off-label use paired with strong scientific evidence and will therefore provide coverage. For example, CMS will reimburse for off-label anti-cancer chemotherapy regimens if there is a “medically-accepted indication” listed in one of five nationally recognized, authoritative compendia.
Improper Drug Promotion
While prescription drug advertising is required to be truthful, improper drug promotion has resulted in pharmaceutical companies paying sizeable legal settlements. In response, the FDA designed the Bad Ad Program to help raise healthcare practitioner awareness about misleading drug promotion and provide a way to report violations.A statement in the FDA’s “Off-Label” and Investigational Use of Marketed Drugs, Biologics, and Medical Devices information sheet sums it up: “Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics, and devices according to their best knowledge and judgement. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects.”
Risk Recommendations
Minimize Organizational Risks Related to Off-Label Use
- Develop a policy and procedures for off-label use that includes these essential elements:
- A process or means to determine the appropriateness of off-label use prompted by:
- Standard treatment guidelines or “medically indicated” by drug compendia.
- Consistency with off-label use regulations.
- A review by ethics, pharmacy and therapeutics, or quality committee when necessary to determine the appropriateness of off-label use.
- An indication of when to obtain written informed consent for off-label use.
- A process or means to determine the appropriateness of off-label use prompted by:
- Develop a mechanism to track ADEs associated with off-label use.
- Know what constitutes appropriate prescription drug promotion and how to report possible violations.
- Educate prescribers on off-label use.
Ensure Prescribers Know How to Minimize Risks of Off-Label Use
- Document off-label use thoroughly. Include:
- Rationale for using the medication.
- Discussions with the patient regarding the off-label use.
- Response to the medication, including any adverse events.
- Know all prescribed medications before prescribing. Scrutinize information provided by pharmaceutical manufacturers.
- Read and understand package insert and label information.
- Know and acknowledge on-label use for all prescribed medications.
- Ensure that strong scientific evidence exists prior to prescribing an off-label medication.
- Never assume that a medication is safe for a pediatric patient simply because a drug has been established as safe and efficacious in the adult population.
- Confirm reimbursement prior to prescribing an off-label drug to avoid surprises.
- Obtain informed consent. Include the patient in the decision to prescribe an off-label medication and document the discussion.
Resources
- American Academy of Pediatrics, Hospital Pediatrics, Off-label Medication Prescribing Patterns in Pediatrics: An Update
- American Medical Association (AMA), JAMA, Association of Off-Label Drug Use and Adverse Drug Events in an Adult Population
- Centers for Medicare and Medicaid Services, Update to the List of Compendia as Authoritative Sources for Use in the Determination of a “Medically-Accepted Indication” of Drugs and Biologicals Used Off-Label in an Anti-Cancer Chemotherapeutic Regimen
- FDA:
- National Cancer Institute, Off-Label Drug Use in Cancer Treatment
- Therapeutics and Clinical Risk Management, Adverse Events Related to Off-Label Drugs Using Spontaneous Adverse Event Reporting Systems
Copyrighted. No legal or medical advice intended. This post includes general risk management guidelines. Such materials are for informational purposes only and may not reflect the most current legal or medical developments. These informational materials are not intended, and must not be taken, as legal or medical advice on any particular set of facts or circumstances.