The US Food and Drug Administration (FDA) requires manufacturers to demonstrate safety and efficacy of a medication as a condition of approval for indications in the product’s package insert. Often, the initial approved indications for a drug are narrow, based on the projected utility of the medication and the effort/expense for the manufacturer to conduct research establishing safety and efficacy supporting other uses. Such other labeled indications may follow, as new research validates broader supported use, as in the case of Opdivo (nivolimib), a chemotherapy agent initially approved in 2014 for the treatment of melanoma. Over the next 4 years, this drug has gained FDA approval for over a dozen indications.
Other medications experience a broadened scope of use based on published studies or anecdotal experience. Such expanded use may begin as a logical extension of approved indications and/or pharmacologic principles. However, the likeliness of the innovator manufacturer to pursue FDA approved indications is limited given the expense and complexity of that process. Therefore, the particular use of a drug may be come standard of care – even guideline supported – despite the “off-label” (e.g. not FDA approved) indication. Levetiracetam (Keppra) received initial FDA approval for adjunctive treatment of partial onset seizures in adults in 1999. Over the years, it secured several other approved indications. Additionally, its use as seizure prophylaxis in head trauma patients evolved from anecdotal experience to guideline supported use. Yet, this latter indication remains “off-label.”
Indeed, in the US, prescribers are not prohibited from using a medication in a patient based on FDA approved labeling. However, the risk of litigation from an adverse medication event seems greater for “off-label” versus approved indications. Yet, the crux of pharmacy litigation cases involving “off-label” use of drugs is not such use empirically constitutes malpractice or fails to meet standards of care. Critical factors in establishing a prescriber’s negligence in a litigation case involving patient harm associated with “off-label” use of a medication are: the degree of evidence supporting the indications beyond those approved by the FDA, and the reasonableness of a decision to not select a drug with an FDA approved indication for the condition being treated, if present.
Prescribing (and in some cases, dispensing and/or administering) a medication at a dose/frequency/duration or for an indication that differs substantially from accepted uses should be substantiated by findings from controlled research AND supported by principles of a drug’s pharmacologic benefit in the condition being treated. Deviation from such an approach may hinder the defensibility of a litigation case.