Informed consent for off-label drug prescribing should be considered on a similar level as informed consent for a surgical procedure, especially if the evidence base is sparse and the risks rather high.
Explore This Issue
December 2019
Evidence
The second element of OLDP for physician decision is evaluating both the evidence for the on-label medication use and the available evidence for its off-label use. The on-label evidence will usually be quite extensive, based on clinical trials evidence submitted to the FDA and subsequently published in the drug information. Additionally, information often is reported in the medical literature as clinicians record and report their clinical outcomes with the drugs. FDA approval of drugs for indicated disorders does not mean that they are completely safe and innocuous, as is well known to clinicians.
Simply put, FDA approval indicates that a drug has met certain testing standards and has shown a predominance of benefit over risk. Likewise, a physician has an obligation to search for the evidence base of any drug that she is contemplating prescribing to a patient for an off-label indication. The evidence may range from sparse to plentiful, from anecdotal small-case studies to larger systematic reviews and meta-analyses. The burden of proof for benefit over risk for a given patient does, of course, eventually rest with the physician. Medical societies may give clinical guidance to physicians on OLDP in specificity, or may simply encourage general best effort attempts to use discretion and judgment.
The physician should be aware of the evidence base, if any, for OLDP and contemplate how that information would pertain to her specific patient with a certain disorder. The on-label warnings, drug interactions, and adverse reactions known for a certain drug will clearly be the same for off-label use—there is not much variance—so these must be considered in light of each patient’s medical condition. OLDP to patients in a group not originally included in the clinical trials (i.e., children, pregnant women, elderly) is considered to be potentially riskier, and such risk should be taken seriously. Adverse reactions that occur in a patient while taking a drug prescribed for an off-label condition should be reported to the FDA in the same manner as for on-label indications (800-FDA-1088).
Due Diligence
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The third element in the decision-making process for an OLDP is the ethical considerations, which can be significant and multiple. While patient autonomy (self-determination) is often considered the primary ethical principle from the patient’s viewpoint, for the physician who is considering an off-label drug use it is a proper balance of the dyad of beneficence and non-maleficence. In the author’s perspective, OLDP requires an enhanced level of due diligence over that required for on-label prescribing because of the potential quality of the evidence base and the implications for patient safety. The patient and physician may be more assured for an off-label use when the patient’s condition is more closely related to the on-label indications than if there is little similarity. Physicians have an ethical duty to obtain as much information as feasible about off-label use before obtaining informed consent from the patient to prescribe the drug.
Additionally, it is most appropriate for the physician to have clinical experience with on-label prescribing of the drug before considering off-label indications, including its use in patients with co-morbidities similar to the patient’s.