Medications cannot be marketed in the United States without an FDA determination that they are safe and effective for their intended use. To obtain such certification, pharmaceutical companies submit their products to rigorous scrutiny (eg, in vitro studies, animal studies, human clinical trials) and present the subsequent data to the FDA, which determines whether the medication in question is safe and effective for a specific purpose. FDA approval comes with specific labeling requirements for the product, including the approved indications for use, the appropriate dosing, and the specific populations for its use. Once a medication has been approved for a specific use, physicians and other prescribers are permitted to prescribe the medication for conditions not covered by the approved use.
Several recent studies have demonstrated that off-label prescribing is very common among physicians, particularly among psychiatrists. Legal scholars have estimated that approximately 40% to 60% of prescriptions are for off-label use.1 In one important study, researchers examined office-based prescribing patterns for 160 commonly prescribed medications and determined that approximately 21% were for off-label use. In this study, off-label use was most common for cardiac medications (46%), anticonvulsant medications (46%), and asthma medications (42%). The investigators also found that most off-label use (73%) had limited or no scientific support.
The greatest disparity in the percentage of scientifically supported versus unsupported off-label use occurred with psychiatric medications. In 96%, the off-label use was determined to have little or no sound scientific evidence for the condition for which the drug was prescribed.2
A review of the psychiatric literature shows that mental health clinicians use medications for off-label indications in the treatment for insomnia, schizophrenia, bipolar disorder, anxiety disorders, personality disorders, and dementia.3 A large percentage of atypical antipsychotic medications are prescribed for nonapproved uses that are not logical extensions of their FDA-approved indications, and most of these uses lack supporting data.4
Off-label prescribing poses particularly difficult issues for clinicians who treat children because approximately 50% to 75% of pediatric medication use is off-label.5 Very few medications are approved for use in children, and clinicians have limited data to use when attempting to practice evidence-based prescribing. Once they have exhausted clinical guidelines and the approved medications for the treatment of a disorder, they are left to extrapolate treatment from adult studies and combine these data with less rigorous pediatric trials and their own clinical experience.6
Despite the scarcity of supporting scientific evidence, the number of psychiatric prescriptions for even very young children is increasing.7 Between 1987 and 1996 there was a marked increase in the use of psychotropic medications by children; the greatest increases were seen in stimulant use, antidepressant use, and the coprescription of different classes of psychiatric medications.8
The most common indication for off-label prescribing has been for childhood-onset conditions, such as severe attention-deficit/hyperactivity disorder and developmental disorders.3 The difficulties of having few FDA-approved psychotropic medications for children have been exacerbated by the new black box warnings placed by the FDA on antidepressants, antipsychotics, and psychostimulants regarding their use in children and young adults.9
The pros and cons of off-label use
There is significant controversy surrounding the appropriateness of permitting off-label use for FDA-approved medications. The debate focuses on a central dilemma—whether to emphasize an approval process that ensures safety and efficacy or to allow physicians and patients early access to novel treatments.10
Proponents of the current hands-off approach point out that allowing off-label prescribing permits innovation in clinical practice—which is paramount when approved treatments have failed. Proponents also point out that some off-label treatments have been validated by high-quality research and have proved to be immensely beneficial to patients. This is frequently observed in specialties such as pediatrics and oncology and among physicians who treat HIV-positive patients, for whom few approved medications are available.10
Supporters contend that if patients had to wait for use-specific FDA approval, many would lose the opportunity to benefit from innovations that develop as a drug is used in clinical practice. This is particularly true for psychotropic medications, which are often fine-tuned based on individual and sometimes idiosyncratic re-sponses of patients to these medications. In a recent letter published in the Archives of Internal Medicine, the National Mental Health Association stated its support for off-label use of medications in psychiatry: “For many mental health consumers, access to a full range of medications is a crucial component of successful treatment and recovery because of the complexity and individuality of mental health disorders. With close monitoring from a physician, the off-label use of medications can help an individual reach his or her full potential.”11
Opponents of unfettered off-label prescribing contend that failure to regulate off-label use leaves patients vulnerable to inadequately tested medications and undermines the public’s expectation that they will be given drugs with known safety and efficacy.12 Critics assert that off-label use undermines efforts to institute evidence-based medicine. They voice concerns that busy physicians will not have the time to gather supporting data regarding off-label use and will rely on what many perceive to be more biased sources, such as industry-sponsored CME programs or industry-distributed journal articles on off-label use.13
Proponents of greater FDA regulation point out that allowing off- label use provides a financial disincentive for manufacturers to seek expensive secondary indication approvals from the FDA. This hampers rigorous testing of medications for relatively small populations, such as children or patients with rare illnesses.
Does off-label prescribing increase liability risk?
Prescribing approved medications for off-label use is common and has been explicitly sanctioned by the FDA, professional medical organizations, and the federal courts.14 The rationale is that the FDA regulates only the manufacturer’s promotion, distribution, and labeling of medications and was never authorized to regulate the practice of medicine.10 The FDA has long taken the position that prescribing off-label is at the discretion of physicians, who are considered “learned intermediaries” between the manufacturers and the public.15