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
The AMA has taken a similar position, indicating that off-label use is reasonable “when such use is based on sound scientific evidence and sound medical opinion.”16 Similarly, the American Psychiatric Association (APA) Board of Trustees recently reiterated its “strong support for the autonomous clinical decision-making authority of a physician” and use of a drug for an unlabeled indication “when such use is based on sound scientific evidence in conjunction with sound medical judgment.”17
Several courts around the country have ruled that off-label use of medications is an accepted practice and is not considered “experimental.”15 Furthermore, the United States Supreme Court has commented that off-label use of medical devices is “an accepted and necessary corollary of the FDA’s mission to regulate in this area without directly interfering with the practice of medicine.”18
How then can off-label prescribing increase the physician’s potential liability in a malpractice claim? To prevail in a malpractice claim, a plaintiff must demonstrate that the physician’s actions or omissions deviated from the relevant standard of care. While these standards vary from state to state, they typically express the requirement that physicians must practice with that degree of care, knowledge, and skill ordinarily possessed and exercised by other physicians in similar circumstances.19 Plaintiffs may allege that the particular off-label use at issue constituted a deviation from the standard of care in prescribing.
While the off-label use of a medication may not be a violation of the standard of care per se, depending on the state, any deviation from Physicians’ Desk Reference prescribing guidelines may constitute evidence of a deviation from the standard of care in prescribing. In extreme cases, the use of a medication for a nonapproved indication may shift the burden of proof from plaintiff to defendant and require that the defendant practitioner prove why he or she was not negligent.15
Plaintiffs may also allege that the defendant physician was negligent in failing to obtain proper informed consent from the patient for the off-label use. All clinicians are required to obtain proper informed consent from patients before prescribing a medication. Again, while standards vary depending on the jurisdiction, they typically require clinicians to inform patients of the nature of the proposed treatment, the risks and benefits of the proposed treatment, available alternatives and their risks and benefits, and the risks of forgoing treatment.20
With respect to obtaining informed consent for off-label use, most commentators believe that clinicians are expected to explicitly discuss with their patients the fact that they are recommending a use that is not FDA-approved and engage in a risk/benefit discussion that takes this use into account.15
Minimizing the risks while maximizing good clinical care
A review of the risk management literature reveals the following strategies for minimizing the risk of untoward outcomes and legal liabilities.3 Practicing these risk management strategies will have beneficial effects not only on the management of prescribing risk but also on the quality of patient care.
1. Document that you considered medications that were FDA-approved. While the choice of medications is at the prescriber’s discretion, a physician in a malpractice action may have to defend choosing an off-label medication when he had an option to choose a medication specifically approved for that use, with known safety and efficacy. Make sure that you have sound clinical reasons for choosing the off-label medication and document this reasoning in the patient’s chart. Documentation of sound clinical reasoning will go a long way toward demonstrating that your medication selection was warranted and met applicable standards of care.
2. Make sure that your decision to prescribe an off-label medication has solid scientific support. The AMA and APA have endorsed off-label prescribing that is predicated on sound scientific evidence and sound medical opinion. It is important to base your selection of medications on such support, and documenting this scientific basis will be proof that you lived up to the standards of reasonable prescribing should the use be challenged. This requires that practitioners are able to support the use in question with scientific literature, continuing medical education information, federal agency contacts, professional guidelines, or learned treatises that endorse the off-label use. Stay current with the professional literature about the safety and efficacy of the medication you are prescribing off-label because prescribing indications change rapidly with expanding clinical knowledge.
3. Maintain an office file containing scientific evidence for the use in question. Experts in risk management recommend that practitioners maintain a file of supporting evidence for off-label use, and that this file should be kept apart from patient charts. Ideally, this file would contain peer- reviewed literature regarding this use, as well as professional contacts that support this use.
It is not necessary to distribute these materials to patients, as physicians bear the responsibility for making appropriate clinical decisions and ensuring that they are recommending treatments with a favorable risk/benefit profile. If a patient later alleges that he was damaged by an inappropriately selected agent, this file can be used as evidence that the physician had documented support for his choice.
4. Monitor the patient for adverse effects associated with the off-label use. While prescribers are always required to monitor their patients for signs that they are experiencing adverse medication effects, this duty is heightened when prescribing off-label substances. The use of off-label medications increases the risk of unknown drug-drug interactions and should prompt close scrutiny in that regard.
Before prescribing any medication (whether or not off-label), clinicians should ask whether their patient takes other prescribed or over-the-counter medications. If there are known risks associated with a particular off-label use, the clinician should warn the patient of this risk and instruct the patient on how to recognize such symptoms and what to do in the event that they appear. This may include instructions about whom to contact in the event the patient notices an adverse medication effect or has concerns about the medication.
These monitoring parameters may be more specific when prescribing off-label for children and adolescents. Tailored monitoring strategies for each type of psychotropic medication prescribed for children have been described.5
5. Obtain consultation for an off- label use that is controversial or novel. In some circumstances, clinicians may wish to consult outside experts regarding the off-label use they are contemplating. This is seen most frequently with controversial or novel medications for which relatively little scientific support is available. Consulting an expert in either the particular off-label use or the state-of-the-art treatment for the condition in question will demonstrate in a later litigation that the prescriber was thorough and careful regarding the selection of medication, and that experts in the field (who often serve as expert witnesses establishing the standard of care) endorsed this off-label use.
6. Supplement the informed consent process with explicit discussions regarding off-label use. Most clinicians engage in an appropriate discussion with patients regarding the risks, benefits, and alternatives to the treatments they propose. As discussed above, this discussion should conform to state law requirements for disclosure and patient understanding. However, proposing a medication that has not been FDA-approved for the specific use requires a higher standard of informed consent.
A recent poll of over 2000 adults revealed that most patients are not aware that physicians are permitted to prescribe medications for indications that are not approved by the FDA.15 Clinicians should have an interactive discussion with the patient (or the person authorized to make medical decisions on the patient’s behalf) regarding the nature of off-label use, the reasons for choosing a non–FDA-approved medicine, and the risks specifically associated with the proposed use. This discussion, along with any written materials provided to the patient, should be included in the patient’s chart.
If the medication the clinician is recommending also has a black box warning about its use, the clinician must conduct an informed consent discussion that takes into account the regulatory requirements and monitoring schedules set forth by the FDA for these uses. (Dell and colleagues6 provide an excellent discussion regarding informed consent when prescribing psychotropics for children.)
As with other sources of liability for prescribing, the best defense against malpractice liability for prescribing off-label is to provide high-quality care when selecting, prescribing, and monitoring medications, and to engage in meaningful informed consent discussions with your patients.