Off-Label Prescribing
J. Edersheim, JD, MD; April 14, 2009; Psychiatric Times


Medications can't be sold in the United States without an FDA determination that they are safe and efficient for their intended use. To acquire such accreditation, pharmaceutical drug companies submit their products to rigorous scrutiny (for example, in vitro studies, animal studies, human clinical trials) and provide the subsequent data to the FDA, which ascertains whether or not the medication in question is safe and effective for a distinct intent. FDA authorization comes with specific labeling requirements for the product, including the sanctioned indications for use, the appropriate dosing, and the specific populations for its use. As soon as a prescription medication has been approved for a specific use, doctors 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 quite common among doctors, especially among psychiatrists. Legal scholars have predicted that approximately 40% to 60% of prescriptions are for off-label use. In one important study, researchers analyzed office-based prescribing habits for 160 frequently prescribed prescription drugs and determined that approximately 21% were for off-label use. In this research, off-label use was most prevalent for heart medications (46%), anticonvulsant medications (46%), and asthma medications (42%). The investigators also found that the majority of off-label use (73%) had confined or absolutely no scientific support.

The greatest disparity in the percentage of scientifically backed versus unsupported off-label use occurred with psychiatric medicines. In 96%, the off-label use was determined to have little or no sound scientific evidence for the condition for which the substance was given.

A review of the psychiatric literature illustrates that mental health clinicians use medications for off-label symptoms in the treatment for insomnia, schizophrenia, bipolar disorder, stress and anxiety disorders, personality disorders, and dementia. A substantial portion of atypical antipsychotic medications are prescribed by doctors for nonapproved uses that are not reasonable extensions of their FDA-approved indications, and many of these uses don't have supporting information.

Off-label prescribing poses particularly tough problems for clinicians who deal with children for the reason that approximately 50% to 75% of pediatric medication use is off-label. Very few prescription drugs are approved for use in children, and clinicians have limited facts to use when seeking to perform evidence-based prescribing. Once they have exhausted medical guidelines and the approved drugs for the treatment of a disorder, they are left to extrapolate therapy from adult studies and blend these facts with less rigorous pediatric trials and their own medical knowledge.

Despite the scarcity of supporting scientific evidence, the number of psychiatric prescriptions for even extremely young children is increasing. Between 1987 and 1996 there was a marked increase in the use of psychotropic medications by children; the greatest increases were observed in stimulant use, antidepressant use, and the coprescription of various classes of psychiatric medications.

The most common indicator for off-label prescribing has been for childhood-onset conditions, such as severe attention-deficit/hyperactivity disorder and developmental issues. The complications of having few FDA-approved psychotropic medications for youngsters have been exacerbated by the new black box warnings inserted by the FDA on antidepressants, antipsychotics, and psycho­stim­ulants regarding their use in children and young adults.

The benefits and drawbacks of off-label use
There is substantial controversy surrounding the appropriateness of permitting off-label use for FDA-authorised medications. The debate centers on a central predicament—whether to emphasize an authorization procedure that ensures safety and efficacy or to allow doctors and patients early accessibility to novel treatments.

Advocates of the current hands-off approach declare that permitting off-label prescribing creates innovation in clinical practice—which is vital when approved solutions have failed. Advocates also point out that many off-label treatments have been confirmed by high-quality research and have proved to be profoundly beneficial to patients. This is often seen in specialties such as pediatrics and oncology and among medical doctors who treat HIV-positive patients, for whom very few authorized medications are available.

Proponents contend that if patients had to hold out for use-specific FDA authorization, many would lose the opportunity to benefit from innovations that develop as a medication is used in clinical practice. This is especially true for psychotropic medications, which are typically fine-tuned based on personal and oftentimes idiosyncratic responses of patients to these medications. In a recent letter printed in the Archives of Internal Medicine, the National Mental Health Association stated its support for off-label use of medications in psychiatry: “For numerous mental health consumers, access to a complete variety of medications is a crucial component of effective therapy and recovery because of the complex­ity and individuality of mental health disorders. With close supervising from a physician, the off-label use of prescription drugs can help an individual achieve his or her total potential.”

Opponents of unfettered off-label prescribing claim that failure to reg­ulate off-label use leaves patients vulnerable to inadequately screened med­ications and undermines the public’s expectation that they will be given medicines with acknowledged safety and efficiency. Critics claim that off-label use undermines endeavours to institute evidence-based medicine. They express concerns that busy doctors will not have the time to collect 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.

Advocates of greater FDA regulation explain that allowing off- label use gives a financial disincentive for manufacturers to seek out expen­sive secondary indication approvals from the FDA. This hampers thorough testing of medications for relatively small populations, such as children or patients with unusual illnesses.

Does off-label prescribing increase liability probability? Prescribing approved medications for off-label use is common and has been clearly sanctioned by the FDA, professional healthcare organizations, and the federal courts. The reasoning is that the FDA regulates only the manufacturer’s promotion, distribution, and marking of medications and was never authorized to manage the practice of medicine. 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.

The AMA has taken a comparable position, indicating that off-label use is reasonable “when such use is based on sound medical research and sound medical opinion. ” Likewise, the American Psychiatric Association (APA) Board of Trustees recently reiterated its “strong support for the autonomous clinical judgement-making authority of a medical doctor” and use of a drug for an unlabeled indication “when such use is based on sound scientific evidence in conjunction with sound medical opinion. ”

Several courts around the nation have ruled that off-label use of medications is an accepted practice and is not considered “experimental. ” Additionally, the United States Supreme Court has commented that off-label use of health-related devices is “an established and necessary corollary of the FDA’s objective to regulate in this area without directly interfering with the practice of medicine.”

How then can off-label prescribing enhance the physician’s potential liability in a malpractice claim? To prevail in a malpractice claim, a plaintiff must demonstrate that the physician’s decisions or omissions deviated from the relevant standard of care. Although these criteria vary from state to state, they typically communicate the necessity that physicians must practice with that level of care, knowledge, and skill normally possessed and exercised by other professionals in comparable circumstances. Plaintiffs may allege that the specific off-label use at issue constituted a deviation from the standard of treatment in prescribing.

While the off-label use of a prescription medication may not be a violation of the standard of care per se, based upon on the state, any deviation from Physicians’ Desk Reference prescribing recommendations may constitute evidence of a deviation from the standard of care in prescribing. In extreme cases, the use of a medicine 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.

Plaintiffs could likewise allege that the defendant physician was negligent in failing to acquire suitable informed consent from the patient for the off-label use. All clinicians are expected to obtain appropriate informed consent from patients before prescribing a medi­cation. Again, while standards vary depending on the jurisdiction, they typically require clinicians to advise patients of the nature of the suggested treatment, the dangers and benefits of the proposed treatment, available alternate options and their risks and rewards, and the hazards of forgoing treatment.

With respect to acquiring informed consent for off-label use, the majority of commentators believe that clinicians are expected to clearly discuss with their patients the fact that they are suggesting a use that is not FDA-authorised and participate in a risk/benefit discourse that takes this use into account.

Reducing the risks while capitalizing on good medical care
A review of the risk management materials reveals the subsequent techniques for minimizing the risk of untoward outcomes and legal liabilities. Exercising these risk management tactics will have valuable effects not only upon the management of prescribing risk but also on the quality of patient care.

1. Record that you considered medications that were FDA-sanctioned. While the selection of drugs is at the prescriber’s discretion, a doctor in a malpractice action may have to defend choosing an off-label remedy when he had an option to select a medicine specifically sanctioned for that use, with acknowledged safety and efficiency. Make sure that you have sound clinical explanations for choosing the off-label medication and record this reasoning in the patient’s chart. Proof of sound clinical thinking will go a long way toward demonstrating that your prescription medication choice was warranted and fulfilled applicable standards of care.

2. Make sure that your decision to recommend an off-label medication has strong scientific support. The AMA and APA have supported off-label prescribing that is predicated on sound medical research and sound medical opinion. It is essential to base your choice of drugs on such support, and recording this scientific foundation will be proof that you lived up to the standards of sensible prescribing should the use be challenged. This requires that professionals are able to support the use under consideration with medical materials, continuing medical instruction information, government agency associates, expert recommendations, or learned treatises that endorse the off-label use. Keep current with the professional literature regarding the safety and effectiveness of the prescription medication you are prescribing off-label since prescribing indications change rapidly with expanding clinical knowledge.

3. Maintain an office record that contains scientific evidence for the use in question. Professionals in risk management recommend that providers maintain a file of supporting evidence for off-label use, and that this file should be kept separately from patient charts. Ideally, this file would likely contain peer-evaluated materials concerning this use, as well as professional acquaintances that support this use. It is not necessary to disperse these resources to patients, as doctors carry the responsibility for making suitable clinical selections and ensuring that they are recommending therapies with a favorable risk/benefit profile. If a patient later alleges that he was damaged by an inappropriately chosen agent, this record can be utilized as proof that the physician had documented support for his selection.

4. Keep an eye on the patient for undesirable consequences connected with the off-label use. While prescribers are always required to observe their patients for indicators that they are suffering from negative medicine effects, this duty is heightened when prescribing off-label substances. The use of off-label drugs increases the chance of unidentified drug-drug interactions and should induce close scrutiny in that context. Before prescribing any medication (whether or not off-label), clinicians should ask whether their patient takes additional prescribed or over-the-counter drugs. If there are identified risks associated with a particular off-label use, the clinician should warn the patient of this risk and advise the patient on exactly how to recognize such symptoms and what to do in the event that they show up. This may consist of guidelines about who to get in touch with in the event the patient notices an adverse medicine effect or has fears about the medication. These kinds of monitoring parameters may be more specific when prescribing off-label for children and adolescents. Tailored monitoring methods for each type of psychotropic medica­­tion prescribed for children have been described.

5. Acquire consultation for an off-label use that is controversial or novel. In some circumstances, clinicians may wish to seek advice from outside professionals concerning the off-label use they are considering. This is observed most frequently with controversial or novel medications for which relatively little scientific support is accessible. Consulting an expert in either the specific off-label use or the state-of-the-art therapy for the condition in question will illustrate in a later litigation that the prescriber was thorough and careful regarding the selection of medicine, and that experts in the discipline (who typically serve as expert witnesses establishing the standard of care) supported this off-label use.

6. Supplement the informed consent practice with explicit discussions regarding off-label use. Most clinicians engage in an appropriate discussion with patients related to the perils, benefits, and alternatives to the therapies they propose. As discussed above, this dialogue should conform to state law requirements for disclosure and patient understanding. However, suggesting a medicine that has not been FDA-approved for the specific use necessitates a higher standard of informed consent.

A recent poll of over 2000 adults revealed that the majority of patients are not aware that physicians are allowed to prescribe medications for symptoms that are not approved by the FDA. Clinicians should have an interactive conversation with the patient (or the individual authorized to make health care selections on the patient’s behalf) regarding the nature of off-label use, the explanations for choosing a non–FDA-approved medicine, and the risks specifically related with the suggested use. This discourse, coupled with any written resources given to the patient, should be included in the patient’s chart.

If the medicine the clinician is recommending also has a black box caution about its use, the clinician must carry out an informed consent discussion that takes into account the regulatory requirements and monitoring schedules set forth by the FDA for these uses. (Dell and colleagues offer an outstanding discussion concerning informed consent when prescribing psychotropics for children. )

As with various other sources of liability for prescribing, the best protection against malpractice liability for prescribing off-label is to offer high-quality care when selecting, prescribing, and monitoring medications, and to engage in meaningful informed consent conversations with your patients.




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