Off-Label Use of Drugs: What Is It, Why Is It a Problem, and How Can We Solve It?

Off-label use is the use of drugs in a manner that has not been approved by the regulatory agencies—the FDA in the United States. Specifically, off-label use can represent: (1) the use of a pharmaceutical agent to treat an approved indication in a population for which it has not been approved, such as the use of anesthesia in children; (2) the use of a drug in a dose or a pharmaceutical form not approved, for instance, prescribing the antidepressant venlafaxine at 300 mg/day of (the maximum approved dose is 225 mg/day); or (3) the use of a drug to treat a non-approved indication, eg, the use of anticonvulsant drugs to treat pain. Using a drug for a non-approved indication—what I plan to discuss further—is arguably the most relevant from a healthcare policy perspective, and one with the most economic impact.

It should be clarified that not all off-label use is non-evidence based. In some cases, there is evidence supporting the use of a drug for a non-approved indication. Owing to the extended approval process, drugs are sometimes used off-label to treat conditions for which they are eventually approved. In other cases, non-approved use may stem from the fact that there are no other therapeutic alternatives to treat a particular condition. This type of off-label use is common in oncology, where chemotherapy agents may be used to treat non-approved types of cancer when there are no other treatments available. This off-label use is generally justified on the basis of a favorable benefit-risk ratio.

Off-label use is of concern when there is evidence on the low effectiveness or high risks associated with the use of a drug for a non-approved condition, and yet, it is regularly used. This type of off-label use is most common in psychiatry. Antipsychotics are one of the therapeutic classes of drugs where off-label use has been most controversial. Most antipsychotic drugs are approved for the treatment of schizophrenia and bipolar disorder; however, they are also used to alleviate behavioral symptoms such as psychosis among patients with post-traumatic stress disorder, obsessive compulsive disorder, dementia, depression, personality disorders, or autism. Such off-label use of antipsychotic drugs is of concern for 3 reasons:

• The frequency of use; for instance, over 25% of veterans with post-traumatic stress disorder where threated with atypical antipsychotics between 2003 and 2010.
• Lack of evidence of effectiveness.
• Antipsychotic drugs have serious side effect; they have been shown to increase the risk of diabetes, metabolic syndrome, and among patients with dementia, their use has been associated with increased risk of death.
• To prevent this potentially harmful off-label use of antipsychotics among patients with dementia, the FDA introduced a boxed warning on the package of atypical and conventional antipsychotics in 2005 and 2008, respectively. However, the use of boxed warnings to prevent off-label use is not an effective mechanism for 2 reasons: first, it has not been specifically designed to target off-label use, rather to warn about severe side effects, which could also be observed when the drug is used as indicated. Second, the influence of boxed warnings varies based on the drug, and its long-term effectiveness remains unknown. In this context, more aggressive policies that contain off-label use with little benefit are much needed. In the era of value-based insurance, this off-label use could be prevented by excluding coverage when drugs are used off-label, or by decreasing the reimbursement rate. Regulating the marketing of drugs for off-label uses is another option.

Currently, the FDA allows the promotion of off-label use of drugs when there is supporting evidence on the safety and efficacy of such use. However, the capacity of the FDA to enforce such requirements has been a matter of controversy, and there have been relevant cases of promotion of potentially harmful off-label use. Such was the case with the promotion of risperidone, an atypical antipsychotic, among patients with dementia; this use in treating dementia has been widely linked with increased mortality, especially among the elderly. The pharmaceutical company Johnson & Johnson paid a $2.2 billion settlement in 2013, one of the biggest pharmaceutical settlements in US history, for the improper promotion of this antipsychotic medication.

In summary, more aggressive policies that target the use and promotion of off-label use are needed to prevent the use of drugs for non-approved indications with little benefit or with harmful outcomes. In order to design such policy interventions in the most effective way, it is also necessary to examine the factors that affect off-label use in the real-world clinical setting.