Off-Label Use – A Free Speech, Scientific and Safety Issue Save

Off-label use of a drug implies use outside of the boundaries established by the label.  This topic has been recently highlighted in the news.

The Food and Drug Administration regulates how drugs are marketed and promoted to the public. Regulatory approval exists to safeguard patients, and to ensure both the appropriate use and promotion of new drugs to practitioners and patients.

The Food, Drug and Cosmetic Act prohibits pharmaceutical companies from selling a drug outside of the limits of approved indications. While physicians can use drugs off-label, promotion of off-label use (OLU) is frowned upon by regulators. The FDA has taken measures against companies who knowingly promote a drug or medical device for OLU, even if there is interest, need or scientific evidence to support such use.

This issue took a new turn this month as a NY Federal District Court found that the First Amendment can be extended to drug companies who make truthful statements about their drugs, even if it is for an unapproved use. This decision sets up a likely appeal to determine just how far the government can go to punish speech that is truthful. (Citation source:http://buff.ly/1EfVRz5).

A small pharmaceutical company, Amarin, and four doctors sued the FDA after the agency threatened them with civil charges if they used the published studies to help sell off-label use of their drug, Vascepa. They claim that FDA policy on off-label promotion violates their First Amendment right to free speech and therefore, asked the district court to block any enforcement action.

The judge in this case pointed out that the FDA does not prohibit doctors from prescribing medications for nonapproved uses because it does not have direct authority over them. The judge pointed out that “the therapeutic — indeed, sometimes lifesaving — value of off-label uses of F.D.A.-approved drugs has been widely recognized.” For some conditions “off-label prescription is the norm rather than the exception,” a fact the FDA is aware of and even encourages on occasion.

This issue plays out every day in practice. Have you ever prescribed rituximab for lupus or myositis? How about adalimumab for uveitis or hidraadenitis? Since none of these medications are currently approved for use in these select and often rare conditions, these are examples of OLU.

OLU is a common practice throughout medicine. OLU implies that a medication is being used outside the scope of clinical indications sought by the manufacturers and approved by the FDA or appropriate regulatory agencies (1). OLU is common in the care of children, pregnant, psychiatric and other orphan disorders (e.g., GPA, sarcoidosis, JIA) with limited therapeutic options owing to few studies and limited market. It is estimated that it takes over 10 years and over $1 billion USD to bring a new drug to market. Thus, most FDA approved drugs are for prevalent conditions with the opportunity for a return on investment.

OLU is legal, prevalent and usually supported by scientific evidence - although the extent of evidence is often far less than that required for regulatory approval. While it is reasonable to use the best medication for each situation, prescribers may not have the luxury of having a list of “approved” treatment options to choose from. Such situations may put physicians at risk, and may put the manufacturers at risk as they respond to requests from practitioners about the OLU of their new medication.

While patients may be unaware if a prescribed therapy is being used "off-label”, regulatory agencies, insurers and 3rd party payers are keenly focused on the appropriate use of available treatments. While they may point to patient safety, clearly payers benefit from not having to pay for unapproved OLU as these usually involve newer and more expensive medications. Nonetheless, "off-label" use of medications is necessary clinical practice for which there is little guidance and at times unknown risks.

There are numerous examples of OLU in rheumatology - some with strong evidence, others not. OLU in rheumatology occurs most commonly in rare and orphan disorders and in conditions not typically subject to drug development and clinical trials research. This includes chronic pain, FM, SLE, vasculitis, pediatric rheumatology, scleroderma and inflammatory myositis.

OLU also exist when the use of an approved drug is given in an unapproved: 1) space (e.g., viscosupplementation of the shoulder instead of knee); 2) population (e.g., sildenafil for pulmonary hypertension or in tofacitinib in children with JIA); 3) route (e.g., intraarticular etanercept or intravenous anakinra); or 4) dose (e.g., weekly leflunomide or pulse doses of solumedrol).

Lupus is a common disorder for OLU given the limited availability of approved medications. The only approved drugs for lupus in the USA are aspirin, glucocorticoids, hydroxychloroquine and belimumab. Over-reliance on corticosteroids in lupus may be dangerous, thereby motivating some of the OLU of agents including methotrexate, mycophenolate, rituximab and other biologics. Rheumatologists who are loathe to use rituximab in RA (owing to other options and concern over a 1 in 30,000 risk of PML) have used this drug in lupus, even though clinical trials have not demonstrated its efficacy and the drug may yield an even higher risk of PML in lupus patients. This example reflects the inherent risks of off-label use when managing a difficult, uncommon disorder with limited treatment options. One way of dealing with these difficulties is through careful examination of supportive evidence, participation in research to generate evidence or to rely on guidelines.

Safety concerns with OLU should only be undertaken when realizing you may not know: 1) optimal dosing; 2) potential drug interactions; 3) relative and absolute contraindications to OLU; and 4) the long term effects of OLU (especially in neonatal and pediatric indications).

Recommendations: It is the physician’s duty to treat each patient in the most effective and safest manner possible, which may reasonably include OLU. To ensure patient safety, limit liability and provide cost-efficient therapy, health care professionals should carefully review of the product label and educate the patient about the OLU of a particular medicine. Informed consent is not necessary but shared decision making with the patient is advisable.