Prescribing off-label medications is commonplace in the field of medicine. Despite the indisputable value of off-label uses and the corresponding need for doctors and other prescribers to be informed about them, the FDA has categorically banned manufacturers of drugs and devices from promoting their use for unapproved purposes to the medical profession. Here, we summarize and discuss the risks and benefits of off-label promotion and how this relates to pharmaceutical companies in the RARE disease space and personalized medicine.

Therapeutics are often found to have additional benefits for uses that exceed those listed on its FDA approved label. This off-label use often includes treatments for disorders that the therapeutic was not initially investigated for by the FDA, dosages or delivery mechanisms that have not been approved, or use of the therapeutic in a patient population that was the focus of the clinical study. Conducting a clinical trial for each indication of the therapeutic could cost a company millions of dollars and lasts for an average of 8 to 12 years, making it infeasible or illogical for a company to conduct clinical trials for every possible indication of the therapeutic. (1)

The FDA began cracking down on pharmaceutical companies’ promotion of off-label use in 1968, after members of Congress became concerned with the Methotrexate scandal. The FDA was made aware of a medical journal article that encouraged physicians to suggest to their patients the off-label use of Methotrexate, which members of Congress believed was linked to the recent deaths from the therapeutic. Congress began pressuring the FDA to develop a clear policy on off-label use by physicians, but the medical community fought the FDA’s efforts.(1) Under the pressure of Congress and the medical community, the FDA decided to focus on the “dissemination of information about off-label use by the product manufacturers, and not the use itself. “

The FDA argues that legalization of off-label promotion will lead to an increase in false and misleading labeling, resulting in less effective and safe medication. Pharmaceutical companies have argued that these therapies have already undergone a phase 1 clinical trial, proving their safety, and that it has a right to disseminate information if it has data that truthfully shows its effectiveness. This assumes that therapies that have undergone its rigorous process are safer and more effective than off-label therapies, which is not an absolute truth. Merck’s blockbuster anti-inflammatory drug Vioxx went through the FDA’s rigorous testing and was approved, but ultimately lead to the death of thousands.(1)

The FDA’s stance on off-label use assumes that physicians are unable to determine what is scientifically and medically substantial. Much of the standard care in oncology have come from doctors prescribing off-label therapies for their patients. In fact, the off-label use of drugs has significantly contributed to the therapeutic armamentarium of many different diseases in medicine.(1) A great example of benefits that have come from off-label use would be aspirin, which is now being used to help reduce the risk of heart attacks. (1)

The effect of the FDA’s stance:
Should we expect a pharmaceutical company to remain silent when it knows that the off-label use of one of its drugs could save the life of a patient with a rare disease?

The FDA’s guidance for the industry restricts communication between industry professionals and physicians, if the indication is not specified within the label. The FDA’s stance could be problematic for a few sectors in the pharmaceutical market such as rare disease. Lives of patients suffering from rare diseases rely on the information that their physicians have access to, and physicians have been shown to have a limited knowledge of many orphan diseases and new treatment options. In the case of rare disease, where the number of patients suffering from the disease rarely exceeds 200,000, the most knowledgeable individuals often work for the pharmaceutical company developing the therapy.(1)

When roughly 90% of the thirty million patients suffering from a rare disease are prescribed at least one drug for off-label use, should we stop the free flow of information and advancement between physician and pharmaceutical company? (1) This would mean that by following the FDA’s guidance, both the physician and pharmaceutical company would be doing a disservice to the very patient population that the guidance was aimed to protect. The current stance of the FDA would leave health professionals and patients in the dark about potential advances. “With diseases of such rarity, proper diagnosis is often a major challenge. Getting appropriate treatment is even harder.” (2) Pharmaceutical companies should be able to provide information about advances in the rare disease, giving doctors more treatment choices for the patient. Unfortunately, physicians face a time constraint and are unable to see patients, attend rare disease conferences, and or read every journal for newly released advances.

1. Tim Mackey & Bryan A. Liang, Off-Label Promotion Reform: A Legislative Proposal Addressing Vulnerable Patient Drug Access and Limiting Inappropriate Pharmaceutical Marketing, 45 U. Mich. J. L. Reform 1 (2011).

2. Coleen Klasmeier and Martin Redish – “Off-Label Prescription Advertising, the FDA and the First Amendment: A Study in the Values of Commercial Speech Protection,” American Journal of Law & Medicine, Volume 37, Numbers 2&3 (2011).