The Basics Behind Off-Label Use of Medicines in Clinical Care

Both medical providers and medical patients find medical care in the United States complicated. Both want optimal care with the least complications. Therefore, product makers, such as the pharmaceutical businesses, seek approval from the Food and Drug Administration (FDA) to market their products that help patients. The FDA has the responsibility to make sure that the pharmaceuticals, biologicals, and medical devices are safe and effective. Unfortunately, the drug development (DD) process is time-consuming and costly. Many times, DD can be more than 13 years, from the bench to the patient, and more than half of this period involves clinical studies.1 Even with these ardent requirements, doctors have the qualifications to access medicines not approved for specific conditions. If the drug has an approved use, the practitioner can legally prescribe this to a patient for other purposes. This type of access is called off-label use (OLU). OLU involves the use of an FDA-approved medicine for anything other than that for what it is approved. Unapproved therapy or unproven therapy are alternate names for OLU. OLU can involve an alternative route, dose, or a different disease than that its approved application. The objective of this paper is to review the fundamentals, benefits, and problems of OLU medicines.

Overview of OLU

The first purpose of OLU is for practitioners to get a treatment specific for the patient. The Physician Desk Reference (PDR) lists more than 24,000 prescriptions and over-the-counter FDA-approved medicines.2 The World Health Organization (WHO) lists roughly 12,000 diseases under 22 categories.3 Even with this favorable ratio, clinicians can have a difficult time getting the right medicine for the individual patient. Patients themselves may also use medicines off-label.

The second purpose of OLU is to compensate for the particular processes utilized in the for drug approval. At present, drug approvals are validated on data collected from a small population, under controlled conditions. Clinical trials in DD are set up to study the product in less than 5,000 people over a year or two. The remainder of the population (300 million people) use this extrapolated clinical data for their safety, and this translates to the medicine or the product only examined in only less than two-one thousands percentage of the population. Additionally, the average patient ends up taking the medication for a much longer time than that spent on studying the medicine.

The last purpose of OLU is to advance medical knowledge. OLU is used routinely in certain challenging conditions or understudied specialties, such as orphan diseases,4 cancer treatments,5 chronic pain, or psychiatric conditions. When OLU works, not only may it treat the patient, it may help to identify the mechanisms of the disease.

In the past, all clinical studies excluded certain groups such as pregnant women and children. As a result, OLU efficacy is justified by anecdotal evidence in this population.6

Who can prescribe OLU medicines? Because of the licensing regimen, practitioners are not bound to use OLU medicines as indicated by FDA. Medical professionals can use a drug in any manner as long as the drug is FDA approved. If a drug is not effective, the practitioner can try an alternative. In this manner, OLU may be considered personalized medicine. OLU is acceptable as long as the practitioner prescribes drugs from the drugs that are already approved by the FDA.

OLU Statistics in the U.S.

Between 2005 and 2008, 48% of office visits resulted in at least one prescription drug, which amounts to 2.3 billion prescriptions in the U.S. per year. A separate study found that OLU involves 21% of all prescribed medicines.4 Most of these treatments are for the management of pain, elevated cholesterol, and depression.

Unfortunately, three-quarters of OLU are ineffective,4 and 29% of OLU medicines cause adverse drug reactions (ADR).5 OLU medicines often result in black box warnings, but typically only after ten years on the market.5 Therefore, both the ineffectiveness of OLU and its complications may contribute to the high cost of health care.

In 2010, 10% of all U.S. healthcare costs were prescription drugs and amounted to $260 billion.7 Even though OLU accounts for 21% of all prescription drugs, OLU costs $55 billion of 2010 healthcare costs.5

One of the highest rates (>50%) of OLU medicine is biologics.4,8,9 Biologics include agents such as recombinant enzymes, cytokines, and monoclonal antibodies, which are used to treat cancers and diabetes.10,11 Biologics have been growing 20% per year and account for more than $40 billion in sales.12 Unfortunately, they are usually the most expensive, often costing more than $1,000 per month and are potentially risky.13 Due to past court cases and the Omnibus Budget Reconciliation Act of 1993, Medicare and third-party payers must cover OLU of biologics for cancers.5

Controversies of OLU

If OLU costs much with little assurance of effectiveness and safety, who should pay for OLU medicines? Patients, doctors, manufacturers, insurance carriers, or government?5 Most of the time, insurance carriers will not pay for a treatment that is not proven. However, biologics for treating cancer are covered by Medicare and insurance carriers. Some people wonder why the costs of cancer are covered while costs of many other diseases are not. Also, if a generic is available, then who pays for the off-label drug, and how much more should be allowed over the cost of the generic?

Should OLU be regulated? The biggest problem with off-labels is the lack of clinical evidence of efficacy and safety. Even with the lack of proof of the effectiveness of OLU, there is little the FDA can do to regulate this practice. The only authority the FDA has for regulating OLU is for misbranding violation, for inappropriate use, or for misleading advertisement/promotion.14 While some prefer the freedom of regulation, others want laws to prevent practitioners from practicing non-evidence-based medicine.15

When patients are subjected of OLU, should patients be informed? Currently, practitioners are not required to inform patients that the drug being used is off-label. Malpractice laws and the courts often favor OLU in medical practices because medical practices are considered honorable. Some people support general disclosure on whether the drug is approved for a condition because they believe a revelation gives the patients enough information to evaluate their treatment options (similar to that in a research study). Nearly all specialties practice uninformed OLU. Only the American Academy of Pediatrics (AAP) believes in full disclosure of OLU. Therefore, in a pediatric setting, the providers inform the legal guardians of the off-label use of medical products utilized in individual patient care.6


While OLU medicine has value, there should be a greater role of institutions and government in identifying best practices and regulation of OLU.15. Several suggestions for improving OLU include: restricting prescriptions to be utilized only evidence supported medications; obtaining informed consents for OLU drugs; setting up a database or registry to collect ongoing research of OLU medicines regarding safety and effectiveness; and, considering sanctions for doctors who violation measures to study OLU medicines more effectively.15 Clearly, there is a lot that could be done.


OLU is useful and sometimes necessary alternative, but can be risky and costly. Nevertheless, OLU in America continues to grow. It is unclear when the value of OLU outweighs the risks, and additional studies are needed. The primary cause of OLU is that the lack of understanding of the diseases involved, and the dearth of FDA-approved medicines to treat the disease. Practitioners must demand more fundamental research and further studies of products currently in use for a wider set of people and illnesses.


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15. Rosoff PM, Coleman DL. The case for legal regulation of physician’s Off-Label prescribing. Notre Dame L. Re

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