Off-Label But On Point?

Something is definitely wrong if nearly 50 percent of all prescriptions written in the US are "off-label." Are physicians becoming reckless; is the FDA having trouble keeping pace; are patients making unrealistic demands on the health system, or is it all of the above?

Dr. Albert Wertheimer

When a drug product is approved for marketing by the FDA, it is given that approval for a specific indication. FDA approval of a prescription drug requires substantial evidence of efficacy and safety for that specific indication. Once the drug is approved for marketing, the manufacturer is legally able to promote the drug only for use in the approved indications. Yet, in the course of widespread use, it often becomes known by the clinician community that certain drugs also possess effectiveness against other medical conditions for which there has been no clinical data submission to the FDA. Even though new indications may be added to a drug's label through a supplemental new drug application (sNDA), this is not a common practice because the additional clinical trials—which might not provide sufficient evidence to grant a new indication—are costly and lengthy. Moreover, drug manufacturers have only a limited incentive since the drug is already marketed.

Off-label use is the practice of prescribing drugs for a purpose outside the scope of the drug's approved label, most often concerning the drug's indications; but it could also be for the use of a drug in unapproved subpopulations. For example, in a study analyzing prescriptions for children ages 0 to 16 in the Netherlands, it was found that 22.7 percent of the prescriptions for children were used off-label. In another study in the US, it was found that off-label prescribing of 160 commonly used drugs was 21 percent. Off-label use has been most common among cardiac medications (46 percent) and anticonvulsants (46 percent); whereas gabapentin/Neurontin (83 percent) and amitriptyline (81 percent) had the greatest proportion of off-label use among specific medications. Neurontin was used off-label for neuropathic pain (it was only indicated in controlling epileptic seizures and in pain from post-herpetic neuralgia); it is also commonly prescribed for chronic back pain.

With more than 3.5 billion prescriptions written in the US each year, estimates suggest that up to 50 percent of these prescriptions are for an off-label indication—this is an international, widespread, and growing practice. The scope of off-label use includes even the practice of Aspirin use for prophylaxis against cardiovascular disease.

Perhaps the largest area of off-label use is in pediatrics. If a drug is approved for patients 16 years and older, what physician should not assume that the drug would be equally effective in 14 and 15 years olds? This age limit was due to the budget and inclusion criteria of the sponsor during the NDA clinical trial studies and does not at all reflect the effectiveness of the drugs in younger patients.

An Innovation Factor

If one argues that there is not rigorous scientific evidence to support effectiveness for a "new indication," why do physicians prescribe drugs off-label? Physicians are free to prescribe a drug on the market for any indication. This prescribing freedom allows innovation in clinical practice. Off-label use is a delicate balance between the regulatory objective of protecting patients from unsafe or ineffective drugs and the physician's professional role to use their best judgment in treating their patients.

Medical practice often moves faster than the FDA, for example, among physicians treating AIDS patients where the drug trimethroprim/sulfamethoxazole was found to be effective for treating pneumonia long before it was labeled for this use by the FDA. As was stated earlier, many non-approved uses of drugs are for conditions and populations different from those for which the drugs are initially approved. Beta blockers are now used to prevent tremors and perspiration, antiseizure medications are used as mood stabilizers, antihistamines are used as sleeping aids, and so on.

In many cases the drug of choice fails to stem a patient's disease, such as in cancer. Patients with terminal diseases demand new approaches despite risks and low odds of success. Those patients are more open to experimental or innovative treatments.

No patient wants to hear the words: "I'm sorry but there is nothing further we can do." Those words often drive patients into therapies in Mexico or elsewhere, to unorthodox healing systems, or to request the physician use X or Y or Z based upon what the patient read on a website or learned from a neighbor. In order to satisfy the patient (read: customer), the physician prescribes some vitamins or bioflavinoids, folic acid, or mineral complexes.

Off-label prescribing is also common for so-called orphan populations and for orphan diseases. Too small and too rare to justify costs to undergo the FDA approval process for new indication labeling, manufacturers do not invest in new studies. Finally, getting the FDA to approve a new use for an old drug is an expensive, lengthy, often unprofitable process. The FDA requires an sNDA, which calls for extensive clinical trials that are costly and take years to complete, and then the approval itself can take even longer before the label can be changed.

The Downside

Off-label use has negative attributes. First of all, it may be misleading to patients. They assume that any approved drug is effective and safe. They might not know that drugs are approved for a specific indication. Therefore, when prescribing off-label, physicians might consider informing patients about the lack of indication information and then evaluate together the risks and benefits of such a prescription. A legal problem for physicians could arise if they were faced with a malpractice suit, since off-label use often does not reflect a "standard of care" treatment. This leads to possible concern about the risk of prescribing off-label should a patient have serious side effects or a bad outcome from treatment.

Regarding reimbursement for off-label prescribing, some managed care organizations and other payers will not pay for off-label prescriptions, increasing the patient's out-of-pocket expense for medicines. Many insurance companies will not pay for an expensive drug that is used in a way that is not listed in the approved label; insurers claim that its use is "experimental" or "investigational."

Permitting companies to promote off-label use diminishes the incentive for manufacturers to apply for new indication labeling. If the market for a product is small, the investment in a clinical trial would not be warranted. That is the same situation if a product had only three or fewer years remaining of patent protection, since the benefits would only accrue to future generic manufacturers.

Perhaps the FDA now takes the most progressive stance, allowing drug companies to give physicians journal articles that discuss off-label uses of products not yet approved by the FDA. This approach replaces the relevant provisions in the FDA 1997 Modernization Act (FDAMA), which expired in 2006. The new guidelines include provisions allowing dissemination of information if a drug company meets certain criteria. In this way, the FDA is making it easier for pharmaceutical companies to distribute more truthful, non-misleading, and objective information than had been possible in the past. It is assumed and hoped that this will benefit patients who might gain access to products which their physicians were previously unaware of, or reluctant to try.

Even with these protections and the additional latitude provided to drug companies and prescribing physicians, there are still some who object, claiming that there are insufficient protections for the patient. They argue that there should be a strict requirement compelling doctors to obtain informed consent from patients who are prescribed drugs for an off-label use just as they would before enrolling patients in a clinical research study.

Off-label prescribing of medications cannot automatically be criticized, as often this is the optimal therapy for some conditions. Unfortunately, there are numerous medical conditions and other morbidities where there are no approved, effective drug therapies available. Moreover, some very effective therapies have been discovered by serendipity in this way—an off-label use today may lead to tomorrow's effective and officially approved use of a drug. It is becoming possible for the practitioner to gain some legitimate and non-commercial information. The reference work "Facts and Comparisons" includes information about known off-label uses of many drugs. In addition, the US Pharmacopeia reference compendium lists at the end of a monograph information about any known off-label use of that drug.

As with many other situations where not all of the facts may be known, it seems that the wisest path is to approach the use of drugs for off-label conditions with great caution and as much knowledge as may be gained before the prescribing decision is arrived at.

Dr. Albert Wertheimer is director of the Center for Pharmaceutical Health Services Research and Professor, Temple University School of Pharmacy. He can be reached at albertw@temple.edu