Off-Label But On Point?

Apr 01, 2011
By Pharmaceutical Executive


Dr. Albert Wertheimer
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?

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.