Many physicians believe it is sometimes appropriate to prescribe drugs for indications that have not been approved by the U.S. Food and Drug Administration (FDA). In this issue of American Family Physician, Stone, Viera, and Parman¹ base their review article on this premise and discuss some of the unapproved (or, “off-label”) uses of selective serotonin reuptake inhibitors (SSRIs).

Off-label use is legal and, with important qualifications, generally embraced by physicians and other health care providers, health care institutions, insurers, pharmaceutical companies, and even the FDA. The FDA has observed that unapproved uses may be appropriate and rational in certain situations, and that advances in medical knowledge and practice inevitably precede labeling revisions.

Off-label prescribing presents a challenge as well as an opportunity involving effectiveness and safety. Concerns include the applicability of labeling for specific uses in respect to administration, contraindications, warnings, precautions, abuse, and dependence, which were developed for a different use. Controversy has surrounded such issues as the authority, wisdom, and risks of off-label prescribing; reimbursement and coverage for off-label uses; physician liability; and the conditions under which manufacturers can disseminate literature about off-label uses.^2–5

Physicians who treat children often prescribe drugs for off-label uses because little information is available from well-controlled studies on dosage, formulation, effectiveness, and safety in children. Recent federal legislation and programs are addressing these problems.⁶

Successful patient care requires that physicians be free to use drugs according to their best knowledge and judgment.⁷ When a physician prescribes a drug for a use not on the approved label, he or she “has the responsibility to be well informed about the drug and to base such use on a firm scientific rationale or on sound medical evidence.”^7,8 The American Medical Association⁹ (AMA) and the American Academy of Pediatrics¹⁰ (AAP) have developed similar policy statements.

Since the early 1960s, the FDA has been required by law to base its approval of drugs and their labels on substantial effectiveness and safety data for a specific use in a particular population based on well-controlled trials.

Legally, the FDA may not base its approval of a drug solely on anecdotal information or consensus recommendations. The FDA's review of a company's marketing application includes a thorough scientific analysis of the clinical trial data and supporting documentation submitted with the application, and visits to clinical trial sites to inspect and validate data. Before an off-label use can be added to the label of an approved drug, safety and effectiveness must be demonstrated as in the initial application. Only when the manufacturer receives a supplemental marketing approval from the FDA for a new use can it advertise or promote the drug for that new use.

Lack of approval for an off-label use can be due to many factors. For example, the company may not be interested in pursuing approval for the off-label use for commercial or financial reasons. Another possibility is that the company may have carried out some studies on the off-label use as part of its initial application for marketing approval, but the FDA did not find that the studies met the required standards for approval.

Considerations in Prescribing for Off-Label Uses

If a physician is considering off-label prescribing for a particular patient, the following information can be helpful in facilitating a decision.

COMPENDIA AND GUIDELINES

Off-label uses appear in a number of compendia that use expert committees to review approved and unapproved uses.^11,12 Some of these compendia have been recognized in Federal legislation for reimbursement purposes.

Some professional organizations, such as the AAP, have guidelines for prescribing drugs for specific off-label indications, diseases, or population groups under consideration, and their Web sites may yield useful information on specific off-label uses. (For example, see www.aap.org/policy/re0112.html.)

FDA AND THE MEDICAL LITERATURE

It can be helpful to review the most recently updated FDA labeling for the drug, especially any black-box warnings, contraindications, drug-drug interactions, and side effects, especially as these might pertain to the proposed off-label use. In addition, the following should raise concern and be factored into the physician's decision-making: higher doses, use in different populations, use in patients with other underlying diseases, and use in patients taking concomitant medications different from those originally anticipated and appearing on the label approved by the FDA for a specific disease and population. Information is available from the FDA's Center for Drug Evaluation and Research (www.fda.gov/cder/), the FDA's MedWatch program (www.fda.gov/medwatch/index.html), and a Web site with the most recent pediatric labeling changes (www.fda.gov/cder/pediatric/labelchange.htm).

The most reliable scientific articles on off-label use appear in peer-reviewed medical journals whose editorial policies foster the publication of high-quality randomized controlled trials and evidence-based reports. Nonetheless, on occasion, the FDA has found serious violations in the conduct of some clinical trials, which has led to the disqualification of investigators and retraction of published articles.

It also can be useful to know the length of time the approved drug has been on the market, the magnitude of the off-label use, and whether or not the drug is approved for the off-label use in another country that has a sophisticated drug regulatory authority.

THE PHYSICIAN'S ROLE

In the opinion of the treating physician who has detailed knowledge of the medical history and clinical status of a given patient, off-label drug use may be a reasonable choice for that specific patient in that setting. The drug may be more effective or less effective, safer or less safe, than an alternative drug labeled for that use. Or the drug may be ineffective and unsafe. Fortunately, much information about off-label prescribing is now available in the medical literature, from professional associations, pharmaceutical sources, and the FDA through the Internet to help physicians make appropriate decisions. The physician has a difficult but important job in sorting out what specific off-label use might be appropriate for a particular patient.