Stuart B. Goodman, MD, PhD; Shep J. Friedman, MD; Ivan Cheng, MD; A. Seth Greenwald, DPhil (Oxon); and Barbara D. Buch, MD

Many innovations in orthopaedic surgery and other medical subspecialties have evolved from off-label use of approved devices, biologics, and pharmaceutical products. Examples include the use of antibiotic-loaded bone cement, early use of cementless total joint replacement, cardiovascular stents (which evolved from biliary stents), numerous adult medications or devices used in children, and the perioperative use of beta-adrenergic blocking agents, among others.

According to a study published in 2010, approximately 85 percent of bone morphogenetic protein (BMP)-2 use in spine surgery has been off-label. An earlier study (2008) noted that only about 30 percent of off-label medication prescriptions have been supported by adequate scientific evidence. Thus, it’s important that orthopaedic surgeons know the regulations surrounding off-label use of medical products so they can deliver safe and effective care to their patients and comply with federal regulations.

What does off-label mean?
The U.S. Food and Drug Administration (FDA) regulates the marketing approval or clearance, labeling, and promotion of approved medical devices, biologics, and pharmaceuticals. These products may only be labeled and promoted for the uses that the FDA has approved or cleared.

Pharmaceutical companies and device manufacturers generally comply with FDA regulations rather than face substantial penalties, even though a 2012 court ruling determined that government restrictions on off-label marketing of medications may violate the right to free speech under the First Amendment.

The AAOS position statement on Off-Label Use of Medical Products defines off-label use of approved prescription drugs, biologics, and medical devices as “any use that is not specified in the labeling approved by the FDA.” For medical products that have been previously cleared/approved or licensed by the FDA, off-label use is the application of the product in a way that has not been cleared or approved by the FDA as shown in the indications for use or instructions for use on the FDA-approved product label. For devices, drugs, and biologics, this includes any written material that accompanies, supplements, or explains the product.

Off-label use in the practice of medicine
Although the FDA regulates medical products and not the practice of medicine, it also recognizes that off-label use of approved drugs and devices by physicians may often be appropriate and may represent the standard of practice. Furthermore, “good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics, and devices according to their best knowledge and educated good medical judgment,” as one of the authors wrote in a previous article.

When using approved drugs, biologics, and devices in an off-label manner, the physician has a responsibility to be well informed about the product, use sound medical evidence, and have a transparent discussion with the patient that puts the best interests of the patient above all else. In addition, subsequent documentation of this discussion in the medical record provides assurance that an informative interaction between doctor and patient was undertaken. The physician must also maintain records on the use and effects—both adverse and beneficial—of the product’s or device’s off-label use and know when an FDA investigational new drug or investigational device exemption may be needed.

FDA regulations prohibit pharmaceutical and device manufacturers from actively promoting and distributing written materials on off-label uses. Although truthful and non-misleading scientific or medical published information on as-yet unapproved new uses of drugs and devices may be of value to healthcare professionals, it is not a substitute for the FDA premarket review process.

Recently, the FDA published revised draft guidance for industry to clarify these processes. The document also provides information for drug or medical device manufacturers and their representatives to follow when distributing scientific and medical publications (scientific and medical journal articles, scientific and medical reference texts, and clinical practice guidelines) to healthcare professionals who discuss unapproved new uses for approved drugs, biologics, or approved or cleared medical devices marketed in the United States. Physicians should be aware of these recommendations and review the information in such publications accordingly.

Issues of concern
The FDA’s main concern is that off-label uses of medical products and devices are not subject to a rigorous premarket review process to identify adverse events. Therefore, the safety of the product for that particular use is not known. In some cases, appropriate testing to address even the most basic applicable mechanical, physiologic, or metabolic requirements or potential adverse events have not been adequately assessed. Thus, off-label use may lead to unsupervised experimentation, unclear health risks, or ineffective interventions.

Off-label uses may also diminish or eliminate the incentive to study or seek FDA approval for new indications. Moreover, the lack of systematically conducted clinical studies may ultimately impede reimbursements and payments by insurance companies for what could be a medically important application, because the Centers for Medicare and Medicaid Services will not have the appropriate necessary evidence to make a coverage determination. This lack of coverage could then make the product legally inaccessible to a large portion of the population.

The FDA posts approvals of FDA-regulated products by product type on its website (www.fda.gov). As healthcare providers, physicians also have a responsibility to understand the regulatory process; know what products are FDA cleared, approved, or licensed; understand the need for high-quality clinical trials; obtain adequate training for new technologies prior to widespread use; and participate in postmarket surveillance studies.

Stuart B. Goodman, MD, PhD; Shep J. Friedman, MD; and Ivan Cheng. MD, are members of the AAOS Biological Implants Committee. A. Seth Greenwald DPhil (Oxon) is director of Orthopaedic Research Laboratories in Cleveland, Ohio; Barbara D. Buch, MD, is an orthopaedic surgeon and associate director for medicine in the FDA’s Center for Biologics Evaluation and Research.

Disclaimer: This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Information you can use
The FDA website (www.fda.gov) includes information on the status of drugs, biologic products, and medical devices.

• To find out if a prescription or over-the-counter drug is approved by FDA, visit Drugs@FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm). For more information, call 301-827-4573 or 888-INFO-FDA (1-888-463-6332) or email druginfo@fda.hhs.gov
• To find out if a vaccine or other biologic product is approved, visit Biologics Products Establishments (http://www.fda.gov/BiologicsBloodVaccines/ucm121134.htm).
• To find out if a medical device is cleared or approved, visit Device Approvals and Clearances

Additional information:

• FDA Regulatory Status and Informed Consent
• Symposium tackles off-label “conundrum”
• AAOS adopts ‘off-label’ statement
• Off-label device use: Advice from the frontlines

References:

1. Ong KL, Villarraga ML, Lau E, Carreon LY, Kurtz SM, Glassman SD: Off-label use of bone morphogenetic proteins in the United States using administrative data. Spine (Phila Pa 1976) 2010;35:1794-1800. http://www.ncbi.nlm.nih.gov/pubmed/20700081
2. Field RI: The FDA’s new guidance for off-label promotion is only a start. P T 2008;33(4):220-249. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730097/#
3. American Academy of Orthopaedic Surgeons Position Statement 1177: Off-Label Use of Medical Products. June 2009.
4. Buch B: FDA medical device approval: Things you didn’t learn in medical school or residency. Am J Orthop (Belle Mead NJ) 2007;36(8):407-412. http://www.ncbi.nlm.nih.gov/pubmed/17849025
5. Guidance for Industry Distributing Scientific and Medical Publications on Unapproved New Uses: Recommended Practices
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9. US Food and Drug Administration: Approvals of FDA-Regulated Products: Approval information by product type.