In the United States, the FDA oversees the formal approval of medications, biologics, and devices (MBD). Device and pharmaceutical manufacturers bear the burden of responsibility for obtaining FDA approval. Manufacturers spend significant resources to demonstrate safety, efficacy, and clinical benefit of MBD. Following FDA approval, any marketing or promotion of a given MBD is strictly restricted to the approved indication.
Discretion on how to use devices on the market for patients is the responsibility of clinicians. Use of MBD for any indication or manner that is different than what has been approved by the FDA constitutes “off-label” use. This practice includes using a medication or biologic at a different dosage, in an unapproved age group or population, or via an alternate route of administration than what was originally indicated and approved. Similarly, for medical devices, off-label use is defined as using an implant originally approved for one function or anatomic location in a different way than originally approved. Therefore, use of MBD in a non-FDA-approved fashion is considered off-label use.
The federal government has long recognized off-label use as appropriate when physicians are acting in the best interest of patients and when choices made by the physicians are safe and supported by scientific and clinical information. The issue then lies in the subjective nature of the legal definition of what constitutes a “reasonable” standard of care or medical judgment. A proxy would be standard of care provided by a “reasonably” competent physician under similar patient circumstance. Although the term “reasonable” is vague, one thing remains clear—MBD have to serve patients in a manner equivalent or better than other currently available FDA-approved options. The legality of what constitutes “reasonable” standard of care as it pertains to off-label MBD use varies based on jurisdiction and the unique circumstances of each individual case. Nonetheless, off-label use is permitted by the U.S. government based on physician discretion if it is used in the best interest of the patient in a safe fashion, in accordance with standard of care, and when supported by scientific and clinical literature.
Orthopaedic surgeons need to be uniquely aware of off-label use guidelines for medications, biologics, and surgical implants. Treating surgeons must also be aware of on-label use of MBD they plan to use in off-label ways. Off-label use is permissible when it is in accordance with common orthopaedic practice and if peer-reviewed scientific or clinical evidence supports such use. For example, this can include fashioning an antibiotic-coated intramedullary nail/plate, using bone cement for induced membrane technique, or using a foot mesh plate to treat a comminuted patella fracture (Fig. 1).
Publications of common, safe off-label use of MBD provide support for continued usage by establishing precedence and by providing empirical evidence with peer-reviewed support. However, if published literature is lacking, it is challenging to establish legal support. In such a situation, the surgeon should disclose off-label use to the patient and/or family member serving as legal representative during informed consent. This is within accordance with AAOS guidelines that treating surgeons should counsel patients appropriately regarding the risk, benefits, and alternatives of any proposed treatment modality. In addition, surgeons should document patient/family counseling and off-label MBD use in their notes.
The vast array of orthopaedic injuries necessitates creative surgeons equipped with principle-based knowledge and finite tools to provide optimal patient care. Accordingly, off-label use by orthopaedic trauma surgeons involves three general categories: (1) use of fracture-related implants in areas of the body or bone for which the implants were not originally designed; (2) a different route of antibiotic administration, such as antibiotic-coated intramedullary nails or plates or local application of antibiotic powder (i.e., vancomycin); and (3) off-label use of biologics to promote bone union.
Orthopaedic devices such as intramedullary nails and plates can be used successfully in anatomic locations for which the implants may not have been specifically tested or designed. Common examples include using proximal humerus plates upside down in buttress fashion for larger posterior malleolar fragments, on the lateral aspect of distal tibia for tibiotalar fusion, or medial aspect of the distal femur for comminuted supracondylar/intercondylar distal femur fractures (Fig. 2, page 24). Another common instance would be using mesh plates originally designed for the foot on the patella or a distal femur plate upside down on the proximal femur around a femoral hip prosthesis. These instances have been documented, and due to rapid technological adaptation superseding regulatory review, this type of off-label use in orthopaedic trauma is fairly common.
In the field of biologics
Bone morphogenetic proteins (BMP) are the most common off-label biologic device utilized in the field of orthopaedics and trauma. Recombinant human BMP-2 (rhBMP) is FDA-approved for two indications: (1) anterior lumbar fusion and (2) acute open tibial shaft fractures treated with an intramedullary nail. rhBMP-7 is approved for use in long-bone non-unions; however, when such products are used to facilitate bone regeneration or osteoinduction such as for large cavitary defects or to fuse certain prepared joints, such practice is considered off-label use. For further information on the safe use of orthobiologics, the AAOS Committee on Devices, Biologics & Technology (DBT), under the leadership of David Jevsevar, MD, MBA, FAAOS, has created the Biologics Dashboard, which is accessible to all AAOS members at aaos.org/biologics. This resource provides a simple understanding of the regulatory status of several biologic products separated by tissue type, graft type, and manner in which the biologic is processed.
In the field of medication
One of the most common current off-label medication uses in orthopaedic trauma is placement of local powdered antibiotics as prophylaxis or treatment for surgical site infection. For example, vancomycin powder is FDA-approved for preparing intravenous infusions, whereas local application of vancomycin powder is considered off-label use. Nonetheless, clinical peer-reviewed literature documents use of 1,000 mg of topical vancomycin powder in orthopaedic surgical wounds. Such use has been published by O’Toole et al. and includes a safety profile with minimal elevation in serum vancomycin levels after local use, with no significant increase in kidney creatinine levels. Published medical literature informs surgeons on safe local usage of vancomycin powder and tempers the liability associated with off-label use. Accordingly, treating surgeons are obligated to understand the packaging inserts of medications in terms of FDA-approved dosages, indications, and methods of administration and preparation. Similarly, preparation of antibiotic-coated implants (plates/nails/pins) entails mixing safe dosages of various heat-stable antibiotics and/or antifungals to treat fracture-related infections.
As a cautionary tale of off-label use gone horribly wrong, in 2009, Synthes was implicated in off-label marketing and a non-FDA-approved clinical trial of Norian XR and SRS bone cement to treat vertebral compression fractures. Several spine patients injected with Norian for vertebroplasty in the early 2000s sustained acute hypotension, cardiovascular collapse, and death, which resulted in multiple lawsuits and indictments. It was later determined that several Synthes executives withheld data on adverse events from the FDA and conducted illegal clinical trials, resulting in incarceration of four corporate executives.
Orthopaedic trauma encompasses a wide array of injuries in various anatomic locations, necessitating creative surgeons who innovate solutions and technological advancements and publish clinical research that routinely outpaces FDA regulatory review. With innovation and technological advancement, orthopaedic trauma surgeons will continue to have an obligation to practice in an ethical manner consistent with professionalism guidelines published by AAOS. To learn more, those interested are encouraged to review online resources such as the AAOS Biologics Dashboard, as well as the FDA website, which publishes information on the status of MBD.
Arun Aneja, MD, PhD, is an assistant professor of orthopaedic trauma at the University of Kentucky, as well as a member of the DBT committee.
Jonathan Grabau, MD, is a post-graduate year-2 orthopaedic resident at the University of Kentucky.