Off-Label Use in Orthopaedic Surgery

Benjamin C. Taylor, MD; Jacob J. Triplet, DO; Taleed El-Sabawi, MS, JD

Disclosures

J Am Acad Orthop Surg. 2019;27(17):e767-e774. 

In This Article

Obstacles of Off-Label Use

Regulatory and Legal Compliance

With an ever-changing environment in technological and scientific advances, regulatory requirements pose challenges to the orthopedic community. Often, an orthopedic device used off-label may become widely accepted among the orthopedic community. Still, its off-label use is surrounded with a certain degree of ambiguity. The surgeon is obligated to be familiar with the FDA-approved or "on-label" use of an orthopedic implant they intend to use in an off-label manner. Additionally, although off-label, or "physician-directed," use of implants are permitted, they must be used in a "reasonable" manner. Although the term "reasonable" has not been definitively defined, it is generally stated that the device must be used in the best interest of the patient and supported by appropriate scientific and clinical information.[6,12] Reasonable use can pose a problem because peer-reviewed information of off-label use of medical implants remains deficient in the current literature; publications of common off-label use of orthopedic devices are merited to help provide peer-reviewed support to such use.

Manufacturers spend a significant amount of resources in developing and obtaining FDA approval for orthopedic devices. For a manufacturer to obtain FDA approval, they must demonstrate safety, efficacy, and clinical benefit to the FDA's Center for Drug Evaluation and Research.[12] Following FDA approval for specific indication(s), the manufacturer may market the product accordingly. However, as continued use of the product in an off-label manner occurs and becomes widely accepted, the manufacturer would need to invest additional time and resources to satisfy regulatory mandates to obtain expanded approval. Such mandates vary depending on the product requesting expanded approval, such as biologics or devices. Similarly, postapproval modifications must again demonstrate safety and efficacy.[13] However, because of the rapid advancing technology, many manufactures may use the 510(k) pathway that allows for a more rapid, easier, and cheaper alternative to premarket approval.[14–16] However, this pathway maintains the initial indications.[16] Nevertheless, although being able to market postapproval indications may be advantageous to the manufacturer, the added economic and practical barriers, including preclinical, laboratory, clinical, and epidemiological assessment of the post-approved use, may not be worth the monetary investment if its off-label use has gained clinical acceptance and has expected continued utilization.[17] Widespread off-label use provides the manufacturer with the financial incentives of a device's expanded use without the required investment in studies that explore the risks to the patient. Therefore, the product is used without FDA review to validate safety, efficacy, and clinical benefit. Bypassing FDA approval may increase the risks to the patient.

Despite the off-label use, manufacturers are generally restricted from directly promoting or advertising off-label use of their product.[6,10–13,18] They are similarly restricted from sponsoring continuing medical education programs, promoting off-label use.[10,19] The most recently updated FDA guidelines clarify the exchange of information related to unapproved usages of medical implants and that promotional exchanges of off-label descriptions must be limited to scientific or medical journals, texts, or clinical practice guidelines.[6] Executives of manufacturers who fail to comply with these regulations may be held civilly and criminally liable. Most popular was the Synthes off-label marketing and unauthorized trials related to the use of Norion in vertebroplasty, a non–FDA-approved indication. Several cases of cardiovascular collapse, fatal in some cases, were reported, and this situation was further confounded by the withholding of adverse events from the FDA.[6] This case resulted in incarceration of several corporate executive; lawsuits were also filed against several orthopedic surgeons. Since then, off-label promotion has been contended in court, with several pharmaceutical companies receiving penalties worth of $500 million (United States v. Caronia, 703 F.3d 149 [2d Cir. 2012]).

The legal definition of what constitutes a reasonable standard of care when physicians engage in off-label use of a device varies by jurisdiction, especially as related to the need to disclose the off-label use to the patient.[6] Moreover, there is disagreement as to whether the fact that the use was off-label is even admissible in court as evidence of medical malpractice—with some courts, Blazoski v. Cook, 787 A.2d 910 [NJ 2002], holding that its off-label descriptor is immaterial to the risks of surgery, whereas others, Corrigan v. Methodist Hospital, 885. 127 [Fla 1995], consider the information material and admissible.[6] In jurisdictions in which this information is admissible, physician defendants will need to demonstrate to the jury that the off-label use was safe and in accordance with the standard of care.[6] If the off-label use is not a common feature of practice or empirical evidence does not exist supporting the use, then physicians may have difficulty in providing the necessary evidence. Given this case law, it is in the best interest of the surgeon to disclose off-label use to all patients and to ensure that off-label use is in accordance with common practices and the available scientific evidence. The American Academy of Orthopaedic Surgeons Position similarly suggests that surgeons should counsel patients appropriately regarding risks, benefits, and alternatives to any proposed treatment[6,11] (Table 3). We encourage that such counsel be documented within the physician's notes and should include any information regarding off-label usage.

Limitations to Research

Research is a cornerstone to technological and scientific advances, with publications related to utilization, outcomes, and complications of devices remaining critical in establishing appropriate clinical applications. However, publications related to off-label use are seriously limited.[12,16] High-quality research necessitates institutional review board approval. However, obtaining institutional review board approval for research purposes is challenging with off-label use, and therefore, projects including off-label implants are not commonly performed.[10,12] This lack of peer-reviewed research limits information pertaining to potential risks when disclosing off-label use to a patient. Moreover, it deprives the orthopedic community of potential benefits of novel device use. Recently, off-label total joint arthroplasty demonstrated greater length of stay, costs, long-term complications, and discharge to inpatient facilities compared with on-label use.[16] Additionally, it is estimated that as much as 86% to 92% of total joint arthroplasty may be used in an off-label manner by 2040.[16]

Manufacturers do not commonly support studies of implants already established as a generally accepted medical standard or treatment option because the return on investment to add an FDA-approved indication can be quite low. However, these companies can support research financially and materially to allow peer-reviewed publication of the off-label use of a particular implant in a non–FDA-approved indication because the findings and descriptions would be legally distributable to practicing surgeons. Manufacturing companies are not legally at risk with financial or material resource support of off-label research as long as off-label promotional activities are not tied into the research; this off-label support should be encouraged because clinical use can be critically evaluated, and the companies can also use the information to attempt to gain FDA approval for these off-label strategies.

Insurance Coverage and Reimbursement Issues

Off-label medication use is extremely common, with reported rates of 20% to 73% in the literature, and formal policies have been created by public and private insurance providers in regard to coverage indications.[17,20] However, if a use is not specifically identified in FDA approval or listed as a medically acceptable indication in one of several published compendia, reimbursement will not be given by public or private payers.[17,21]

Orthopedic implants are typically not an issue in regard to reimbursement when used in an off-label manner because reimbursement for these implants are indirect and given as part of the diagnosis-related grouping payment, even when FDA approval is not available for the implant(s) used during a certain covered procedure. Implantable devices are also included in bundled payments for ambulatory surgery centers as of January 1, 2008, regardless of FDA ruling on the particular device(s) implanted during the surgical procedure.[21]

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