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Off-label use of orthopedic drugs and devices: A common, but sensitive, decision
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The nuances of off-label use and the need to improvise underscore the challenges orthopedic surgeons face daily in their efforts to provide safe and proven effective therapies for their patients.
In his opening remarks to a symposium at the 2010 Annual Meeting of the American Academy of Orthopaedic Surgeons, A.Seth Greenwald, D.Phil.(Oxon), provided a historical background on off-label device use. “The 1976 Safe Medical Devices Act (SMDA) brought medical device oversight under the auspices of the United States Food and Drug Administration,” he said. “The Act, however, does not regulate physician-directed off-label use that is in the best interest of a patient. What have evolved are standards of patient care often out in front of regulatory device approvals.”
The decision to cross the line between approved indications and patient needs is one that orthopedic surgeons often find themselves having to make. For example, the FDA has approved a partial elbow replacement system as a substitute for the capitellum and the radial head, “However, there are instances where the patient has a diseased capitellum, but the radial head is normal or intact,” Bernard F. Morrey, MD, a professor of orthopedics at Mayo Clinic in Rochester, Minn. told Orthopedics Today. “So even though the formal approval is to replace both the capitellum and radial head, it is in the patient’s best interest to only replace the diseased part. In my practice, I will replace the capitellum and leave the native radial head, recognizing that at a later date I can replace the radial head if the patient becomes symptomatic. This is a much more conservative approach to patient management and it is clearly in the patient’s best interest.”
Perfect example
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Image: Morrey BF |
Morrey points out that his off-label use of the uni-elbow replacement system is a perfect example of an acceptable off-label use. You don’t replace something that is normal just because the FDA approval was written that way. But you want the ability to replace both sides if that is in the patient’s best interest.”
Similarly, there are times when the distal humerus is diseased or arthritic, but without the involvement of the radius and ulna. Thus, Morrey only uses half of a Sorbie-Questor Total Elbow System (Wright Medical Technology) to replace the humerus.
“I leave the ulna and the radius intact, if those joints are normal,” he said. “We most commonly use this elbow system in cases of trauma, where there is a fracture that cannot be fixed. The best treatment for these patients, without question, is to replace the non-salvageable fracture portion with a metallic implant that replicates the contour in the anatomy of the humerus. But it is absolutely in the patient’s best interest not to replace the part of the joint that did not suffer a fracture.” However, this hemi-replacement strategy is not the same as the total joint replacement approved by the FDA.
Legal issues
According to Kathleen McDermott, JD, a partner at the Washington, DC, law firm Morgan Lewis, off-label use is “permissible, if it is in the best interest of the patient and supported by objective and appropriate peer-reviewed scientific and clinical information.”
McDermott said she is not aware of any case in which government enforcement action was taken against an orthopedic specialist by the U.S. Department of Justice for abusing off- label use. “I think that generally there is an acknowledgement of the practice-of-medicine exception recognized in FDA law, as well as by state law. The government’s enforcement focus has not been on the physician who is undertaking medically necessary procedures.”
There are several investigations pending, however, that may entangle surgeons and involve government prosecutors seeking interviews and documents of hospitals and surgeons, she told Orthopedics Today.
That said, McDermott — a former federal prosecutor who specializes in health care fraud and compliance matters — noted that the physician “has an obligation to be familiar with the approved or cleared label of the product. Frequently, that information may come from the manufacturer of the product. However, it is important that the physician further be aware that if there is any use of the product beyond the approved or cleared label, he or she needs to be familiar with the clinical, scientific or other peer-reviewed literature that may support that use.”
Furthermore, a physician should be aware of whether insurance, including Medicare, will reimburse for a particular off-label use. “But this is less of an issue among device products because they are not directly reimbursed,” McDermott said.
The Centers for Medicare & Medicare Services (CMS) standard for coverage is whether “it is reasonable and necessary, and its support in the medical community (standard of care),” McDermott said. “There is no CMS strict prohibition on using products beyond their cleared or approved label. It happens every day.”
Off-label drugs
Aaron G. Rosenberg, MD, FACS, a professor of surgery at Rush Medical College in Chicago, noted there are several medications that physicians use off-label. “These may have been originally developed for a particular application for FDA approval, but as time goes on, clinicians who are looking for solutions that are not readily present with other available medications begin to try a particular drug for other indications because of suspected scientific reasons for efficacy, such as the drug being similar to other drugs or it has been noted to have side effects that are appropriate in a particular setting,” he said.
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One drug frequently used off- label postoperatively to reduce pain in patients who have undergone lower extremity surgery, particularly knee arthroplasty, is Lyrica (pregabalin, Pfizer), in lieu of gabapentin. “The label use of Lyrica is for certain other types of chronic pain conditions, including neuropathic pain from diabetic neuropathy or post-herpetic neuralgia (PHN),” Rosenberg said.
“Gabapentin was a medication that was kind of difficult to control the dosage effectively,” Rosenberg said. “Therefore, gabapentin was reformulated as another medication (Lyrica) that is similar in chemical structure, but apparently is more consistently taken up in the bloodstream, so dosing is easier to do for a more consistent therapeutic effect.”
Rosenberg routinely prescribes Lyrica after knee replacement for the first week or so after surgery. “Our studies show there is a substantial decrease in the need for other pain medicines when using Lyrica,” he said. “It is important for physicians to make appropriate ethical decisions when they feel they can achieve a better outcome for their patient with off-label drugs. The risk-to-benefit ratio must be appropriate. It is not the FDA’s role or job to decide about the treatment of a given individual. It is the physician’s job. However, we should do no harm to the patient.”
Biologics
The recombinant human growth factor rhBMP-2, which is approved for use in the lumbar spine, is used in cervical fusion applications and has seen use in hip and knee replacement with significant bone deficiency “as a facilitator of bone regeneration or osteoinduction,” Greenwald, an Orthopedics Today Editorial Board member said. “It is a physician responsibility to inform patients when they are considering the off-label use of a product.”
“Physician-directed use is a decision which practitioners must make in the best interest of their patients,” Greenwald said. “If it involves an off-label application of a particular product, the physician should be fully informed about the science and benefits as well as the complications that have been associated when treating a patient in that manner, for example, through the peer-reviewed literature.”
Pediatric devices
Stuart L. Weinstein, MD, a professor of orthopedic surgery at the University of Iowa in Iowa City, uses a number of spinal implants in small children. “We think of these as pediatric devices, but basically they are very small adult devices that are approved under the 510(k) process: substantially equivalent,” he said. For example, Weinstein has used spinal rods in legs of children because “they are the only thing that really fits.” He has also used adult arm implants in a child’s leg, specifically a humeral nail in the tibia.
Likewise, pins normally reserved for fixation of small bone fragmentation are sometimes used as intramedullary rods in extremely small children. As a pediatric orthopedic surgeon, Weinstein finds off-label use fairly common. “The children’s market is small, so companies really don’t develop products. There are few financial incentives for product developers,” he said. “And when you deal with children, I think there are increased medical liability concerns. From my perspective, I have to use adult devices off-label because there is nothing else available.”
In addition, Weinstein sometimes modifies an adult device for a child, due to a lack of a pediatric equivalency. “Overall, we have to improvise quite frequently by using available products,” he said. “The FDA is cognizant of off-label use and tries to be sensitive. Children have different needs. They are just not small adults.”
The FDA is alerted to issues related to off-label use “through professional society presentations, published scientific literature or through adverse events that may be reported to the agency,” said Mark N. Melkerson, the FDA’s director of the Division of Surgical, Orthopedic, and Restorative Devices. “Because of this, it is nearly impossible for us to estimate the amount or increase/decrease of such use with any clarity. But we encourage physicians who intend to use device off-label to conduct such use under appropriate Investigation Device Exemption (IDE) authority. Doing so allows both the physician and the FDA to track and utilize data with the patient’s permission. This data would become extremely helpful in evaluating the impact of how a device is used off-label.” – by Bob Kronemyer
- A. Seth Greenwald, D.Phil.(Oxon), can be reached at Orthopaedic Research Laboratories, 2310 Superior Ave. East, Cleveland, OH 44114; 216-523-7004; e-mail: seth@orl-inc.com.
- Kathleen McDermott, JD, can be reached at Morgan Lewis, 1111 Pennsylvania Ave. NW, Washington, DC 20004; 202-739-5458; e-mail: kmcdermott@morganlewis.com.
- Mark N. Melkerson can be reached at FDA/CDRH/ODE/DSORD, White Oak Building 66, Room 1410, W066-1410, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002; 301-796-6383; e-mail: mark.melkerson@fda.hhs.gov.
- Bernard F. Morrey, MD, can be reached at 200 1st St. SW, Rochester, MN 55905; 507-284-3659; e-mail: morrey.bernard@mayo.edu.
- Aaron G. Rosenberg, MD, FACS, can be reached at 1725 W. Harrison Ave., No. 1063, Chicago, IL 60612; 312-243-4244; e-mail: aarongbone@aol.com.
- Stuart L. Weinstein, MD, can be reached at UIHC, Department of Orthopedics, 200 Hawkins Dr., Iowa City, IA 52242; 319-356-1872; e-mail: stuart-weinstein@uiowa.edu.
What do orthopedic surgeons most need to know about off-label use of devices and drugs?
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Questions every orthopedist should answer
First, what is the possible medicolegal liability for usage of the drug or medical device in an off-label fashion? For example, if a hyaluronic acid substance is utilized in a joint that is not allowable according to the substance’s approved indications and the patient suffers a complication, does the patient have a legitimate claim? How would such action be defended? In this era of “legal opinions for hire” by several orthopedists around the country, complications are clearly a factor that must be seriously considered because there are orthopedists who make their living by testifying against other orthopedists despite there being minimal clinical or scientific basis for their testimony in support of the plaintiff’s claim.
Secondly, an important question that orthopedic surgeons must ask themselves is whether there is a legitimate, clinically scientifically appropriate basis for considering usage of the drug or device in a method for which it has not been approved.
When I utilize a medical device or drug in an off-label fashion these are the critical questions that I have to personally answer. And we should all do our best to try to answer them for ourselves and our patients.
Jack M. Bert, MD, is the section editor for the Business of Orthopedics in Orthopedics Today, and practices orthopedic surgery in St. Paul, Minn.
Legal aspects
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Orthopedic surgeons should know that according to the U.S. Supreme Court, off-label use of a device or drug “is an accepted and necessary corollary of the FDA’s mission to regulate in this area without directly interfering with the practice of medicine.” Most court rulings have regarded FDA regulatory status as immaterial in obtaining informed consent. However, some court rulings have allowed non-disclosure of off-label use as one factor to be considered by a jury.
Illustrative case law rulings follows:
- FDA-approved drug labeling is not, in itself, prima facie evidence of the prescribing physician’s standard of care; however off-label use can provide assistance in finding the relevant standard of care. Accordingly, off-label use is admissible at trial, along with expert testimony, to help the jury in its fact-finding inquiry (Richardson v Miller, Tenn. 2000).
- The court found that a hospital was vicariously liable for credentialing a surgeon who implanted metal rods in an off-label use for cervical fusion, where the rods migrated and caused severe injury (Columbia Medical Center v Sangounchitte, Fla. 2008).
- A physician was held not liable for the off-label cosmetic use of silicone injections into facial wrinkles, where other physicians in the community commonly performed similar injections, even though the risks of such injections were well known in the professional literature (Osburn v Goldman, Ga. 2004).
- The off-label use of pedicle screws during spinal surgery did not constitute negligence in a case where subsequent surgery was required to remove the screws. Such screws were commonly used in spinal surgery, and their use in the spine has not been prohibited by the FDA (Southard v Temple University Hospital, Pa. 2001).
Practically, unless the contemplated off-label use of a drug or device is so common among other, similar professionals in one’s community that such off-label use essentially constitutes the standard of care, orthopedic surgeons should protect themselves by telling the patient that: Off-label means that the device or drug is neither approved nor disapproved by the FDA for the contemplated use; the term does not have a negative connotation; that the contemplated off-label use is common among other surgeons; the risks and benefits of the intended off-label use should be discussed; the reasonable alternative treatments to the off-label use should be presented. Additionally, these steps should be documented in the record.
B. Sonny Bal, MD, JD, MBA, is Associate Professor of Hip and Knee Replacement, at the Department of Orthopaedic Surgery, University of Missouri School of Medicine.