How does one describe the issue of “off-label” use of an orthopaedic device? As a thicket of thorny clinical questions? A morass of ethical dilemmas, which may ensnare even the most well-intentioned practitioner?

Whether it’s called “physician-directed” or “off-label” use, this issue confronts many orthopaedic surgeons. It crosses specialty lines and encompasses not just devices, but drugs and new therapeutic agents.

With a goal of providing some guidance and clarity, a panel of medical professionals and legal and regulatory experts addressed the particulars and pitfalls of off-label use during a symposium held at the AAOS 2010 Annual Meeting.

What it is, and isn’t
The panelists emphasized the importance of understanding the fundamental definition of off-label use and how the federal government regulates it. At the core is the fact that the practice of medicine is regulated under individual state laws, said Kathleen McDermott, JD, of Morgan Lewis & Bockius, Washington, D.C.

“U.S. Food and Drug Administration (FDA) regulations and other applicable law recognize that physicians may prescribe or administer any legally marketed product for an off-label use within the practice of medicine laws of licensed jurisdictions, according to the physician’s well-informed medical judgment for the best interest of the patient,” she said.

The FDA polices off-label use by regulating commercial practices, specifically off-label promotion, which Ms. McDermott described as conduct by a manufacturer or company to proactively sell or support commercial product sales for uses in ways not yet approved by the FDA. Promotion may involve written labeling and sales materials, interactions with company sales representatives, Web sites, distribution of journal articles, trade show presentations, physician education and training, and reimbursement advice. Certain medical education activities may be viewed as promotion when designed to induce commercial product sales rather than bona fide education.

Although these activities entail a raft of ways for physicians to wander into the gray zone of company-prohibited conduct, Ms. McDermott noted that the regulations do not prohibit the exchange or dissemination of scientific information regarding a product’s unapproved uses in specific circumstances. The rules also allow a manufacturer to respond to a request from a physician, to provide information as part of medical education programs, and to provide information contained in peer-reviewed scientific and medical journals (reprints).

Children’s story
Orthopaedic surgeons often describe the issue of off-label use as a dilemma, one that forces them to make choices between the welfare of their patients and their desire to steer clear of litigation or prosecution. Probably no group of surgeons tiptoes through the regulations as frequently as those who care for pediatric patients.

Stuart L. Weinstein, MD, described the interface between the regulations and pediatric medicine as a “conundrum.” Noting that “Children are not just small adults!” Dr. Weinstein said that because children have diseases and conditions that are distinctive, they respond differently to treatment interventions, and growth potential may be a critical factor in treatment. Yet orthopaedic surgeons frequently must make do with products designed for adults.

Dr. Weinstein ruefully described how he and his colleagues must modify adult devices for use in children—using an implant designed for another purpose, using suboptimal implants designed decades ago, or using custom devices. Such practices lead to problems such as bulkiness or poor fit.

The dynamics of how devices get to market accounts for much of the conundrum, Dr. Weinstein said. Most products for children are small-volume items, yet manufacturers are geared for large runs and face economy-of-scale issues in the pediatric segment. With weak financial incentives, increased liability concerns, and methodological challenges of premarket clinical trials, companies see the cycle of obstacles to the development and approval of pediatric devices as self-perpetuating.

“We can’t teach their use, and we can’t gather data for effectiveness,” Dr. Weinstein said. “Double-blind studies are impossible to do, and sham surgery is not ethical.”

He said he is “a bit pessimistic” that much will change in the near future. “Using off-label devices has been part of my life for 37 years,” he said. “I think we’ll continue to use devices in adaptive ways until the end of my career.”

The tale of the screw, the case for cement
In a cautionary tale, Bernard F. Morrey, MD, related the story of the pedicle screw and its 15-year journey toward approved use.

Dr. Morrey described the pedicle screw tale as one of “need and greed” that began as the use of the screw “took off,” and, driven by corporate marketing, entrepreneurism, and efficacy, became the standard of care. After the litigation storm erupted, catastrophe was averted only through the relationship formed between the AAOS and the FDA, and the result was one consistent with FDA principles, which encourage the development of products and therapies that protect and promote health.

In another presentation, Steven J. MacDonald, MD, a professor at the University of Western Ontario, summarized the status of antibiotic-impregnated cement in the United States. Currently the product is approved for the second stage of a two-staged revision total knee arthroplasty (TKA) following the elimination of infection, but not for routine prophylaxis or for use as cement spacers and beads. Noting that 35 to 40 percent of the antibiotic-impregnated cement currently being used is in the United States, Dr. MacDonald hypothesized that it is either regularly being used off-label or second-stage revisions are being done at an incredible rate.

By contrast, more than a dozen antibiotic cements are approved for use in Canada, with no restrictions on indications, and the cements are widely approved for use worldwide. Dr. MacDonald cited several studies, including two in Sweden and Norway, which supported the efficacy and safety of antibiotic cements in various applications. The cements have been shown to reduce the septic loosening rate, he said, and evidence exists that they can reduce failures classified as aseptic loosening, because such complications might actually result from undetected infection.

Dr. MacDonald also said that concerns about resistant organisms and allergic reaction are largely theoretical and are not supported by evidence. In his view, the evidence supports approval of the cements.

Closing up the symposium, Aaron G. Rosenberg, MD, reminded the audience that they can use products that are FDA-approved even if the approval is for indications not present in the patient. He urged surgeons to be well-informed about the product, to base their decisions on scientific rationale and evidence, and to maintain records of use and effects.

Advantages of off-label use include clinical innovation, Dr. Rosenberg said, especially for patients who don’t respond to standard treatments. Off-label treatment may be the only option for uncommon conditions or populations not studied. Among the disadvantages are the promotion of use in untested populations, unknown safety problems, and the blunting of incentives for industry to perform studies for FDA label changes.

To act in the best interest of the patient, Dr. Rosenberg advised physicians to be informed, to inform the patient, and to be partners with the patient “to use available technology to get the best outcome of treatment.”

Terry Stanton is the senior science writer for AAOS Now. He can be reached at tstanton@aaos.org

Bottom Line

• Physician-directed use of drugs and devices is legal, based on the doctor’s informed medical judgment and the patient’s best interest.
• “Off-label” marketing or promotion or a drug or device by a company for a use not approved by the FDA is not legal.