FDA Advisers Hear About Problems, Research Needs With Metal Implants
By Mary Jo M. Dales, Contributing Writer
Reports of adverse events related to metal-containing implants are on the rise. While still rare on a proportional basis, the numbers are increasing as the sheer volume of surgical implants has expanded, an FDA advisory committee was told Wednesday.
At the first day of a two-day meeting of the Immunology Devices Panel of the Medical Devices Advisory Committee, members heard from experts that it isn't easy to tease out which patients are likely to have an adverse event. While patients with a known metal allergy might be an obvious risk group, the ability to screen for these allergies is limited.
And while these devices each have a unique identifier, the metallic components within individual devices are seldom detailed in this labelling further limiting the patient's ability to avoid a known metal allergy, based on public testimony given during the meeting. Over 50 registered speakers were granted speaking time at the two-day meeting.
In a discussion of an array of histologic, imaging, and serologic studies that might be useful for selected out patients at risk for metal-related adverse events, experts pointed out that these measures alone fell short. Abnormal test results do not reliably predict adverse events. Further, the combinations of tests that might be indicative would be prohibitively expensive to perform on a large population of patients to determine a small sub-population at risk.
As device implantation has grown in recent years, so have problems tied to them. In 2012, for instance, the FDA held a two-day advisory committee meeting to address failure rates and adverse effects from metal-on-metal hip implants. That led the agency a few months later to put restrictions on these products. Still, issues remain around management of patients who received them. And that's just one type of metallic implant, of which there are hundreds if not thousands.
Earlier in 2019, the FDA announced efforts to further evaluate the safety of specific materials used in medical devices and how to better identify patients who might be at increased risk of experiencing a hypersensitivity response. The agency is accepting public comment on the issue until December 16.
The FDA hopes the knowledge gained can be used to help mitigate potential risks by allowing for more informed patient selection and follow-up, including new diagnostic tests, design, and adaptation, the agency's Aron Yustein said during his presentation to the committee. In recognition that the risks of implants may be associated with risks beyond metal corrosion products, he added that "we also plan to extend our efforts to other major medical device materials beyond metals."
"While the majority of patients experience no clinically significant local or systemic adverse health effects," he said, "we believe that a small subset of patients may develop more severe and persistent inflammatory [reactions that] may not be detected, even in larger or longer clinical studies. Furthermore, in clinical practice, it may be difficult to link these reactions to the device, which may have been implanted years before, and may be functioning well. For these subsets of patients, we must determine what additional actions we should take to make sure they are protected and understand the unique risks they may encounter."
Wednesday's testimony was mostly expert summaries of published studies and evidence related to immune responses to implants and their corrosion products. Risk related to dental amalgam was addressed as a separate topic.
Yustein summed up the research landscape. Current findings are inadequate to identify either a patient at risk preoperatively, or those who may have an adverse response to an existing implant, he said. Gender appears to be associated with significant differences in the biology response to some of these implants. But there are patients who have well-functioning, well-tolerated implants accompanied by abnormal diagnostic tests. The proportion of these patients is unknown. All of this adds to the difficulty in evaluating patients with potential adverse reactions to metal-containing devices.
On Thursday, the panel's charge is to sort out the needs for research and innovation to better understand and mitigate patient- and device-related factors that affect an individual's risk for a heightened or prolonged response to a metal implant or insert. They will consider the roles of sex, age, and reproductive status; comorbidities, especially inflammatory and autoimmune disease; modifiable behaviors including smoking, tattooing, and use of metal jewelry; genetic and demographic variations; and the location and duration of device implants. Additionally, they will be asked to identify next steps for diagnostic tests to predict the potential for post-procedure reactions.
In public testimony Wednesday, Karin Pacheco, MD, MSPH, an allergist at National Jewish Health and the University of Colorado in Denver, presented data on 1,500 patients with unexplained joint failure referred by their orthopedic surgeons who have ruled out infections and mechanical issues. The findings indicate that half of these patients are sensitized to something in the joint -- about a quarter of them to the relevant metal in their implant, about 20% to bone cement, and a smaller proportion to both components.
Further, people with allergies and revised to another implant with different components do "extremely well," she said. The implications are that sensitization to implant components is a cause of joint failure. "We think that nickel, cobalt and chromium, and maybe titanium, are the culprits, but we need more research."
"If you have a history of skin reactivity [to device components], then you probably need to be tested" before receiving an implant, she said. Pacheco emphasized that over a million joint replacements are done each year in the U.S. and more of them are going to people ages 45-64.
Diana Zuckerman, PhD, president of the nonprofit National Center for Health Research, urged comparative effectiveness research.
"If certain implants seem to be causing certain reactions with certain kinds of patients, wouldn't it be very important to know how that compares to other alternatives of the same kind of implants? We can't treat all hip implants that are polyethylene and metal as if they're all the same," she said.
"We can't treat all metal-on-metal implants as if they're the same. We need to compare different models, different implants made in different ways with different materials by different companies and get some kind of real data" that patients and physicians can use to make informed decisions, Zuckerman added. Until then, figuring out how much is due to patient vulnerabilities and how much is the difference between various devices will remain challenging.
Several speakers detailed their personal experiences of adverse events, including neurologic and rheumatologic events that followed their receiving an implant. Linda Radach said she received a metal-on-metal hip implant requiring two subsequent revision surgeries, concluding, "The bottom line between all the harm is the materials. Go after that. Set rigid standards for biocompatibility testing."
Sue Francis, a ceramic-on-polymer hip implant recipient, emphasized the need to label implants with their component materials. "The medical device labels are ... incomplete. The FDA needs to enforce strict labelling of metal composition in medical devices with additional labeling for the device coatings " in the agency's device identification system.
Patients "can't even get a straight answer from the manufacturers about what's in their hip implant," Francis said. She told the panel that there are 16 possible variations of metal coating components that could be in her hip implant, and she and her physician "still don't know what I have."
"Doctors need to know what they're putting in patients," she said. "Protect us, the patients and the doctors, and do not be complicit in the manufacturers' incomplete labeling."
Speaking on behalf of the device industry group AdvaMed, Susan Alpert, MD, PhD, acknowledged the need for better labeling and acknowledged that "considerable work is still need to develop the next generation of tests for evaluating patients." Additionally, new alternative materials may need to be developed for some patients and tested, which will be a lengthy process.
William Van Alstine, director of veterinary pathology for Cook Research, said that "replacing metal implants with alternatives that have lower rates of adverse reactions while maintaining the benefits, if even possible, will likely require many years or decades of further research."
"Allergic reactions to metal implants can be important, we acknowledge that. But in our experience with interventional devices, those reactions are rare," he said.
The Immunology Devices Panel will hear additional comments on Thursday, especially in regard to dental amalgam, and will respond to a series of questions posed by FDA staff.
