With help from a wide-reaching FDA advisory committee meeting starting Wednesday, FDA is looking to expand its potential "toolbox" of methods to assess how a patient might respond to a metal implant.
"Our goal is to have a full set of effective tools that will predict adverse effects before implantation, for quantifying and visualizing adverse effects, or can quickly identify problems before they are clinically significant," FDA said prior to the first public discussion of its kind exploring the safety of specific medical device materials.
In September, FDA released an approximately 150-page report on biological responses to metal implants, drawing on decades of findings since the mid-20th century when the first generation of hip implants hit the market. But it was a critical mass of adverse event reports related to high-profile, now-off-the-market products like birth control implant Essure and metal-on-metal hip replacement systems that drew greater attention to the subject.
The expert panel is tasked with highlighting areas with greatest need for research and suggesting next steps on how to better assess biocompatibility. A federal docket drew more than 280 comments ahead of the meeting, with many appearing to come from patients and patient advocates.
Over time, corrosion of devices can result in metal ions prompting an adverse tissue reaction surrounding the implant or in other parts of the body.
The agency will first need to gather a better understanding of which characteristics — in a device or in a person — might increase the likelihood of an adverse immunological or allergic response. Those variables may include an implant's manufacturing, composition, coating, location and duration in a patient, as well as that patient's sex, age, reproductive status and medical comorbidities.
The materials in question extend far beyond hips and birth control. At the crux of the discussion: At what level does each metal or alloy go from a safe, sometimes essential substance, to one that is toxic?
For example, cobalt, a naturally occurring metal, can in excess prompt cardiomyopathy and alter thyroid function, FDA outlined. And nickel, an example of a non-essential metal found in implants, may lead to acute symptoms like headache, vertigo, vision changes and GI distress, as well as cardiovascular, respiratory or kidney disease.
Nitinol (named for its combination of nickel and titanium), the material making up Essure, is used increasingly in devices like vascular stents for its superelasticity and ability to maintain its original shape amid temperature changes. The meeting's purview covers metal- and metal alloy-containing devices spanning neurology, gastroenterology, urology and gynecology, and dentistry, too.
The agency's review called out lofty challenges, including a fundamental lack of scientific understanding of the mechanisms potentially spurring the problems listed in myriad adverse event reports.
"Because of this, it is difficult to distinguish between the device- and patient-related factors in addressing safety and effectiveness concerns," FDA said in the paper. "Overcoming this challenge is necessary to help manufacturers design appropriate pre-market studies and develop appropriate acceptance criteria."
To better track patient relationships with metal devices, FDA is seeking a diagnostic or screening tool that's both sensitive ("to enable detection before a serious adverse event") and robust ("to promote confidence that the signal detected is real"), the agency described. Existing tests don't sufficiently strike that balance, it said.
"Standard tests, such as metal ion levels in the blood stream or skin patch tests for metal allergies, correlate poorly with adverse responses. In some cases, patients with adverse diagnostic findings present no symptoms," FDA wrote. "[T]hese techniques are not able to predict whether an implant will fail in the patient."
The Immunology Devices Panel is set to offer recommendations on FDA's questions on Thursday. The two-day event will also cover potential adverse health impacts stemming from mercury exposure from dental amalgam. FDA is webcasting the meeting.