The Immunology Devices Panel of the FDA’s Medical Device Advisory Committee met in November to discuss the topic of immunological responses to metal-containing products regulated as medical devices. The panel focused on metal-containing implants as well as dental amalgam. Recent post-market issues with some metal-on-metal orthopedic implants and gynecological metal-containing implants have raised questions about the potential for some patients to develop unexpected or heightened biological responses to the implant. The topics covered included metal corrosion, toxicological and immunological mechanisms associated with adverse events, clinical manifestations of adverse events, the current FDA biocompatibility premarket review approach, biomarkers and diagnostic tests for screening patients and diagnosing adverse events, and finally, a summary of the science, knowledge and tool gaps.
As part of premarket submission requirements, medical device manufacturers must submit biocompatibility data to the FDA to show that the materials they plan to use in their device can safely be implanted in the human body. The data may include test results from engineering, bench, design verification, human factors, animal testing, and clinical studies. Part of the FDA's evaluation of the safety and effectiveness of a medical device involves reviewing information about those materials and their use in the device.
Clearly, the use of metals and alloys has been on the collective mind of the FDA.
Metals and metal alloys are commonly used in implanted medical devices and inserts such as amalgam dental fillings; these materials are sometimes in contact with parts of the body for extended periods. The most common metals and alloys used in implants include stainless steel, cobalt-chrome alloy, titanium, and nickel-titanium alloy (nitinol). Other metals, such as gold, platinum, silver, iridium, tantalum, and tungsten, are also common in many medical devices. Part of the FDA's evaluation to determine whether a medical device is safe and effective involves reviewing information about metals and other materials used in the device.
The FDA conducted this comprehensive review of metals used in medical devices due to concerns raised by patients as well as reported adverse events potentially related to biological responses caused by certain types of materials in medical devices. This is part of a broader review of the use of select materials in implantable devices and it builds on prior work and steps outlined in the Medical Device Safety Action Plan announced in 2018. The paper and the November panel discussion covered how metal materials are impacted by a physiological environment, expected and potential toxicological and immune system responses to the metal associated with an implant, and subsequent clinical manifestations.
Currently, the FDA recognizes the international standard ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process. The standard provides information on evaluating the biological response to medical devices, like considering the physical and chemical characteristics of device materials, as well as the nature, degree, frequency, and duration of device exposure to the body. The current international standard approach to biocompatibility testing, however, is not designed to identify individuals who are likely to experience an inflammatory reaction to a particular metal because in the past this risk and its clinical manifestations were not well recognized. For medical device manufacturers using metals that might be called into question, this paper identifies the gaps and opportunities that would allow for further research in scientific evidence related to immunological responses caused by metal-containing implants.