In recent years, the FDA has grown increasingly concerned about the impacts that certain common medical device materials – especially metals – have on human systems when implanted. Two new contract notices point to areas where the agency is still seeking information about the basics of how metallic implants behave over time, and whether patient-specific factors come into play.
The issue of implanted devices and metal-containing materials
- Some implanted devices contain metals. As AgencyIQ has previously explained, over the last decade the FDA has become increasingly concerned that longer-term exposure to certain materials – and particularly metal – in implanted devices could be causing long-term issues for patients. Following highly publicized issues with the gynecological Essure implant and metal-on-metal hip implants, the agency heard concerns about metal-based implants causing sensitization; another focus of concern is the potential from metal ions for metal-based products that became corroded or degraded over time to reach systemic circulation. In March of 2019, then-Commissioner Scott Gottlieb announced that the FDA would be taking a closer look at the long-term, and potentially systemic, impacts of implanted medical devices – citing metal-containing devices as top priorities.
- In a 2019 Medical Device Advisory Committee (MDAC) meeting, FDA convened experts specifically to “discuss advances in the scientific community’s understanding of immunology and how related emerging and evolving scientific data may help address certain risks to specific patients.” At the meeting, a key topic for both panelists and presenters was the FDA’s assertion that it “continues to believe that the significant majority of patients experience no clinically significant local or systemic material related adverse health effects from these implants and their benefits outweigh the risks.” Presenters from the FDA, however, outlined several gaps in the FDA’s regulatory science and frameworks that could reasonably evaluate systemic material impacts, including limitations of currently recommended protocols, study designs that typically wouldn’t seek to asses device failures from mechanical loading (e.g., coating delamination, particulate generation) and a lack of scientific research on corrosion and metal ion release in vivo. Additionally, some participants raised concerns that adverse events related to these types of devices may be underreported, because in clinical practice a provider may not recognize that certain symptoms would be linked to an implanted device that has been functioning as intended for several years.
- While the meeting opened with agency representatives and panelists asserting that adverse events from implanted devices were rare, by the second day panelists were divided on whether it would be “biologically plausible” that an implanted device could directly cause a sustained, systemic immunological response in a patient. A key issue highlighted during the meeting was a significant lack of available clinical data and gaps in existing science. These gaps include a lack of data on long-term wear and tear on devices, corrosion, and toxicological and immunological mechanisms by device-type. Additionally, participants noted that individual patient factors, including age, gender, medications, existing medical conditions and certain biomarkers, could influence the type of response experience.
- At the time, panelists cited serious evidence gaps. The consensus recommendation from the advisory committee meeting was that additional information about immunological responses to metal-containing medical devices were needed, although the panel expressed uncertainty about how this research should be conducted. The panel recommended that the FDA “consider the utility of developing an appropriate animal model, retrieval studies, as well as tissue and blood testing in patients who have had immunological responses.” The panel concluded that the outstanding questions largely fell into two buckets – first, questions about what responses were linked to what materials (and at what rates) and then, as one panelist asked, whether some of the instances of adverse events were “really something related to the actual patient themselves as opposed to the actual device.” Notably, an increased likellihood that a certain patient would have a certain reaction could skew the risk/benefit profiles for a given product, and therefore impact the FDA’s regulatory decision-making or the product’s labeling and testing requirements.
- The agency has been working to address the issue. In August 2020, the agency requested a slate of research projects related to isolating and quantifying the specific biological impacts of medical device materials. These included projects looking into how different tissue types react to different materials, cell and immunological responses to certain materials and textures, and potential biomarkers for device failures. The agency also issued new guidance for peripheral vascular atherectomy devices that addressed concerns about long-term risks from potential exposure to particulates from the devices’ coating, and updated guidance on non-clinical testing for devices containing nitinol, a nickel-titanium alloy.
- The agency also issued a framework that would include information about materials in a device’s labeling. In May 2021, the FDA issued a discussion paper outlining a policy that would potentially include specific information about device materials to be included in labeling for devices intended for long-term exposure. Theoretically, this information would help providers and device users stay informed regarding potential risks or adverse events from long-term exposure to these materials, helping these groups identify and report any adverse events. In September 2021, the agency issued the first four material safety summaries – followed by an additional round of material safety reports in January 2022. However, there has been no further word on the material-specific labeling proposal.
The agency has now posted two notices indicating that it is still assessing the issue
- The first project focuses on standards for metal ion release in stainless steel and nitinol. Per the notice, the Center for Devices and Radiological Health (CDRH) is working to “establish in vitro to in vivo correlations for metal ion release,” to understand how using standard test corrosion methods relate to “patient exposure and ultimately risk” of metal ions from implanted devices made of stainless steel and nitinol. The agency is seeking a vendor to assess metal ion release using “miniaturized devices and other test specimens” that are implanted into a mouse model. As the notice acknowledges, “It is recognized that standard corrosion methods, such as ASTM F3306, are not yet conducted under physiological conditions” and that the results of the testing will be “used to support modifications to the international recognized standard ASTM F3306 to improve the clinical relevance of the test method.” In effect, it appears that the agency is looking for more information about how the metal ion release of nitinol and stainless-steel samples can be appropriately accounted for in future updates to the testing methods in ASTM F3306.
- ASTM F3306 is the standard that FDA recommends sponsors use for certain ion release testing – but only when a device that uses nitinol “does not meet [the sponsor’s] pre-specified acceptance criteria for corrosion resistance or does not employ an established surface finishing process.” Per that guidance on non-clinical testing for devices using nitinol, which was finalized in 2020 but updated in July 2021, sponsors were directed to assess the impact that corrosion could have on the integrity of their device and the potential for nickel ion release. While sponsors were largely directed to leverage pre-specified acceptance criteria for ion release, if testing did not meet those thresholds then the FDA “recommend[s] characterizing the extent of nickel ion release” following a series of steps laid out in a flowchart (page 14). However, updates to ASTM F3306 to better reflect the risk of ion release, and its impact on a patient, could help fill the gaps in translating ion release to adverse event risk.
- The second project will look at local and systemic immune responses for certain patients. Specifically, the project will entail an “immunohistochemistry analysis of patient tissue samples from cardiovascular and/or orthopedic device implants.” Per the scope of work, the agency cites “safety concerns associated with metal-containing implants,” and is seeking research into the “specific and systemic tissue responses to metal exposure.”
- While the agency acknowledges other recent research into the topic of metal-containing implants, “little is known about how patient-specific traits play a role in the allergic response to metal-containing implants.” Notably, the agency has previously contracted for research on the impact of anatomical location on device-related immune responses, but this contract notice seems to take things one step further. Per the notice, there are two key goals: characterizing patient tissues for the potential immunological and cellular or molecular responses to certain implant materials and identifying specific immune markers that are “uniquely expressed” with exposure to these metal alloys.
- The agency is specifically looking for “metal-specific immune markers… involved in metal-mediated adverse outcomes following implantation with medical devices.” These include markers such as cytokines, chemokines, cell surface receptors or markers or genomic variants that could play a role in such adverse events. Additional work could be done to identify “suitable biomarkers which predict poor medical outcomes following metal device implantation.”
- As AgencyIQ has previously explained, a key point of discussion at the 2019 panel meeting was not only questions about what materials could potentially cause adverse reactions, but also questions about what specific anatomical locations and patient-specific factors could make potential reactions more or less likely (or severe). Following the August 2020 round of research notices, which focused on pinpointing potential biological effects from metals, metrics of nitinol/stainless steel corrosion, how anatomical locations impact the risk of immune responses and NGS sequencing for potential markers of device failure, it appears that the FDA is still working to address these outstanding questions.