FDA publishes second round of material safety reports for medical devices
Following an increased interest in the long-term impacts of common medical device materials, the FDA’s Center for Devices and Radiological Health has published five new materials reports. Overall, the reports highlight significant research gaps in how materials used in implanted medical may affect a patient’s system over years – or a lifetime.
Quick Background: The FDA’s recent work on medical device material safety.
- Medical implants are devices or tissues that are placed inside or on the surface of the body. Many implants are prosthetics, intended to replace missing body parts. Other implants “deliver medication, monitor body functions, or provide support to organs and tissues,” according to the FDA. These devices provide invaluable support and function to patients who need them, but also present unique risks. Implanted devices can be intended for use for an extended period of time extending to years or even a patient’s entire lifespan. This means that while a device may have been tested comprehensively prior to approval or clearance, the materials used in the device may have unexpected long-term patient impacts and may even break down over time.
- Several catastrophic examples of issues with implanted devices have caught the attention of both the agency and the public. These include the injuries associated with the Essure gynecological implant and metal-on-metal hip implants, as well as concerns about the link between the materials used in breast implants and certain cancers and autoimmune diseases.
- The FDA has previously announced efforts to address these concerns. 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. At the time, he noted that the agency would be looking into what information is required in assessing biocompatibility and associated risks, adding that the review could lead to updated premarket review practices. That announcement specifically cited breast implants and metal-containing devices as top priorities.
- An FDA Advisory Committee urged action: At a November 2019 Advisory Panel meeting, FDA averred 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.” However, some panelists said it would be “ biologically plausible” that an implanted device could directly cause a sustained, systemic immunological response in a patient.
- Over the past few years, the FDA has taken several steps to advance its own understanding of the long-term safety of implanted devices. 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.
- 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. [Read AgencyIQ’s analysis of the draft framework here.]
- In September 2021, the FDA released the first four material safety summaries. According to the FDA in Brief post, the new materials safety data page is intended to serve as “a useful tool for innovators in selecting materials and components for future medical products, resulting in patients and doctors having better access to more effective and safer medical device.” Ed Margerrison, the director of FDA’s Office of Science and Engineering Laboratories, had previewed this demonstration research program at the FDA Regulatory Education for Industry meeting in July. The research into device material safety, conducted in partnership with the Emergency Care Research Institute (ECRI), is intended to augment the FDA’s library of regulatory science tools that the agency provides for early development of innovative and safe medical devices.
- The first four material summaries covered magnesium, polypropylene, polyurethanes, and siloxanes. These four materials are used broadly use in medical devices and are mostly well-researched. Some of the materials are associated with specific safety concerns in certain devices (e.g., breast implants, vaginal mesh). Magnesium is a constituent in a wide range of commonly used implants, including orthopedic clips and pins or coronary scaffolds. Polypropylene is a widely researched material that is most closely associated with vaginal mesh but is also used in hernia repair and transabdominal prolapse devices. Polyurethane, also the subject of thousands of research citations, is used in intravascular catheters, other blood access devices and cardiovascular pacemaker electrodes. Finally, siloxanes are used for silicone gel breast implants, silicone injections, silicone oil used in retinal surgery and in neuromodulatory systems. [Read AgencyIQ’s analysis of this action.]
The agency has now posted a second batch of materials reports, adding an additional five materials.
- The new material summaries include those on polyethylene terephthalate (PET), polyethylene glycol (PEG), silver, acrylic acid derivatives, and polyhydroxy acids (e.g., PLA, PGA). As in the first batch, the research team focused on five key questions: expected or typical local host response; persistent or exaggerated response potential that could lead to “systemic signs or symptoms;” patient-related factors that could heighten the potential for systemic response; material-related factors that could predict, increase or mitigate the potential for an exaggerated, sustained response; and the current information gaps. To answer these questions, ECRI conducted comprehensive literature reviews and analyzed data from ECRI’s Patient Safety Organization, “accident investigations, problem reporting network (PRN), and healthcare technology alerts.”
- Polyethylene terephthalate (PET) is a type of polyester that’s widely used in medical devices, including in surgical-use devices such as suture extrusion, implantable products and tubing. According to the report, the most common complications with PET devices are device malfunction or fracture, “accounting for approximately 75% of all” reports, with the “vast majority” representing issues with stents and balloons. However, while ECRI’s review found a significant amount of research on the use of PET in medical devices in general, it appears that the particular questions for which the FDA is seeking answers are not well-researched. “Overall, the literature for PET lacked data on patient-related or material-related factors that influence the likelihood and/or severity of sustained, exaggerated systemic responses. There were very few studies on any PET devices that reported on systemic responses, indicating areas of potential future research,” the report states. Further, most PET research has “relatively short follow-up periods,” and may not be useful for the longer-term outcome research that FDA is seeking.
- Polyethylene glycol (PEG) is also a polyester used in a variety of medical devices, such as sealant systems for surgical suturing and other closure devices. According to the report, bleeding and hematoma are the most common issues with PEG devices, although there is only a “moderate to very low quality of evidence.” As with PET, ECRI’s review found significant research in general but very limited information on the FDA’s research questions. The review highlights long-term research “for all PEG device categories” and systemic response as significant data gaps. In general, the review found that there was limited-to-no randomized control trial data on PEG devices, likely because such trials may not be required in regulating such medical devices as suturing or closure devices. Overall, the review highlights the significant gaps in existing research that could inform the FDA’s questions of interest. Interestingly, PEG is also used in dermal filler devices, albeit with the support of essentially no evidence and “very low” information quality, according to ECRI. Dermal filler devise are a device type that has recently faced increased scrutiny from the agency given its unique benefit-risk profile.
- Silver is used as an antimicrobial agent in a broad array of medical devices, including as a coating in certain implanted prostheses, orthopedic devices, and vascular implants. According to the report, “[t]he vast majority of studies [reviewed by ECRI] reported that no adverse local responses/device events were observed.” Overall, the review identified limited concerns with the use of silver, such as studies that identified “elevated concentration of silver” or argyria in the areas closes to an implant, but “no toxic effects related to the elevated silver concentration.” However, the majority of the evidence on potential toxicological or sensitization responses appear focused on orthopedic (bone and joint) devices, and research on other anatomical locations is lacking, as well as research on the maximum tolerated dose of silver concentrations.
- Di-, tri- and glycerol-methacrylates are acrylic acid derivatives that are often used in dental resins. According to the report, there is “low quality” evidence of a series of potential sensitization/systemic harms, such as local skin reactions, inflammatory responses (especially for four types of dental devices), and in certain circumstances B-cell activation. However, while the review was again able to identify a significant number of studies on the use of these acrylic devices, “with the exception of the host response to dental sealants, the quality of evidence of host and systemic responses to all products was low or worse,” the review concluded. This means that significant research gaps still need to be addressed to answer the FDA’s questions of interest.
- Polyhydroxy acids, including PLA, PGA and other blends and copolymers, are the “most common class of bioresorbable polymers” according to the FDA. As the report explains, there is some evidence that mild inflammatory response is a consistently identified local response with these products, supported by “moderate” evidence. Other local responses “were associated with low or very low quality of evidence,” although there is some “low” quality evidence that drug-eluting stents/scaffolds for coronary use using this material can be associated with in-stent restenosis and stent thrombosis. However, ECRI found no research on systemic issues with these products, revealing a significant gap in available information on the materials’ use in medical devices.
What’s next? The list of expected upcoming reports outlines potential policy interests at the agency.
- Overall, the reports published so far indicate that there isn’t good information available on the areas in which the FDA is interested. Identifying that the evidence gaps exist is the first step to filling them in. Moving forward, it’s likely that the FDA will seek additional research into the areas of interest identified.
- A list of the upcoming material safety reports can be found on page 5-6 of this report. In 2020, FDA asked ECRI for research on only six materials: siloxane, polypropylene, polyether ether ketone (PEEK), polylactic-co-glycolic acid (PLGA), polyurethane and polyethylene terephthalate (PET) as detailed on page 5 of this report. While the reports on PLGA and PEEK are still outstanding, the others have been completed and are available for review.
- For 2021, FDA significantly expanded the list, asking for reports on 18 materials – two of which have already been published (magnesium, silver). The list of upcoming reports includes several widely-used materials including acrylics, fluoropolymers, hyaluronic acid, and nitinol, each of which have been of increasing interest to the agency in recent years.
- Further, the agency has asked for deeper dives on certain topics, including the specific complications related to polypropylene mesh use in pre-, peri- and post-menopausal people and how complications with mesh use relate to different procedural/anatomical locations or device properties.
- While it’s not clear yet just how the FDA will use these reports, it does appear that the agency is building out its own reference guides for potential areas of concern with these materials – including areas where the agency has long highlighted research gaps and the potential for long-term safety or performance implications that aren’t adequately addressed in clinical studies, such as sensitization in implanted mesh products for specific uses or in specific locations. How the FDA intends to use the information, though, remains to be determined.