FDA proposes first update to orthopedic device coating guidance since 1990s
The FDA’s Center for Devices and Radiological Health (CDRH) has issued a new draft guidance specifically laying out the types of information it would want to see in pre-market submission for orthopedic devices with specific coating types. The guidance appears to be explaining current review processes, rather than updating the agency’s existing policies; once finalized it would supersede a guidance from 1995.
Orthopedic, implanted medical devices and coatings: Regulatory recap
- Medical device materials, and coating: In general, the types of materials and components of which medical devices are constructed need to be evaluated for their impact on a device’s performance and safety. For devices that are implanted and therefore intended to be in contact with the patient for long periods of time, the question of how materials hold up over time and interact with a patient’s system is a high priority one for device manufacturers and regulators. In recent years, the FDA’s Center for Devices and Radiological Health (CDRH) has been working to better understand different materials used in implanted devices, and establish best practices for working with different materials.
- Medical device coatings: The FDA has maintained guidance on coatings of certain implanted orthopedic medical devices for decades, but at an extremely high level. The current 1995 guidance on the subject was last revised in 1997. However, the agency has worked more recently on coating-specific guidance documents for other device types, including a final guidance from October 2019 on intravascular catheter systems with lubricious coatings. Further, the agency issued guidance in 2021 on peripheral vascular atherectomy devices that focused, in part, on concerns about coating integrity (and coating particulate testing), and has contracted research on long-term effects of other coating materials.
- That said, there’s little specific guidance from the FDA on coatings more generally. Device-type-specific guidance documents may address testing or information needed to describe and categorize a coating in a product submission, and specific testing may be required under a particular product’s special controls. However, there’s no overall FDA guidance giving broad recommendations on what it expects for coating information in orthopedic implanted devices as a category, beyond the limited guidance from 1997. On January 22, the agency issued a new draft guidance that would do just that – and would, if finalized, supersede the 1997 guidance.
The new guidance focuses on how sponsors should characterize certain coatings in orthopedic device submissions
- The guidance has a particular scope, giving recommendations specifically on the ways that a sponsor should characterize two specific coating types in regulatory submissions: metallic coatings and calcium phosphate coatings (or a dual coating of the two). The guidance will, when finalized, apply to both Class II and Class III devices –and therefore to 510(k) pre-market notifications, Pre-Market Approval (PMA) and De Novo applications, as applicable.
- That said, it doesn’t address the specifics of the rest of a submission for orthopedic devices, including the particulars of the special controls for a certain product, or content in a submission outside of the coating information. Further, other types of coatings or surface modifications are outside of the scope of the guidance – although, notably, the guidance may be able to provide some recommendations about coatings that contain a drug or biologic, but doesn’t “discuss drug or biologic characterization recommendations” – solely the coating material itself.
- The recommendations in the guidance are intended to lay out what the agency currently expects to see in submissions for these products. The guidance appears to be one that lays out the agency’s views on its current practices, rather than the FDA working to set new policy or standards, which is typically indicated in the guidance with language stating that the document is to “promote consistency and facilitate efficient review.” In short: The guidance lists the things that the FDA is already looking for, based on its experiences with reviewing orthopedic devices with these types of coatings.
- This is the second general orthopedics-related devices guidance that the FDA has issued in the last few months. As part of the FDA’s trio of guidance documents it touted as a step in modernizing the 510(k) pathway, the agency issued a draft guidance on general evidentiary expectations for implanted medical devices, an umbrella that includes many orthopedic medical devices. As noted above, questions about implant device materials and coatings have been a key priority for the FDA for several years – though this work was a bit derailed during the pandemic – but it appears that the agency is now looking to move these policies forward.
The specifics of the guidance
- The guidance is focused on characterization of certain coatings for orthopedic devices. First, it addresses metallic coatings “which can be manufactured using thermal spray (e.g., plasma spray), sintering (e.g., sintering of powders, beads, or fiber mesh pad), chemical vapor deposition/infiltration, physical vapor deposition (e.g., ionic plasma deposition), additive manufacturing (e.g., electron beam manufacturing, selective laser sintering) or other methods.” Second, it covers calcium phosphate coatings, “which can be manufactured by plasma spray, solution precipitation, electrochemical deposition or other methods” – or a combination of the two materials.
- It focuses on pre-market submission recommendations, with the guidance organized into the different parts of a submission and descriptions of what information on coating characterization would be expected in each section. As would be expected, the longest single section is on non-clinical bench testing, which is broken out by the type of coating (i.e., metallic coatings, calcium phosphate coatings, dual coatings) and coated substrate/device testing. Finally, the guidance provides some information specifically for 510(k) submissions related to modifications to the device.
- Coating description: The information to be included in this section includes the name of the coating, coating method (pre- and post-processing), starting materials, physical structure of the coating, and the location of the coating and how it covers the device. The agency also notes that if the coating is applied by a third party – or a coating vendor – then the sponsor may reference their master file (MAF) and an associated letter of authorization (LOA).
- Sterility: Since these devices are implanted, sterility information is a core component of a submission; “we recommend that manufacturers sterilize all coated orthopedic devices as it is unclear how processing (cleaning and sterilization) by the end user may affect the integrity of a coating… or if a porous coating can be adequately cleaned.” If the sponsor still intends the device to be provided non-sterile, the agency wants to see a rationale and justification for the proposed reprocessing instructions. For devices labeled as sterile, the agency outlines a list of necessary components, including information on the sterilization method, the validation of that method, and sterility assurance level (SAL). Interestingly, the guidance specifically recommends that “all calcium phosphate coated devices be sterilized using gamma radiation” – to the point that if any other method is used, “supporting data or scientific rationale should be provided.”
- Pyrogenicity: This section of the new guidance is short, and largely points sponsors back to FDA’s existing guidance on pyrogen and endotoxins testing and the use of ISO 10993-1 biocompatibility guidance. For devices for which the sponsor is proposing to include a claim of “non-pyrogenic” on the label, the FDA recommends “that both bacterial endotoxins and material-mediated pyrogens be addressed.”
- Shelf life and packaging: The guidance offers information on what FDA reviewers would need to see related to shelf life testing in two areas: sterility and device/coating function. The recommendations include the types of descriptions (including of the device’s packaging) and validation studies that the agency would want to see, points to recognized consensus standards for these types of testing, and asks that sponsors include protocols for shelf-life testing, as well as results and conclusions. Specifically for accelerated testing of resorbable calcium phosphate coatings, the agency recommends “testing on real-time aged samples to confirm the results of the accelerated aging study. This testing should be conducted in parallel with submission review, with results documented to file in the design history file (i.e., complete test reports do not need to be submitted to FDA).”
- Biocompatibility: In general, if the coating is identical to coatings in a legally marketed device “with a history of successful use,” then sponsors may be able to reference previous testing – and may, as appropriate, include a LOA for a device MAF. However, “if you are unable to identify a legally marketed device with similar location/duration of contact and intended use that uses the same coating” as the new device, the agency notes that biocompatibility evaluations may be needed. As in the section on pyrogenicity, the guidance points back to the existing recommendations in the ISO 10993-1 biocompatibility guidance, and outlines the relevant sections for long-term implanted devices. The FDA has added some additional material-specific context for biocompatibility assessments, such as considerations related to the processing and manufacturing of the coating and device and differences in the new product (compared to an existing device) that could affect biocompatibility. Finally, specifically for “new formulations of degradable or resorbable calcium phosphate coatings,” the guidance recommends additional content related to biocompatibility over the life of the device (i.e., starting, intermediate and final degradation).
- Non-clinical bench testing: This is the longest single section of the guidance, offering general recommendations as well as specific recommendations for testing based on the materials (metallic, calcium phosphate, dual coatings) – with minimum sample sizes for each, although “unexpected tests results (e.g., a large variability in results) or device design may suggest a larger sample size should be utilized.” In general, the agency recommends that sponsors use final sterilized devices from multiple lots for bench testing, unless there is a recognized consensus standard that specifically describes a coupon. Further, the sponsor may seek to use an alternative method, but should provide a rationale as to why the test sample would be equivalent in variability. Specifications for each test for specific coating properties should, if applicable, align with the special controls of the particular device, and ranges should be justified based on the device and the specific coating property.
- For metallic coatings, the agency offers recommendations on coating chemical analysis, coating microstructural characterization, coating mechanical testing, and then gives recommendations for three specific types of metallic coatings (i.e., “a) beaded, sintered cobalt-chrome coatings on a cobalt-chrome substrate, b) beaded, vacuum-sintered titanium coatings on a titanium substrate, and c) vacuum-sintered titanium fiber mesh pads on a titanium substrate,” which may be “sufficiently evaluated” using only three testing items. For testing of calcium phosphate coatings, the guidance recommends, and provides specific content on, coating physiochemical analysis, coating microstructural characterization, and coating mechanical testing. For dual coatings, the agency notes that a combination of the different components may be necessary. Finally, the agency recommends bench testing for evaluating the effect of the coating process on the device’s performance, including comparative physical and chemical testing of the coated substrate and comparative fatigue testing of the coated substrate.
- Nonclinical animal testing: Due to the limitations of bench testing methods, animal studies may be used – but are “generally unnecessary for most metallic and calcium phosphate coated devices,” unless there is a novel material, composition or phases that are not well categorized or “cannot be evaluated through bench tests or in a clinical study.” Generally, the agency recommends that sponsors considering an animal study, or another non-animal method in lieu of an animal study, should plan to use the Q-submission process before proceeding.
- Clinical performance testing: Generally, clinical studies are not necessary for metallic and calcium phosphate coated devices. However, they may be needed in the contexts of novel technologies or when bench/animal testing has flagged issues. In these contexts, the agency points to its existing regulations on clinical testing, including the Investigational Device Exemption (IDE) regulations (and its relevant exemptions) and considerations for investigations outside the US, or leveraging real-world data (RWD).
- Labeling: Per the guidance, “Specific labeling information will vary depending on the device on which the coating is used,” but the agency does offer three specific recommendations. First, the agency notes that calcium phosphate coatings can adversely impact cemented fixation, so all devices coated with this substance should be implanted using cementless methods – and that should be clearly specified in labeling. Second, devices with porous coatings may be labeled for biological fixation, but the agency currently does not support labeling for “enhanced fixation claims” like osseointegration. Finally, “If you intend to label a coated device as ‘nano,’” notes the FDA, “characterization data to demonstrate the ‘nano’ characteristics of the coating should be provided in the submission.”
- And finally, 510(k) modifications: While not all modifications to a previously cleared medical device require the submission of a new 510(k), certain modifications involving a device’s coating would require a new submission. The end of the guidance document features a list of these potential changes that would trigger a new 510(k) submission, including changing a coating method, or using a different vendor – even if it’s the same coating. Other items on the list include adding new layers/thickness or modifying porosity, or changes to substrate materials or the surface treatment. Changes that would not likely require a new 510(k) are much more specific, per the list in the guidance. These include changes to suppliers for starting materials for plasma-sprayed metallic coatings (where the material specifications align with FDA-recognized consensus standards and the material specifications are the same) and reducing metallic coating layers or thickness “while other microstructural characteristics… are still within the original specification.”
- What’s next? The guidance is open for comment through March 22, 2024.