Below we discuss emerging trends in biocompatibility reviews at FDA and contemplated alternative proposals that deviate from FDA-recognized ISO 10993 that the testing industry is considering, including benchtop models that may alleviate the need for certain animal studies.
Medical devices that “come into direct contact or indirect contact with the human body" must be evaluated by the U.S. Food and Drug Administration (FDA) "for the potential for an unacceptable adverse biological response resulting from contact of the component materials of the device with the body.” As a result, new FDA final guidance aims to assist medical device sponsors who are preparing premarket applications (PMAs), humanitarian device exceptions (HDEs), investigational device applications (IDEs), premarket notifications (510(k)s), or de novo requests, in assessing the potential for an unacceptable adverse biological response resulting from contact of the component materials of the device with the body.
The guidance informs sponsors that they should “specifically state if the device does not have any direct or indirect tissue contact,” in which case no further biocompatibility information would be needed.” Otherwise, FDA will assess the biocompatibility of the whole device in its “final finished form,” including sterilization, if applicable. Generally, the biocompatibility factors of interest to FDA are the:
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Nature of contact: With which tissues does the device or part of the device come into contact?
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Type of contact: Is there direct or indirect contact?
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Frequency and duration of contact: How long is the device in contact with tissues?
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Materials: What is the device made from?
The guidance notes that the “contact with the human body” could reference the body of either the patient or any other person contacted, such as the medical practitioner. For example, masks or gloves intended to be worn for protective purposes by clinical practitioners should be assessed for biocompatibility even if no patient contact is intended.
The guidance was last updated in October 2020, and this latest final version of the guidance mostly mirrors the prior 2020 guidance. The final version clarifies the use of the latest recognized version of the international standard ISO 10993-1, where endpoints that were previously recommended by FDA as reflected in Attachment A, Table A.1, are now marked as recommended by the standard, thereby making it more likely that FDA will require the full scope of testing for each category of patient contacting device. Full test reports should be provided unless the company is relying on Accreditation Scheme for Conformity Assessment (ASCA) program allowing submission of summary reports, which FDA has also recently transitioned from a pilot to a fully accredited program.
New in the latest guidance is “Attachment G: Biocompatibility of Certain Devices in Contact with Intact Skin,” which proposes alternatives to testing for establishing biocompatibility of certain commonly used materials for medical devices and for which biocompatibility is generally well accepted. FDA highlights the importance of applying the principles of “3R” to replace, reduce, and/or refine animal use in testing when feasible, and has encouraged companies to engage and consult with the FDA in discussions on the suitability and appropriateness of potential non-animal test methods.[1] The current final guidance describes, for example, how manufacturers can and should leverage both literature and clinical experience to better understand the risks and context of biocompatibility risks and to help inform when specific evaluation methods are essential versus when they may not be necessary. We have seen similar efforts to reduce the burden of animal testing in this industry, most notably related to evaluations of the irritation/intracutaneous reactivity endpoint. In particular, for medical devices or components that contact intact skin surfaces only, regardless of duration of contact, where these devices are composed of materials outlined in a provided list included in Attachment G, Section B of the guidance, specific information may be provided in premarket submissions to support the established biocompatibility of these products instead of direct testing. FDA further recommends that companies self-certify that they have established procedures and evaluations to support the biocompatibility of the patient-contacting components which may include sufficient:
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Purchasing controls (21 CFR 820.50) over material suppliers.
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Production and process controls for manufacturing (21 CFR 820.70). Manufacturing materials that could adversely affect device biocompatibility should be removed or limited to an amount that does not pose toxicity concerns.
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Receiving, in-process, and finished device acceptance (21 CFR 820.80) for component and manufacturing materials.
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Analysis of quality data (21 CFR 820.100(a)(1)) to occur at least annually, including complaints, to detect quality problems, such as those that may reveal issues of cytotoxicity, irritation, or sensitization.
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Complaints (21 CFR 820.198) should be received, reviewed, evaluated, and, when necessary, investigated including review of the content in a uniform and timely manner to look for issues related to cytotoxicity, irritation, or sensitization.
The list of accepted materials for which FDA proposes that alternative means of establishing biocompatibility may be acceptable may be updated in the future. FDA also outlines in the guidance certain other categories of products and materials where these principles allowing for alternate means of establishing biocompatibility would not apply and testing would be warranted including for reprocessed single use devices, hydrogels, and adhesives.
If you have any questions on assessing biocompatibility, or on medical device premarket submissions more generally, please contact any of the authors of this alert or the Hogan Lovells attorney with whom you generally work.
Authored by Lina Kontos, Randy Prebula, and Joshua Yao
