Risk Management for Biocompatibility Evaluations 生物相容性的风险管理

As stated in ISO 10993-1, the biological evaluation of a medical device (or a material component of such) should be conducted within the framework of a risk management process. Such a process should generally begin with assessment of the device, including the material components, the manufacturing processes, the clinical use of the device including the intended anatomical location, and the frequency and duration of exposure. Considering this information, the potential risks from a biocompatibility perspective should be identified. Such risks might include chemical toxicity, unacceptable biological response to physical characteristics of the device, and aspects of manufacturing and processing that could alter the physicochemical characteristics of the device, which could lead to changes in the biocompatibility response. Once the risks have been identified, the sponsor should assess what information is already available regarding those risks and identify the knowledge gaps that remain. Considering the potential biological impact, a plan should be developed to address the knowledge gaps either by biocompatibility testing or other evaluations that appropriately address the risks. The interpretation of the overall biocompatibility evaluation should be considered in the appropriate benefit-risk context.

根据 ISO 10993-1 的规定，医疗器械（或其材料组成部分）的生物评价应在风险管理过程的框架内进行。这样的过程通常应从对设备的评估开始，包括材料组成部分、制造工艺、设备的临床使用情况（包括预期的解剖位置）以及暴露的频率和持续时间。根据这些信息，应该确定生物相容性风险。这些风险可能包括化学毒性、对设备的物理特性产生不可接受的生物反应，以及可能改变设备物理化学特性的制造和加工方面，导致生物相容性反应发生变化。一旦确定了风险，主办方应评估已有的有关这些风险的信息，并确定尚存的知识空白。考虑到潜在的生物影响，应制定一个计划，通过生物相容性测试或其他适当的评估来解决这些知识空白，以适当地应对风险。应将整体生物相容性评价的解释考虑在适当的利益和风险背景下。

Risk Assessment of the Medical Device 医疗器械的风险评估

The risk assessment should evaluate the final finished device. The Agency makes a clearance or approval decision for a medical device as it is supplied in its final finished form. The Agency does not clear or approve individual materials that are used in the fabrication of medical devices. Therefore, the risk assessment should evaluate not only the materials used in the device, but also the processing of the materials, the manufacturing methods (including the sterilization process), and any residuals from manufacturing aids used during the process.

风险评估应评估最终的成品设备。当医疗器械以其最终成品形式提供时，机构会对其进行审批或批准决定。机构不会对用于制造医疗器械的个别材料进行审批或批准。因此，风险评估应该评估不仅设备中使用的材料，还应考虑材料的处理、制造方法（包括灭菌过程）以及制造过程中使用的任何辅助材料残留物。

The risk assessment should also consider the proposed clinical use of the device, including the anatomical location, duration of exposure, and intended use population. For example, for pediatric patients with a limited life expectancy, the tolerance for risk associated with a permanently implanted medical device may be higher than the tolerance for risk from the same device in an otherwise healthy pediatric population. The potential exposure duration should also consider which material components of the device have direct or indirect contact with tissue, and whether exposure would be a one-time exposure, a constant exposure over time, or an intermittent exposure over time that could have a cumulative effect. For example, pacemaker pulse generators commonly contain internal electronic components made from chemicals that could be toxic to the body, but appropriate bench testing can demonstrate that the pulse generator is hermetically sealed and will limit exposure of those chemicals to the surrounding tissues.

风险评估还应考虑设备的拟议临床使用情况，包括解剖位置、暴露持续时间和拟定使用人群。例如，对于寿命有限的儿科患者来说，与永久植入的医疗器械相关的风险容忍度可能高于对同一设备在其他健康儿童人群中的风险容忍度。潜在的暴露持续时间还应考虑设备的哪些材料组成部分与组织直接或间接接触，并且暴露是一次性的、持续不断的，还是随时间间歇性的暴露，可能具有累积效应。例如，起搏器脉冲发生器通常包含由对人体有毒的化学物质制成的内部电子元件，但适当的台架测试可以证明脉冲发生器是密封的，会限制这些化学物质对周围组织的暴露。

Identification of Potential Risks 潜在风险的识别

An assessment of potential biocompatibility risk should include not only chemical toxicity, but also physical characteristics that might contribute to an unwanted tissue response. These characteristics can include surface properties, forces on surrounding tissue (e.g., mechanical, thermal, electromagnetic), geometry, and presence of particulates, among others. In addition, changes in manufacturing and processing parameters can also have an impact on biocompatibility. For example, the original processing for an implanted device might include placing the device in an acid bath to facilitate passivation of the implant surface. If this passivation process is changed to eliminate the acid bath in favor of a different method of passivating the surface, removal of the acid bath might unintentionally lead to a smaller reduction in pyrogenic material, which could result in pyrogenic reactions (fever) following implantation of the device. Another common change that might impact biocompatibility is a change in resin supplier. For example, if the new resin supplier does not remove all processing solvents (some of which may be known toxic compounds, such as formaldehyde), the final manufactured device could cause unexpected toxicities (e.g., cytotoxicity, irritation, sensitization, genotoxicity) that were not seen with devices manufactured from the original resin.

对潜在的生物相容性风险的评估不仅应包括化学毒性，还应考虑可能导致不良组织反应的物理特性。这些特性可以包括表面特性、对周围组织的作用力（如机械、热、电磁力）、几何形状和颗粒的存在，等等。此外，制造和加工参数的变化也可能对生物相容性产生影响。例如，原始的植入装置的处理过程可能包括将装置放入酸浴中以促进表面钝化。如果将这种钝化过程改变为使用其他方法进行表面钝化而不使用酸浴，去除酸浴可能无意中导致对致热原材料的减少较小，从而可能导致装置植入后引起致热反应（发热）。另一个可能影响生物相容性的常见变化是树脂供应商的更换。例如，如果新的树脂供应商未能去除所有加工溶剂（其中一些可能是已知的有毒化合物，如甲醛），则最终制造的装置可能引起意外的毒性反应（如细胞毒性、刺激性、致敏性、遗传毒性），而这些反应在使用原始树脂制造的装置中未曾出现。

Sources of information on potential biocompatibility risks can include, but are not limited to, a manufacturer’s previous experience with the same material(s), preferably in the same or similar anatomical location; reported experience from other manufacturers using the same material in the same or similar anatomical location; information provided by the material supplier (e.g., in a master file[1], see Attachment B); chemical or surface analysis of the device in its final finished form; and the published literature. In certain situations, clinical experience, such as postmarket surveillance information, may be informative. For example, for a limited duration, skin-contacting device, patient experience that includes information on potential for irritation or sensitization can be useful to the risk assessment.

关于潜在生物相容性风险的信息来源包括但不限于制造商对相同材料的先前经验（最好是在相同或类似的解剖位置），其他制造商在相同或类似解剖位置使用相同材料的经验报告，材料供应商提供的信息（如主文件中的信息，请参见附件 B），对最终成品设备的化学或表面分析，以及已发表的文献。在某些情况下，临床经验，如事后市场监测信息，可能是有启发性的。例如，对于有限时期的与皮肤接触的装置，包括有关刺激或致敏潜力的信息对风险评估是有用的。

When leveraging data from experience with a particular device for a new device submission to FDA, it is important to understand how the tested device compares to the device under consideration. In general, the more similar the tested device and device under consideration are, including their intended use, the more applicable the risk information is likely to be. For example, for a vascular catheter comprised of a certain polymer, citing experience with the same polymer in a blood-contacting device will be more applicable than experience with a similar polymer in a device that only contacts mucosal membranes. Similarly, experience with device components made using the same formulation and processing (e.g., for devices within a product family) will be more applicable than experience with device components made by a different manufacturer where the formulation and processing are unknown.

当利用与新设备提交给 FDA 的特定设备的经验数据时，了解受测设备与待考虑设备的比较是很重要的。一般而言，受测设备与待考虑设备越相似，包括其预期使用方式，相关的风险信息就越适用。例如，对于由特定聚合物组成的血管导管，引用相同聚合物在与血液接触的设备中的经验将比引用相似聚合物在仅与粘膜接触的设备中的经验更为适用。同样地，对于使用相同配方和加工的设备成分（例如产品系列中的设备），与使用不同制造商制造的成分，配方和加工方式不详的设备成分的经验将更为适用。

A master file for a material, device component, and/or device may be useful if it includes information on recommended processing of the material or component and any biological testing already performed (see Attachment B). A master file should also contain a risk assessment provided by the supplier that includes a discussion of the chemical formulation and structure of the material or component and information on how to evaluate a device made from that material.

材料、设备成分和/或设备的主文件如果包括有关材料或成分的推荐加工信息以及已执行的生物测试的信息，将会非常有用（请参见附件 B）。主文件还应包含供应商提供的风险评估，其中包括对材料或成分的化学配方和结构进行讨论的信息，以及如何评估由该材料制成的设备。

In certain situations, a sponsor may propose to use a material that has known toxicities but where the material could be acceptable for the end use. In this case, the risk assessment should include consideration of the intended use population that will use (e.g., protective mask for clinician) or be treated with the device and a discussion of potential benefits of using the chosen material as well as potential mitigations that have been considered (e.g., hermetically sealing).

在某些情况下，赞助商可能会提议使用已知有毒性的材料，但该材料在最终使用中可能是可接受的。在这种情况下，风险评估应包括考虑将使用该设备的预期使用人群（例如，临床医生的防护口罩）或接受该设备治疗的人群，并讨论使用所选择材料的潜在益处以及已考虑的潜在缓解措施（例如，密封）。

A chemical analysis of the materials used in a device in its final finished form can be informative. Chemical analysis can be particularly helpful to demonstrate that chemical toxicity testing from a previously cleared or approved medical device is relevant to a device under review by the Agency. For example, in some circumstances, a chemical analysis can demonstrate that the extractables and leachables in a biocompatibility extract have not changed, eliminating the need for additional biocompatibility testing using that type of solvent. In addition, chemical analyses can be used to assess the toxicological risk of the chemicals that elute from devices. For example, chemical analysis using exhaustive extraction techniques (per ISO 10993-12) can also be helpful to evaluate long-term toxicity endpoints such as potential carcinogens. Extraction techniques could also be used to identify intermediate and final breakdown products in a material that is either synthesized in vivo (e.g., in situ polymerizing materials) or intended to be absorbable (e.g., degradable materials). However, chemical analysis is usually insufficient to identify all of the risks of the device in its final finished form, because it will not consider aspects of the finished device such as surface properties (e.g., rough versus polished surface) or device geometry that could affect the biological response in certain scenarios (e.g., thrombogenicity, implantation). In addition, the outcomes of chemical analyses are often sensitive to the parameters of the test. Extraction solvents should be selected to optimize compatibility with the device materials and provide information on the types of chemicals that are likely to be extracted in clinical use. Solvents that swell the polymer, cause the polymer to degrade or dissolve, or interfere with detection of chemicals should be used with caution.

对设备最终成品中使用的材料进行化学分析可以提供有益信息。化学分析对于证明先前获得清除或批准的医疗器械的化学毒性测试与正在审查的设备相关性特别有帮助。例如，在某些情况下，化学分析可以证明生物相容性提取物中的可萃取物和可溶出物没有发生变化，从而不需要使用该类型溶剂进行额外的生物相容性测试。此外，化学分析可用于评估从设备中溶出的化学物质的毒理风险。例如，使用详尽的提取技术（符合 ISO 10993-12）进行化学分析，还可以帮助评估潜在致癌物等长期毒性终点。提取技术还可用于识别在体内合成（例如，原位聚合材料）或预期可吸收（例如，可降解材料）的材料中的中间和最终分解产物。然而，化学分析通常无法识别设备在最终成品形式中的所有风险，因为它不会考虑最终设备的表面特性（例如，粗糙与抛光表面）或可能影响某些情况下生物反应的设备几何形状（例如，血栓形成，植入）。此外，化学分析的结果通常对测试参数敏感。应选择溶剂以优化与设备材料的兼容性，并提供有关在临床使用中可能被提取的化学物质类型的信息。使用会使聚合物膨胀、降解或溶解，或干扰化学物质检测的溶剂应谨慎使用。

Finally, there may be potential hazards that are not addressed by available information. In certain cases, such as the addition of a new chemical to a standard formulation, individual toxicity information for the added chemical and starting material may be insufficient due to the potential for chemical interactions between the material and added chemical. Thus, the risk assessment should consider what is known about the additional material, the base material, and potential chemical interactions between the two.

最后，可能存在无法通过现有信息解决的潜在危害。在某些情况下，例如将新化学物质添加到标准配方中，由于材料与添加化学物质之间的化学相互作用的潜在可能性，添加化学物质和起始材料的个体毒性信息可能是不足的。因此，风险评估应考虑关于附加材料、基础材料以及两者之间的潜在化学相互作用的已知信息。

Considering Available Information to Identify and Mitigate Risks 根据现有信息识别和缓解风险

In order to reduce unnecessary testing, including animal testing[2], FDA recommends that sponsors consider all available relevant information when conducting their risk assessment. FDA believes that the following information should be included in your risk assessment, if applicable:

为了减少不必要的测试，包括动物测试[2:1]，FDA 建议赞助商在进行风险评估时考虑所有可用的相关信息。如果适用，FDA 认为以下信息应包括在您的风险评估中：

  1. Literature and other publicly available information: Sponsors should review all available toxicity literature and other publicly available information to determine the toxicity risks for the materials used to manufacture their medical device. If data are not available to evaluate the safety of a compound, then the concept of Threshold of Toxicological Concern (TTC)[3] can be used to assess some biocompatibility endpoints.

    文献和其他公开可获得的信息：赞助商应查阅所有可用的毒性文献和其他公开可获得的信息，以确定用于制造其医疗器械的材料的毒性风险。如果没有数据来评估化合物的安全性，则可以使用毒理学关注阈（Threshold of Toxicological Concern，TTC）[3:1]的概念来评估一些生物相容性终点。

    Sponsors should also review available literature and other publicly available information to identify specific risks associated with the use of their device and possible mitigation measures. For example, literature could inform manufacturers that nitinol passivation of a peripheral stent should be conducted appropriately to ensure that nickel, a chemical with known toxicities, does not leach from the device when implanted. Literature could also be useful in identifying the potential breakdown products of an absorbable device, allowing the sponsor to conduct more focused testing to characterize and analyze these chemicals as a device degrades. Sponsors should be selective in how literature and other publicly available information are used to inform their risk assessment; all available information should be considered in the context of how relevant the information might be to a specific medical device. For example, status of a device material or component as “generally recognized as safe” (GRAS) by FDA as a food additive may or may not be informative for a medical device risk assessment because it may not be appropriate to extrapolate use in food to device-specific tissue contact, such as muscle or circulating blood. In addition, when considering available literature with respect to specific device materials, sponsors should also evaluate whether such information is relevant in light of the manufacturing and processing for the medical device. Similarly, literature or other publicly available information such as clinical data may become less relevant when changes in materials or suppliers occur. Such changes may affect the safety or effectiveness of a medical device and should be considered appropriately in any risk assessment provided to FDA.

    赞助商还应审阅可获得的文献和其他公开信息，以识别与其设备使用相关的具体风险，并提出可能的缓解措施。例如，文献可以告知制造商，为确保植入时设备中已知具有毒性的镍等化学物质不会溶出，外周支架的氮化钛钝化处理应进行适当的操作。文献还可以帮助确定可吸收设备的潜在降解产物，使赞助商能够进行更有针对性的测试，以对这些化学物质进行表征和分析。赞助商在使用文献和其他公开可获得的信息指导风险评估时应选择性地运用，并将所有可用信息与特定医疗器械的相关性相结合考虑。例如，FDA 将某种设备材料或组件视为“FDA 普遍承认为安全”（GRAS）的食品添加剂，并不能直接适用于与肌肉或循环血液等特定组织接触的医疗器械的风险评估，因此不宜将其推广应用。此外，在考虑与特定设备材料相关的文献时，赞助商还应评估这些信息在医疗器械的制造和加工过程中是否具有相关性。同样，在发生材料或供应商变更时，文献或其他公开可获得的信息，如临床数据，可能变得不那么相关。此类变更可能会影响医疗器械的安全性或有效性，因此应在向 FDA 提供的任何风险评估中适当地加以考虑。

If literature is used to waive testing for certain biocompatibility endpoints, the submission should include information on the applicability of the dose, route, and frequency of exposure from the literature report(s) as compared to the proposed device use. In addition, while literature may be appropriate to evaluate certain biocompatibility endpoints, it may not be appropriate to waive all biocompatibility testing. For example, No Observed Adverse Effect Level (NOAEL) and Lowest Observed Adverse Effect Level (LOAEL) data should be derived from studies relevant to the endpoint under consideration. For example, NOAELs and LOAELs from a systemic toxicity study can often be used to waive acute, subchronic, or chronic system toxicity testing, but might not be relevant for genotoxicity, local and systemic carcinogenicity, sensitization, irritation or reproductive toxicity assessments, if these endpoints are not assessed in the studies selected to develop NOAELs or LOAELs. However, NOAEL/LOAEL values developed to consider reproductive toxicity may be used to assess the potential reproductive toxicity of compounds released from devices that are not in direct contact with reproductive tissues.

如果文献用于豁免某些生物相容性终点测试，提交应包括关于文献报告中剂量、途径和频率的适用性信息，与拟议的器械使用进行比较。此外，虽然文献可能适用于评估某些生物相容性终点，但不一定适用于豁免所有生物相容性测试。例如，无观察到的不良影响水平（NOAEL）和最低观察到的不良影响水平（LOAEL）数据应来源于与所考虑终点相关的研究。例如，系统毒性研究中的 NOAEL 和 LOAEL 通常可用于豁免急性、亚慢性或慢性系统毒性测试，但对于基因毒性、局部和全身致癌性、致敏、刺激或生殖毒性评估可能不相关，如果这些终点在用于发展 NOAEL 或 LOAEL 的研究中未进行评估。然而，用于考虑生殖毒性的 NOAEL/LOAEL 值可用于评估与生殖组织直接接触的器械释放的化合物的潜在生殖毒性。

  1. Clinical experience: Clinical experience should be considered in the overall benefit-risk profile for the device where the totality of the data available for the device may inform whether more testing is needed, or if any testing is needed at all. For example, clinical experience may be useful to mitigate problematic findings in an in vitro biocompatibility or in vivo animal study. In other cases, testing to address long-term biocompatibility endpoints (e.g., genotoxicity, chronic toxicity, or carcinogenicity) may not be necessary if the patient’s life expectancy in the intended use population is limited.

    临床经验：临床经验应考虑到设备的整体效益风险概况，以确定是否需要进行更多的测试，或者是否需要进行任何测试。例如，临床经验可能有助于缓解体外生物相容性或体内动物研究中的问题发现。在其他情况下，如果预期使用人群的患者预期寿命有限，可能无需进行长期生物相容性终点（例如基因毒性、慢性毒性或致癌性）的测试。

    Generally, clinical studies are not sufficiently sensitive to identify biocompatibility concerns. Clinical or sub-clinical symptoms that result from the presence of a non-biocompatible material may not be identifiable, or may result in symptoms that are indistinguishable from the disease state such that the clinical data may not be informative to the biocompatibility evaluation. For example, blood vessel occlusion at the site of an implanted stent could be indicative of a toxic response to the stent materials or be related to damage to the stent during implantation (e.g., due to operator error or a delivery device malfunction). However, in limited circumstances, clinical experience may mitigate certain identified risks. For example, if there is previous clinical experience with a particular medical device (either from a clinical study or via marketing outside of the US), and there have been no issues with anaphylaxis, then biocompatibility testing for complement activation may not be necessary. Similarly, in an Investigational Device Exemption (IDE) study, first in human study data may be useful to initiate a study on a revised device design, while biocompatibility evaluations are being completed in parallel, and it may be acceptable to provide complete biocompatibility information once the device design is finalized for commercialization, depending on the risks posed to patients.[4]

    一般来说，临床研究对于识别生物相容性问题的敏感性不足。由于非生物相容材料的存在导致的临床或亚临床症状可能无法识别，或者可能导致与疾病状态无法区分的症状，因此临床数据可能对生物相容性评估无效。例如，植入支架的血管阻塞可能表明对支架材料的毒性反应，也可能与植入过程中支架损坏有关（例如，由于操作者错误或传递装置故障）。然而，在一些有限的情况下，临床经验可能有助于缓解特定的风险。例如，如果已经有关于特定医疗器械的临床经验（无论是来自临床研究还是在美国以外市场上销售），并且没有出现过过敏反应的问题，则可能无需进行补体激活的生物相容性测试。同样，在调查性设备豁免（IDE）研究中，首次人体研究数据可能有助于启动对修订设备设计的研究，同时与生物相容性评估同时进行，根据对患者造成的风险，一旦设备设计最终确定用于商业化，提供完整的生物相容性信息可能是可接受的。

  1. Clinical experience may also inform biocompatibility evaluation of next generation devices. For example, some clinical studies of specific absorbable medical devices demonstrated that the absorption kinetics were not accurately predicted by the nonclinical performance (bench or animal) studies. This information has been helpful when evaluating a next generation device using an improved bench model for the absorption of the device, and for assessing how the type and amount of chemicals released with absorption over time might affect biocompatibility.

临床经验也可以为下一代设备的生物相容性评估提供信息。例如，某些特定可吸收医疗器械的临床研究表明，吸收动力学并不能准确预测非临床性能（台架或动物）研究的结果。这些信息在使用改进的台架模型评估下一代设备的吸收过程，并评估随时间释放的化学物质类型和数量对生物相容性的影响时非常有帮助。

However, there are also situations where FDA has not found clinical experience to provide relevant biocompatibility information. For example, providing clinical information that a particular implant material has a long history of use would not typically be sufficient to support the biocompatibility of an implant made from the same material because manufacturing and processing could affect the final chemistry presented to the body. In addition, such information is often too broad and general to be useful.

然而，也存在 FDA 未发现临床经验提供相关生物相容性信息的情况。例如，提供特定植入材料具有长期使用历史的临床信息通常不足以支持由相同材料制成的植入物的生物相容性，因为制造和加工可能会影响最终呈现给人体的化学成分。此外，这类信息通常过于广泛和概括，不具备实用性。

  1. Animal study experience: Data from an in vivo animal study of the medical device in its final finished form may be used in lieu of some biocompatibility tests. Testing performed in a relevant animal model can be used if the study was designed to include assessments for biocompatibility endpoints. These studies should evaluate the biological response to the test article implanted in a clinically relevant implantation site. For example, separate biocompatibility assessments for implantation, in vivo thrombogenicity, and acute, subchronic, and chronic toxicity may not be needed if these endpoints were included in the in vivo animal study design with an appropriate study endpoint, and the scientific principles and recommendations in the appropriate ISO 10993 test method were considered and applied.

    动物研究经验：在某些生物相容性测试之外，可以使用最终成品形式的医疗器械在活体动物研究中获得的数据。如果研究设计中包括了对生物相容性终点的评估，那么在相关动物模型中进行的测试是可以使用的。这些研究应该评估临床相关植入部位中测试物体的生物反应。例如，如果这些终点在活体动物研究设计中包含了适当的研究终点，并且考虑和应用了适当的 ISO 10993 测试方法的科学原理和建议，那么就不需要单独进行有关植入、体内血栓形成、急性、亚慢性和慢性毒性的生物相容性评估。

    If animal study data (e.g., histology, necropsy) identifies adverse biological responses, some additional biocompatibility testing may be warranted. For example, glutaraldehyde-fixed tissue heart valves may show toxic effects in animal studies as well as some standard biocompatibility assays, such as cytotoxicity and genotoxicity. These findings would usually trigger the need for additional studies, such as chemical characterization and dose ranging cytotoxicity and genotoxicity studies of suspected chemical toxins released from the device to confirm the cause of the adverse findings and to determine if additional mitigations are needed.

    如果动物研究数据（例如组织学、尸检）发现了不良的生物反应，可能需要进行一些额外的生物相容性测试。例如，动物研究中可能显示出戊二醛固定的组织心瓣具有毒性效应，以及一些标准的生物相容性测定，如细胞毒性和遗传毒性。这些发现通常会触发进一步的研究需求，例如对疑似从器械释放的化学毒素进行化学特性和剂量范围内的细胞毒性和遗传毒性研究，以确认不良结果的原因，并确定是否需要额外的改进措施。

    Animal experience may also inform biocompatibility evaluation of next generation devices. For example, animal study data from the literature regarding absorbable adhesion barriers made of a certain material could provide information related to the timeframe of absorption and potential adverse effects for a new or modified device.

    动物经验也可以为下一代设备的生物相容性评估提供信息。例如，关于某种特定材料制成的可吸收粘连阻隔物的动物研究文献可能提供与吸收时间和潜在不良效应有关的信息，这对于新的或修改后的设备是有帮助的。

    However, there are also situations where FDA has not found animal data to provide relevant biocompatibility information. For example, data from the literature indicating that a particular implant material is biocompatible may not be sufficient to support the biocompatibility of a device made from the same material because manufacturing and processing likely will affect the final device chemistry presented to the body. Similarly, animal studies designed to assess human factors and studies conducted in animal cadavers would not typically include assessment of biological response, and therefore may not be useful to support a biocompatibility evaluation.

    然而，也存在 FDA 未发现动物数据提供相关生物相容性信息的情况。例如，文献中表明某种特定植入材料具有生物相容性的数据可能不足以支持由相同材料制成的设备的生物相容性，因为制造和加工很可能会影响最终呈现给人体的设备化学成分。同样，旨在评估人体因素的动物研究和在动物尸体上进行的研究通常不包括生物反应的评估，因此可能无法支持生物相容性评估。

  2. Medical device standards: Standards specific to a particular device type or material may be helpful to inform a risk assessment; however, the extent to which the standard could be utilized may be dependent on the specificity of the standard and/or the specific material. Ideally, a standard would have sufficient specificity to provide useful information regarding material risks. For example, standards that outline both mechanical and chemical properties of a device type with pass/fail criteria may be particularly informative to FDA’s review because of the specificity of such a standard. Standards that address bulk material composition can also be informative as a starting point for incorporating material characterization into a risk assessment. For example, it may be appropriate to use material standards to support the biocompatibility evaluation of 316L stainless steel surgical vascular clamps, as long as any risks associated with manufacturing are appropriately considered and mitigated (see Section IV.A). Given the effects that manufacturing and processing may have on a polymer as incorporated into the final finished medical device, use of material standards may not be sufficient to identify biocompatibility risks for devices made from polymers.

    医疗器械标准：针对特定设备类型或材料的标准可能有助于风险评估；然而，标准的适用程度可能取决于标准的特异性和/或特定材料。理想情况下，一个标准应具有足够的特异性，以提供有关材料风险的有用信息。例如，对于同时概述设备类型的机械和化学性能，并具备合格/不合格标准的标准，可能会对 FDA 的审查提供特别有益的信息，因为此类标准的特异性较高。解决原料物质组成的标准也可以作为将物质特性纳入风险评估的起点参考。例如，对于 316L 不锈钢外科血管夹这类设备，使用物质标准来支持生物相容性评估可能是合适的，只要制造过程中的任何风险得到适当的考虑和缓解（参见第 IV.A 节）。鉴于制造和加工对聚合物在最终医疗器械中的影响，使用物质标准可能不足以识别由聚合物制成的设备的生物相容性风险。

  3. Devices previously reviewed by FDA: Experience with medical device materials previously reviewed by FDA (e.g., in previous generation devices, PMA-approved devices, predicate devices) are also relevant for consideration as part of a risk assessment. Such information may be more informative when a sponsor is able to leverage their own experience, rather than that from another manufacturer or supplier as the manufacturing and processing of the device material may be unknown. Sponsors should be specific in their risk assessment regarding how devices previously reviewed by FDA are being utilized to identify potential risks and/or mitigate identified risks. Sponsors should be as specific as possible when referencing devices previously reviewed by FDA, including submission numbers or master file numbers, and references to specific test reports or data in a submission (if applicable). Sponsors should also provide a specific comparison of the subject device materials to device materials previously reviewed by FDA. It may be helpful to use the documentation examples provided in Attachment F to provide such a comparison.

    FDA 先前审查的设备：与 FDA 先前审查的医疗器械材料的经验（例如，在先前的设备、PMA 批准的设备或基准设备中）也是风险评估的相关考虑因素。当赞助商能够利用自己的经验而不是来自其他制造商或供应商的经验时，此类信息可能更具信息价值，因为设备材料的制造和加工可能是未知的。在风险评估中，赞助商应具体说明如何利用 FDA 先前审查的设备来识别潜在风险和/或减轻已确定的风险。赞助商在引用 FDA 先前审查的设备时应尽可能具体，包括提交编号或主文件编号，并引用提交中的特定测试报告或数据（如果适用）。赞助商还应提供对比受评设备材料与 FDA 先前审查的设备材料的具体比较。使用附件 F 中提供的文档示例来进行此类比较可能是有帮助的。

Submission and Interpretation 提交与解释

FDA recommends that sponsors provide their risk assessment at the beginning of the biocompatibility section in a submission to CDRH or CBER. Based on the considerations outlined above, the sponsor should clearly summarize their conclusions regarding their risk assessment and explain the relationship between the identified biocompatibility risks and the information available to mitigate the identified risks, and identify any knowledge gaps that remain. The sponsor should then identify any biocompatibility testing or other evaluations that were conducted to mitigate any remaining risks.

FDA 建议赞助商在向 CDRH 或 CBER 提交时，在生物相容性部分的开始提供风险评估。根据上述考虑，赞助商应清楚总结他们对风险评估的结论，并解释已确定的生物相容性风险与可降低这些风险的信息之间的关系，并确定任何仍存在的知识缺口。然后，赞助商应说明已进行的任何生物相容性测试或其他评估，以降低任何剩余风险。

The sponsor should also explain any toxicities and adverse effects identified in their biocompatibility testing or other evaluations. As a part of the risk assessment, the sponsor should discuss any other available information (such as the results of in vivo animal studies) that might provide additional context for interpretation. For example, if a device made from polypropylene shows a grade 2 cytotoxicity with L929 cells, which might be acceptable per ISO 10993-5 “Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity,” the sponsor should provide additional information regarding the potential source of the toxicity, since polypropylene is generally not expected to elicit a cytotoxicity response of this level. Conversely, skin-contacting electrodes with adhesives containing detergents might be expected to have higher than grade 2 cytotoxicity with L929 cells, which could be acceptable if the sponsor is able to confirm that there are no other chemical constituents causing the adverse cytotoxic response. In general, potential toxicities identified through biocompatibility testing should be evaluated considering the intended use of the device and as part of the overall benefit-risk assessment.

赞助商还应解释他们在生物相容性测试或其他评估中发现的任何毒性和不良反应。作为风险评估的一部分，赞助商应讨论任何其他可用信息（例如体内动物研究的结果），以提供额外的解释背景。例如，如果聚丙烯制成的器械在 L929 细胞中表现出 2 级细胞毒性，可能符合 ISO 10993-5《医疗器械生物学评价-第 5 部分：体外细胞毒性试验》的要求，赞助商应提供有关毒性的潜在来源的额外信息，因为通常不会预期聚丙烯会引起这个水平的细胞毒性反应。相反，含有清洁剂的与皮肤接触的电极可能会在 L929 细胞中表现出高于 2 级的细胞毒性，如果赞助商能够确认没有其他化学成分引起不良的细胞毒性反应，这可能是可以接受的。总的来说，通过生物相容性测试确定的潜在毒性应在考虑设备的预期用途和整体利益风险评估的一部分进行评估。

During the biocompatibility evaluation, if chemical characterization testing is conducted per ISO 10993-18 " Biological evaluation of medical devices — Part 18 : Chemical characterization of materials" or ISO/TS 10993-19"Biological evaluation of medical devices — Part 19: Physico-chemical , morphological and topographical characterization of materials," it is important to understand that these standards include only general information regarding multiple analytical techniques and no acceptance criteria. Therefore, to support a declaration of conformity, as a part of the supplemental information used to support the use of these standards, we recommend that a rationale for the selected method(s) and protocols be presented with your results so that FDA can assess whether the information obtained will support the biocompatibility of your device.

在生物相容性评估期间，如果按照 ISO 10993-18《医疗器械生物学评价-第 18 部分：材料的化学特性评价》或 ISO/TS 10993-19《医疗器械生物学评价-第 19 部分：材料的物理化学、形态学和拓扑学特性评价》进行化学表征测试，重要的是要了解这些标准仅包含关于多种分析技术的一般信息，没有接受标准。因此，为了支持一份符合性声明，作为用于支持使用这些标准的补充信息的一部分，建议您在结果中提供选择方法和协议的理由，以便 FDA 评估所获得的信息是否支持您器械的生物相容性。

Attachment C provides an example biocompatibility risk assessment summary table, which FDA has generally found useful from a review perspective. Sponsors may find that utilizing this approach and format is helpful when developing their own biocompatibility risk assessment. FDA will review the risk assessment as part of the overall biocompatibility evaluation and determine whether the risks, mitigations, and biocompatibility testing or other information is appropriate to support the biocompatibility of the medical device. Sponsors may wish to discuss their plan for conducting an appropriate risk assessment with FDA early in their device development process. FDA recommends that sponsors use the Q-Submission process to facilitate these discussions.[5] While FDA generally cannot review a detailed risk assessment under the Q-Submission process, it is often helpful to discuss the planned approach for such a risk assessment. Pre-Submissions may be particularly helpful to obtain feedback regarding a risk assessment in the following and other instances:

附件 C 提供了一个生物相容性风险评估摘要表的示例，从评审角度来看，FDA 通常认为这是有用的。赞助商在开发自己的生物相容性风险评估时，可能会发现采用这种方法和格式是有帮助的。FDA 将作为整体生物相容性评估的一部分，审查风险评估，并确定风险、缓解措施和生物相容性测试或其他信息是否适合支持医疗器械的生物相容性。赞助商可能希望在设备开发过程的早期与 FDA 讨论进行适当的风险评估计划。FDA 建议赞助商使用 Q-提交流程促进这些讨论。[5:1]虽然 FDA 通常无法在 Q-提交流程中审查详细的风险评估，但讨论计划中的风险评估方法通常是有帮助的。在以下情况和其他情况下，预提交可能特别有助于获得有关风险评估的反馈：

  • When developing an in vitro test battery for hemocompatibility to determine whether the validation information being developed might be appropriate for a particular clinical indication;
    在开发用于血液相容性的体外测试组合以确定正在开发的验证信息是否适用于特定的临床适应症时；
  • When determining whether additional biocompatibility evaluations may be needed if questionable or inconclusive findings have occurred in any previously conducted biocompatibility evaluations, or in the event that novel materials are used;[6]
    在确定是否需要进行额外的生物相容性评估，如果先前进行的任何生物相容性评估中存在可疑或不确定的结果，或者使用了新型材料时；[6:1]
  • When designing in vivo or ex vivo studies intended to address biocompatibility endpoints;
    在设计旨在解决生物相容性终点的体内或体外研究时；
  • When designing chemical analysis protocols that use accelerating factors (e.g., heat) to simulate patient exposure to medical device materials over time;
    在设计化学分析方案时使用加速因素（例如热）来模拟患者长期接触医疗器械材料的情况；
  • When determining how to prepare absorbable devices for biocompatibility testing (e.g., unpolymerized, pre-polymerized, partially degraded, or fully degraded test articles).
    在确定如何准备可吸收器械进行生物相容性测试时（例如未聚合、预聚合、部分降解或完全降解的试验品）。

  1. Additional Information regarding master files for devices is available online at: https://www.fda.gov/medical-devices/premarket-approval-pma/master-files.
    关于设备的主文件的其他信息可在以下网址找到: https://www.fda.gov/medical-devices/premarket-approval-pma/master-files。 ↩︎

  2. FDA supports the principles of the “3Rs,” to reduce, refine, and replace animal use in testing when feasible. We encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable, adequate, qualified for use with medical devices, and feasible. We will consider if such an alternative method could be assessed for equivalency to an animal test method.
    FDA 支持“3R”原则，即在可行的情况下减少、改进和替代动物使用进行测试。如果赞助商希望使用一种非动物测试方法，并认为该方法适用、充分、适合用于医疗器械并可行，我们鼓励他们与我们咨询。我们将考虑是否可以对这种替代方法进行等效性评估，以替代动物试验方法。 ↩︎ ↩︎

  3. Refer to ICH M7 "Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk"available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/m7r1-assessment-and-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit-potential information on use of the TTC and structure activity relationship (SAR) modeling to address genotoxicity and carcinogenicity issues within a risk management process.
    请参阅 ICH M7《评估和控制药品中 DNA 活性（致突变）杂质以限制潜在致癌风险》（可在 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/m7r1-assessment-and-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit-potential 以了解有关使用 TTC 和结构活性关系（SAR）模型来处理遗传毒性和致癌性问题的信息，这是在风为了减少不必要的测试，包括动物测试 1，FDA 建议赞助商在进行风险评估时充分考虑所有可用的相关信息。 ↩︎ ↩︎

  4. FDA considers biocompatibility information, collectively with other nonclinical and preclinical information, in the review of Early Feasibility Study (EFS) IDE applications and through the review of devices granted Breakthrough designation and determines, through our benefit-risk analysis, what biocompatibility endpoints are necessary for evaluation prior to initiation of clinical studies as well as what evaluations may be appropriately conducted in parallel with clinical data collection. For more information, see “Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies: Guidance for Industry and Food and Drug Administration Staff” available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-device-exemptions-ides-early-feasibility-medical-device-clinical-studies-including and “Breakthrough Devices Program: Guidance for Industry and Food and Drug Administration Staff” available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/breakthrough-devices-program.
    FDA 将生物相容性信息与其他非临床和临床前信息综合考虑，在审查早期可行性研究（EFS）的 IDE 申请以及审查获得突破性认定的设备时，通过我们的利益与风险分析确定在临床研究开始之前需要评估的生物相容性终点，以及可以与临床数据收集同时进行适当评估的内容。更多信息，请参阅“用于早期可行性医疗器械临床研究的调查性装置豁免（IDEs），包括某些首次人体（FIH）研究：行业和食品药品管理局人员指南”，网址为 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-device-exemptions-ides-early-feasibility-medical-device-clinical-studies-including 和“突破性设备计划：行业和食品药品管理局人员指南”，网址为 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/breakthrough-devices-program 。 ↩︎

  5. Refer to FDA’s guidance document "Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program: Guidance for Industry and Food and Drug Administration Staffapos; available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program ↩︎ ↩︎

  6. Novel materials are not commonly used to manufacture medical devices. Novel materials are mentioned throughout this document to provide transparency regarding FDA’s current thinking and recommendations regarding biocompatibility evaluation of devices made from these materials. However, we recognize that these recommendations will not apply to the majority of device submissions.
    新型材料并不常用于制造医疗器械。本文件中提到新型材料，是为了透明地介绍 FDA 关于使用这些材料制造器械的生物相容性评估的当前思路和建议。然而，我们认识到这些建议不适用于大多数器械提交。 ↩︎ ↩︎