This guidance document is being distributed for comment purposes only.
Document issued on: August 30, 2013
You should submit comments and suggestions regarding this draft document within 30 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov. Identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this document, contact Lisa Lim (Chief of the Peripheral Interventional Devices Branch) at (301) 796-6443 or Melissa Torres (Chief of the Interventional Cardiology Devices Branch) at (301) 796-5576.
When final, this document will update and augment (but not replace) Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems guidance, issued April 18, 2010.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Office of Device Evaluation
Division of Cardiovascular Devices
Office of Science and Engineering Laboratories
Contains Nonbinding Recommendations
Draft - Not for Implementation
Additional copies are available from the Internet. You may also send an e-mail request to CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document number 1826 to identify the guidance you are requesting.
Select Updates for Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems - Draft Guidance for Industry and Food and Drug Administration Staff
This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
I. Introduction and Scope
FDA has developed this guidance to inform the coronary and peripheral stent industry about selected updates to FDA’s thinking regarding certain non-clinical testing for these devices. While FDA is in the process of making more substantial updates to the Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems guidance, we are issuing this “short guidance update” on select sections in order to notify the industry in a timely manner of our revised recommendations.
Section III of this guidance provides cross-reference and updates to the related sections of the existing Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems guidance. Following the close of the comment period on this guidance, FDA intends to consider the comments received, revise this guidance as appropriate and publish it in final. Simultaneously, FDA will issue an update to the existing guidance to cross-reference where this selected updates guidance supersedes the existing recommendations. Subsequently, FDA will incorporate the elements of this final guidance into an anticipated revision of the entire Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems guidance.
This guidance provides updates only for the following topics:
- Pitting corrosion potential;
- Galvanic corrosion;
- Surface characterization; and
- Nickel ion release.
This guidance document addresses self-expanding and balloon expandable extracranial intravascular stents and their associated delivery systems. The scope includes extracranial intravascular stents placed in coronary or peripheral arteries and saphenous vein grafts but is not limited to stents used in these locations; other vascular indications outside of the intracranial vasculature are also included.
Intravascular stents, including balloon expandable and self-expanding stents, are class III devices whose product codes are given in the table below.
Table 1: Product Codes for Stents Addressed in this Guidance
|NIP||Stent, Superficial Femoral Artery|
These devices require a premarket approval (PMA) application before marketing. See sections 513(a) and 515 of the Federal Food, Drug, and Cosmetic Act and 21 CFR Part 814.
II. Background and Rationale
FDA held a public workshop entitled “Cardiovascular Metallic Implants: Corrosion, Surface Characterization, and Nickel Leaching” on March 8-9, 2012 that provided information on current practices for performing these tests. A pre-workshop assignment on test practices and outcomes completed by participants from industry, test houses, and academia served as a basis for moderated discussions at this workshop. Regarding corrosion testing, the general consensus was that no single corrosion assessment can be used to assess in vivo corrosion susceptibility. However, nearly all respondents indicated that they performed pitting corrosion testing, and more than half of the respondents indicated that they performed galvanic corrosion testing. Therefore, in the current guidance, we have updated a key aspect of sample conditioning for pitting corrosion testing that is less burdensome, and included additional information on when galvanic corrosion testing may be omitted with justification, based on information gained from the workshop.
Corrosion of implant devices made of nitinol and other nickel-containing metal alloys (e.g., stainless steel, MP35N) results in the release of nickel ions, which may lead to various modes of toxicities. However, there are no suitable standard test methods for measuring metal ion release from intravascular stents. Therefore, based on currently available scientific evidence and industry practices discussed at the workshop, we have included information on test methods for in vitro nickel ion release testing. Furthermore, both nickel ion release and corrosion characteristics are dependent on surface finishing for nitinol and for some other nickel-containing alloys. While there is insufficient information to quantitatively correlate surface oxide characteristics to device performance characteristics at this time, workshop participants indicated that surface characterization may be most useful as a tool to assess the root cause of poor device performance characteristics (e.g., corrosion susceptibility or nickel ion release). We have therefore modified the recommendations for when surface characterization should be performed to consider outcomes from other characterization testing and surface finishing techniques used.
Based on the information obtained from this workshop, FDA was able to refine existing recommendations on when certain tests should be performed or considered, such that industry can avoid performing tests that would add little valid scientific evidence regarding the safety and effectiveness of the device. In addition, information on test methods for pitting and galvanic corrosion, as well as nickel ion release, has been updated, which we believe will aid in test protocol development. While pitting corrosion potential, surface characterization, and in vitro nickel ion release testing are described in different sections of the Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems guidance, taken together, the results of these tests are interrelated and provide a global perspective on the corrosion and ion leach potential of the stent. We recommend that you initially assess the pitting corrosion potential of your stent. If results are inconclusive or an established surface finishing process is not used, we recommend that you perform surface characterization. If the corrosion resistance and surface characterization results are inconclusive for your device, we recommend that you also quantify nickel ion release from your device. Then, a risk assessment should be performed, basing estimated exposure on in vitro nickel ion release testing, to determine the potential safety risks associated with nickel released from the device. If available, data obtained from other assessments, such as animal or clinical studies, may supplement your analysis of the corrosion and ion leach potential of your device, and should be considered as part of your risk assessment for these potential failure modes.
III. Select Updates
A. Material Characterization
1. Pitting Corrosion Potential
The following recommendations update Section IV.A.3 of the Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems guidance regarding Pitting Corrosion Potential.
We recommend that you characterize the corrosion potential of your as-manufactured stent according to the method described in ASTM F21291 or equivalent method. The test setup should meet the criteria outlined in ASTM G52 (figure 2, Table x2.1). Testing should be performed after subjecting the device to simulated use testing, which includes tracking and deployment of the device through an in vitro fixture that mimics in vivo anatomic conditions (See section B2. Delivery, Deployment, and Retraction in the Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems guidance). This device conditioning is intended to simulate the clinical conditions of the stent at the time of implantation. You should test device sizes that are the worst-case in terms of corrosion susceptibility based on surface area, size, and/or geometry. Considerations should be given to factors such as geometry or size that may affect surface finishing such as adequate polishing of regions of high curvature. Test devices should be representative of final sterilized devices and selected such that potential variations due to manufacturing can be assessed (i.e. by taking samples from multiple (≥3) lots), with a justification for the number of samples tested. Additional samples may be needed if there is wide variability in the test results.
In addition to testing as-manufactured samples, if there is damage, such as but not limited to fractures or significant wear of your device during accelerated durability testing, additional testing of fatigued samples to evaluate the impact of resulting cracks or scratches on pitting and crevice corrosion potential should be considered. If corrosion testing is performed on post-fatigue samples (in addition to the as-manufactured testing described above), we recommend testing the same samples used in the fretting corrosion evaluation described in the Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems guidance according to the methods described in ASTM F2129 or equivalent method. Specifically, one stent from each overlapping pair subjected to fatigue cycling should be evaluated for pitting corrosion potential while the other stent from each pair is evaluated for fretting corrosion.
Test reports for pitting corrosion potential testing should be consistent with ASTM F2129. For example, test reports should include corrosion/rest potentials, breakdown potentials, as well as polarization curves. We recommend that you plot all polarization curves in one graph when practical. You should report whether your test setup met the criteria outlined in ASTM G5. Results should be assessed against your acceptance criteria. You should include images from visual inspection of your device before and after testing to assess evidence of pitting. Images of pitting should be of sufficient magnification to resolve the features of the pits. You should also include a discussion of your visual inspection, such as number and spatial distribution of pits.
The materials, design, and fabrication processes specific to your stent may reduce or eliminate the applicability of generic literature or previous experience with stents that may be used to address pitting susceptibility in lieu of testing. For example, the pitting corrosion resistance of nitinol is sensitive to processing variables such as heat treatment and surface finish; therefore, for a nitinol stent, generic literature is not applicable and you should characterize the corrosion potential of the finished stent.
2. Galvanic Corrosion
The following recommendations update Section IV.A.3 of the Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systemsguidance regarding Galvanic Corrosion.
We continue to recommend the Galvanic Corrosion testing recommendations as outlined in Section IV.A.3 of the Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systemsguidance. However, a justification may be provided, in lieu of testing, if the expected worst-case galvanic coupling potentials are small and if the relative surface ratios of the cathodic to anodic materials are low (e.g., marker band to stent surface ratio).
B. Material Composition
1. Surface Characterization
The following recommendations update Section IV.A.1 of the Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems guidance to clarify when Surface Characterization should be considered.
Surface finish is known to affect other material properties such as corrosion and metal ion release for certain alloys (e.g. nitinol, MP35N, stainless steel). Therefore, if results from other characterization testing (e.g., pitting corrosion) are inconclusive, we recommend that you characterize the material surface of your finished product in terms of passivation layer chemical composition vs. depth. In addition, if you do not use a commonly used surface finishing process (e.g., electropolishing), we recommend that you perform surface characterization of your device. Special attention should be paid to surfaces and geometries that may be affected by heat or finishing processes. Surface characterization should be performed on multiple devices from multiple lots (³ 3). This characterization should include multiple assessments at various representative areas on the device surface including the locations that may be most difficult to polish.
1. Nickel ion release
The following recommendations update Section IV.E of the Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems guidance regarding Nickel Ion Release.
For devices containing nickel, we recommend that you consider the potential for nickel ion release from your device. Specifically, if the corrosion resistance and passivation layer characterization results are inconclusive for your device, we recommend that you quantify nickel ion release from your device over time by measuring concentrations of nickel leached from the device into a fluid at physiologic temperature and pH. To avoid excursions in pH and the need for assessment of pH during sampling, we recommend using a buffered solution, such as phosphate buffered saline (PBS). We recommend testing be conducted for at least 60 days. Solution sampling should be conducted at adequate intervals and for sufficient duration to adequately characterize the nickel release profile of the device in vitro. You should use a sampling regimen that will adequately capture an initial bolus release of nickel. For example, sampling may be performed daily for the first seven days with weekly assessments thereafter.
Testing should be performed on as-manufactured devices after subjecting the device to simulated use testing, which includes tracking and deployment of the device through an in vitro fixture that mimics in vivo anatomic conditions (See section B2. Delivery, Deployment, and Retraction in the Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems guidance). Test devices should be representative of final sterilized devices and selected such that potential variations due to manufacturing can be assessed (i.e., by taking samples from multiple (≥3) lots), with a justification for the number of samples tested. Additional samples may be needed if there is wide variability in the test results. The devices should be selected such that they represent the worst-case for nickel leaching (e.g., largest surface area).
Validation testing should be performed and included in the test report. This validation testing should include validation of the analytical instrumentation as well as an extended (>14 days) spike and recovery test to demonstrate that nickel is not lost out of solution, (e.g., due to adsorption onto the extraction container). The extraction ratio, or the ratio of the surface area of the tested device to the volume of test solution, should be provided along with a rationale for why the ratio was selected. Both the detection limit of the analytical instrumentation and driving force for nickel leaching should be considered in your rationale. Detection limit and driving force for leaching should also be considered when deciding to perform aliquot sampling versus replacing the entire test solution at each time point sampled as well as in your choice of using a different device for each time point or reusing the same device across multiple time points.
Test results should be reported as total cumulative release per device in micrograms, as well as a per day release (µg/day). In addition, if release rates are compared between devices or samples with different geometries, results should also be normalized by device surface area.
2. Risk Assessment
If in vitro nickel leach testing is performed, a risk assessment should also be performed to determine the potential safety risks associated with nickel released from the device. The results of in vitro nickel leach testing should be used as the basis for the exposure estimate. If any in vivo nickel exposure data exists for your device, these values should be included in your risk assessment as well. The risk assessment should consider route of exposure. While much of the literature on nickel toxicity is from studies with oral or inhalation as routes of exposure, and not intravascular exposure, it is known that chemicals that are toxic via one route of exposure may also be toxic via a different route of exposure. Standard route-to-route extrapolation methods should be used to address toxicity from different routes of exposure in the absence of data from the relevant route of exposure. The duration of exposure should be considered as well. In addition to acute and chronic non-cancer endpoints, if your device releases nickel in a chronic fashion (≥30 days) based on in vitro testing, carcinogenicity (including genotoxicity) and reproductive toxicity should be considered. In addition to systemic toxicity, local effects of nickel accumulation should also be discussed as part of your assessment of the device. References used in the risk assessment, as well as a description of how the values used in the risk assessment calculations were derived, should be included in your risk assessment report.