The Food and Drug Administration (FDA) has published guidance dedicated to non-clinical engineering tests and recommended labeling for intravascular stents and associated delivery systems. The document provides additional recommendations to be considered by the medical device manufacturers and other parties involved. It is important to mention that the present guidance itself does not introduce any additional obligations the industry representatives shall follow. Moreover, the Agency also states that an alternative approach could be applied, providing that such an approach is compliant with the current legislation and has been agreed with the authority in advance.
Regulatory Background
The scope of the present guidance covers the intravascular stents intended to be placed on the market under the investigational device exemption application (IDE) or premarket approval application (PMA) frameworks. In particular, the document describes the approach to be applied with regard to non-clinical engineering tests, as well as labeling requirements.
The FDA provides the definition of an intravascular stent. According to the guidance, an intravascular stent constitutes a synthetic tubular structure intended to be implanted in native or graft vasculature in order to provide mechanical radial support after deployment. The intravascular stents covered by the scope of the guidance should be expanded either by a balloon or by the virtue of a self-expanding mechanism.
Thus, the scope of the present FDA guidance on intravascular stents covers the following products:
- Balloon expandable stent. The stent of this type is being expanded due to the expansion of a balloon it contains. Then the device remains expanded.
- Self-expanding stent. The stent of this type expands due to the specific properties of the materials the device is made from, or its geometry.
- Stent delivery system – a special mechanism intended to deliver a stent to a target site and deploy it there. In the case of a balloon-expandable stent, the system contains both stent itself, and also a balloon used to expand it once place on a target site.
The Agency also mentions that the scope of the guidance covers all intravascular stents irrespectively of the intended application site. According to the US risk-based classification, intravascular stents are class III medical devices. Under the general rule, a premarket approval (PMA) application should be submitted before placing such devices on the market. The FDA additionally emphasizes that due to the high risks associated with intravascular stents, the requirement to submit an investigational device exemption (IDE) application could not be waived. Consequently, a party interested in clinical trials (a sponsor), shall not commence a trial before obtaining the necessary approval from the regulating authority. In particular, a sponsor should sustain compliance with the following:
- IDE regulations (21 CFR 812),
- Regulations governing institutional review boards (IRB) (21 CFR 56),
- Informed consent (21 CFR 50).
Upon approval, the clinical studies should be carried out strictly in accordance with the indications set forth in the premarket approval application.
At the same time, the scope of the present FDA guidance does not cover non-vascular stents, as well as the stents used in the intracranial vasculature. The regulating authority also recommends considering the document in connection with its other guidelines, including the ones dedicated to PMA and IDE applications.
The document also contains references to the FDA voluntary consensus standards – the standards recognized by the regulating authority to be used by the medical device manufacturers to demonstrate conformity with the applicable requirements.
Content and Format of Test Data
According to the document, test data should be presented in a summary. Such a summary should contain the following elements:
- Table of contents.
- Test summaries.
- Test data summaries (including minimum and maximum measured values, means, and standard deviation).
- Summary of conclusions.
In addition, it is important to provide full test reports covering any and all tests conducted. Such reports should cover such aspects as:
- Test specimen information (e.g. number of test specimens, their size, the rationale for the number and sizes, etc.).
- Test protocol containing the information sufficient to interpret the test results.
- Protocol deviations, and also the assessment of their impact on the safety and effectiveness of a medical device.
- Test parameters and acceptance criteria (including the rationale for clinical test parameters).
- Raw data.
- Test results.
- Data analysis.
- Conclusions.
In addition to the points listed hereabove, the FDA also emphasizes the importance of the provision of test protocols for all experiments conducted. These protocols should contain information about the acceptance criteria applied. This information will be used to ensure the accuracy of the comparison of data collected in the course of several tests. The Agency also mentions that despite it does not approve the protocol, it is recommended to provide them for review since in response the FDA would provide its feedback and comments to be considered.
With regard to the protocols, the FDA states: the test protocols should assess device performance when exposed to the most extreme clinical conditions that your device is likely to experience. … We recommend that you evaluate extreme device dimensions, tolerances, sizes, and any other important device parameters in your testing program. We also recommend that you examine the outer limits of physiologic variables such as blood pressure, vascular compliance, and anatomic types. You should clearly state all test conditions in the test protocol and support them with references to applicable literature, standards, or both.
According to the recommendations provided in the present FDA guidance, in case if some of the tests are not applicable for the particular intravascular stent in question, the names of such tests should still be indicated in the test summary together with the explanation of why they should not be applied. Later such an explanation would be reviewed by the FDA. Moreover, it is also necessary to explain and justify that the absence of such testing would not result in a lack of information with regard to the safety and effectiveness of a product subject to review.
The FDA also mentions that in case if an intravascular stent subject to review actually constitutes a modification of similar stents already placed on the market, it would be sufficient to provide test data related to the previous version of the device, providing that the changes made are not significant and are not changing dramatically the effectiveness of a medical device, as well as the risks associated thereto.
Intravascular Stents: Sample Selection
The FDA guidance on intravascular stents provides the details on the sample selection process to be applied. According to the document, a statistically significant sample size should be used whenever possible. In case if it is impossible, the appropriate rationale should be provided.
The regulating authority additionally emphasizes that all test samples should constitute the finished products. Should these requirements not be met, the appropriate justification should be provided.
Summarizing the information provided here above, the present FDA guidance describes the most important aspects related to the intravascular stents their non-engineering testing. The document provides additional recommendations to be considered by the parties involved in order to ensure compliance with the applicable regulatory requirements.
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