Report of Prior Investigation: In Vitro Testing

1. Report of Prior Investigation:In Vitro Testing Tina Morrison, PhD Mechanical Engineer / Scientific Reviewer Division of Cardiovascular Devices Food and Drug Administration

2. Goals of Device Testing • Minimize potential for clinical failures • Characterize the device performance • i.e., safety

3. Safety • Prior to study initiation, adequate information must be provided to assure a reasonable level of safety for use of a specific device(s) in a specific patient population(s) • In ODE, we rely heavily on bench-top testing to demonstrate safety before the initiation of the clinical study. • Studies must be adequately defined, conducted and monitored to optimize patient safety Where does it begin?

4. Device Description • 1st section of an IDE application • after the obligatory cover letter and sponsor information • Should contain: • physical description of the device, including all components and accessories • definitions of the conditions of use of the device • description of how the device is expected to work

5. Device Description • At a minimum, the following information should be provided: • Physical Description • what it looks like • Intended Use • what it is supposed to do, under what conditions/environment, for what patient population • Indicated Use • what the labeled use will be • Primary and Secondary Functions • how it does what it is intended to do • Potential Life of the Device • how long it should be able to do what it is intended to do

6. Identify Conditions of Use • Level of invasiveness (e.g., skin contacting, short-term blood contacting, short- or long-term implant) • Determines the amount of biocompatibility testing • Forces imposed on the device under use (e.g., corrosive, pulsatile, bending, torquing) • Determines the type of bench-testing necessary to demonstrate safety • Establish or optimize device design • Identify appropriate testing and test parameters • Based on risk profile and FDA requirements

7. Risk Analysis • Determine the potential failure risks of the procedure and device and rank based on severity • E.g., misdeployment of device, delivery system malfunction, etc. • If any of the potential failures were to occur, describe the effect it would have on the patient • E.g., secondary intervention, infection, etc. • Describe how the test plan you developed addresses the potential failures and demonstrates safety of the device • The test plan is presented in the form of test reports

8. Test Reports • The test report should provide adequate information • to describe and justify the testing methodology • to demonstrate the acceptability of the results obtained to justify the clinical investigation • When possible, tables should be used to aid in the clear presentation of data • Should be based upon a prospectively defined test protocol • The test methodologies should be developed based upon the intended use of the device and the anticipated safety and effectiveness issues.

9. Test Reports • The test report for the pre-clinical in vitro testing should include an executive summary of all testing • The summary should include • identification of tests • with the rationale for the omission of any tests identified in standards or guidance documents • or the selection of alternative tests • summary of results • with prospectively defined acceptance criteria • any potential clinical significance of the results • justification and clinical applicability of acceptance criteria for each test • TOC and pagination

10. Some ISO Documents • ISO 25539 - Cardiovascular Implants • Part 1: Endovascular Grafts • Part 2: Vascular Stents • Part 3: Vena Cava Filters • ISO 5840: 2005 - Surgically implanted Heart Valves • ISO-10555 – Catheters • FDA has published many Guidance Documents • Most recent for DCD: • Guidance for Industry and FDA Staff - Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems

11. Individual in vitro test reports • purpose: state the purpose of the test • materials: list all materials used in performing the test • (e.g. test articles with lot/serial numbers or other appropriate means of traceability, equipment) • use figures and diagrams as appropriate • sampling: state the sampling plan • including the basis for and the number of samples tested • selection of test article(s) should be justified • (e.g. sizes, conditioning)

12. Individual in vitro test reports • acceptance criteria: state the acceptance criteria for the test results • Include adequate scientific justification • test method: describe in detail the method used to perform the test • include any prospectively defined inspection procedures • provide a justification for critical test parameters • E.g., loading magnitudes, cycle numbers, etc. • protocol deviations: describe any deviations and their potential significance on the interpretation of the results

13. Individual in vitro test reports • expression of results: describe testing results expressed in units as indicated in the test method • conclusion: state conclusions • based on comparing results to acceptance criteria • include any potential clinical significance of these results • describe any limitations of the test that should be considered when interpreting the results

14. Caveat • Please note that the level of detail needed is dependant on the novelty of the device/procedure/patient population under study • Additionally, the information we presented in not required. However, the review process may be smoother for both parties if the information is presented in the recommended format

15. Sample Deficiencies • In the Background section of the Report of Prior Investigations, you stated that during flexing of the knee, the SFA/Popliteal arteries can bend, rotate, elongate, and compress dramatically. However, you did not provide the adequate information to demonstrate the in vivo environment of the SFA/Popliteal arteries. Please provide an adequate detailed description of the in vivo environment (ranges and magnitudes of deformation) of the vessels you intend to treat with your device so that we may better assess whether your device will perform in such conditions. You may also provide us with a review of the literature that can support your description of the in vivo environment.

16. Sample Deficiencies • In section 4 Material Characterization, you briefly described some of the material properties of the device implant. In addition to those characteristics, it is important for us to know each step along the manufacturing processes of the device implant from raw material to finished product. Please provide a detailed description of the manufacturing process of the device implant from the raw material to a finished product. Furthermore, please provide material properties of the finalized device.

17. Sample Deficiencies • In the Laboratory Section of your IDE application, you stated that your team referenced the FDA guidance document titled “Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems” dated January 13, 2005 in determination of applicable testing requirements, test planning, execution and reporting. The guidance document recommends that certain tests be completed to assess the performance of the device implant and its delivery system. If there were tests listed that you did not complete, please provide scientific rationale for why those tests were not completed. Alternately, please conduct all tests for self-expanding stents and delivery systems that are listed in the guidance document so that we may adequately assess the performance of your device.

18. Sample Deficiencies • The information provided in your submission to support the initiation of your study, that is, the Report of Prior Investigations (RPI), was not provided in a useful format. For the bench testing sections of the implant and the delivery system of your RPI, please modify them to provide detailed information regarding each test, and include a summary table describing the testing completed on your device. A sample format is provided below:

19. More questions? tina.morrison@fda.hhs.gov