**************CONTINUATION OF FDA GUIDELINES*********
A. PHYSICAL TESTING REQUIREMENTS
All testing must be performed on the final sterilized product or, with proper justification, on subassemblies which have been sterilized using the same sterilization method as the final product. The protocol (including purpose, procedures and test setup), test results and study conclusions based on clinically-relevant performance specifications should be provided in order to independently evaluate the study conclusions.
1. STRENGTH TESTS - Determine the strength of all joints for the different loads which could be encountered during use (e.g., tensile and torsional, compressional and/or bending loads). In cases where the clinical use of the device will encounter a combined load, testing must also be carried out under these combined load conditions. Justification for the test specifications must be based on clinically-relevant requirements, including, for example, information obtained from published articles.
2. CATHETER TESTS - If the device uses a catheter design, determine the physical integrity of the device based on the tests outlined on pages 4-6 under the PTCA section.
3. BALLOON TESTS - If the device contains a component which can be inflated, then the balloon related testing outlined in the PTCA section of this guidance must be performed.
4. TORQUE TESTS - Determine the torque necessary to operate the device
within the coronary anatomy in accordance with the design constraints of the system; determine the maximum torque required for actual cutting of material; and determine the torque transmission and failure
characteristics of all rotating components.
5. FLOW RATE TEST - Determine the flow rate of contrast medium through, or around, the device to demonstrate that the flow rate is sufficient to achieve the desired effect (e.g., flow rate of contrast agent allows adequate fluoroscopic visualization).
6. FLEXIBILITY TESTS - Demonstrate that the device has sufficient flexibility to negotiate the coronary anatomy without compromising the functionality of the device. The likelihood of material fractures in a clinical setting should also be addressed.
7. SAFETY TESTS - Establish the operational parameters of the device and define the potential failure modes. Also address the consequences of such failures and the safety features built into the system to avoid or limit the adverse consequences of such failures.
8. LIFE TESTS - Demonstrate the dependability and longevity of the power source. Also, establish the fatigue life of the device in order to demonstrate the proper functioning of the device under fully loaded conditions over extended periods of time.
9. ELECTRICAL TESTS - Demonstrate the electrical safety of the device, in accordance with ANSI/AAMI ES1 "American National Standard, Safe Current Limits for Electromedical Apparatus" and applicable sections of UL 544, "Medical and Dental Equipment." In lieu of providing the actual test data, a statement certifying conformance with these standards and any other applicable standards must be provided.
B. ANIMAL STUDIES
The in vivo animal studies should be designed to closely approximate the intended use of the device in humans in order to demonstrate the safety ofthe procedure, to evaluate the functional characteristics of the device design and to validate the performance of the device as an atherectomy catheter. The studies must be conducted using models of spontaneous or diet-induced atherosclerosis and the selected treatment sites must have diameters similar to those of human coronary arteries. In order that an independent evaluation of the study conclusion can be made, submission of the following information is necessary: the test protocol (including objectives and procedures); the study results (including the investigator's comments); the study conclusions; and a complete identification of the lesion being treated (i.e., vessel size, percent stenosis, lesion location, number of lesions treated, type of lesions and other descriptive information that would assist in the evaluation of the procedure). Finally, all testing must be conducted using the final sterilized product and should be performed in accordance with the Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies regulation (21 CFR, Part 58). All deviations from the GLP regulation should be described fully, including a justification for accepting the results of these tests.
FDA recommends that the study consist of a minimum of six animals, three acute and three long term, in which the lesions have a > 40 percent luminal diameter narrowing pre-atherectomy. Where appropriate, more than one site per animal should be treated to maximize the information gained from the study. The swine should be considered when determining the appropriate animal model since it enables evaluation of the device's performance listed below and is supported by the published literature 1,10,16,19;
however,
FDA will consider other animal models if adequately justified. Any information gained from ex vivo studies may complement the information obtained in the in vivo studies, e.g., tests performed on isolated segments of atherosclerotic human arteries obtained at autopsy which could be used to demonstrate (a) the effectiveness of the device in increasing the arterial lumen, (b) the safety of the procedure by demonstrating the lack of damage to the vessel wall, and c the presence or absence of distal embolization.
1. SAFETY - Assess the safety of the procedure by analyzing the damage to the vessel wall, the complications resulting from device use both acutely and long term, and device malfunctions. All complications occurring during the procedure and postoperatively must be fully documented. Pathological and histological evaluations must be performed at 24 hours, 4 to 6 weeks and 6 months postprocedure. For the pathological studies, the segment of artery subjected to atherectomy along with the adjacent proximal and distal normal segments should be excised at the time of sacrifice and the gross photographs obtained from crosssections of the artery cut at three to four millimeter intervals. For histological examination, routine histology sectioning and staining should be obtained with the Hematoxylin and Eosin stains, and at least one elastic tissue stain must be performed on the sections. Histological studies should also include a morphometric analysis of the lesions, including detailed descriptions of changes in the vessel wall
(e.g., complications such as dissection, perforation, and irregularities causing flow disturbances resulting in thrombus formation).
2. FUNCTIONALITY - Evaluate the functional characteristics of the device as established in the in vitro bench testing. All device modification or corrective actions implemented as a result of these in vivo studies must also be discussed in detail.
3. PERFORMANCE - Evaluate the devices's performance in vivo consistent with the intended use (i.e., to remove atheromatous material from various target lesions). The performance evaluation should assess the following
areas of concern:
a. introduction into vasculature;
b. navigating tortuous segments;
c. reaching diseased sites;
d. visualization;
e. cutting and/or removal of atheromatous tissue;
f. effectiveness of the removal/retrieval mechanism;
g. removal of device from vasculature; and
h. compatibility with ancillary equipment.
IV. CARDIOVASCULAR LASERS
Cardiovascular lasers are transluminal catheter-type devices that use a laser energy source, such as excimer laser, to ablate atherosclerotic plaque from the coronary or peripheral arteries. These devices are post-amendment Class III devices which require the approval of PMA application prior to commercial marketing. In order to demonstrate that the proposed use of the laser is safe for clinical use, appropriate in vitro and in vivo studies must be conducted to ensure that the use of the laser at its selected operating parameters will not perforate the vessel or cause excessive tissue damage. Therefore, the choice of laser output parameters should be derived from consideration of how the laser is to be used:the mode of tissue interaction - cutting, vaporization or coagulation the absorption characteristics of the target tissue the thermal effects on tissuethe tissue healing characteristics Furthermore, the laser output parameters that characterize the laser must be completely described as follows:wavelengthpower density (MW/mm2)cross-sectional area temporal characteristics (continuous, pulsed) fiberoptic tip temperature medium for transmission (fiber contact, saline/contrast field, blood field) pulse duration energy density (mJ/mm2)pulse repetition rate
Statements made regarding the ability of the laser device to perform its intended function must be substantiated by appropriate data from bench and animal testing, including all theoretical considerations, laboratory tests, results of animal and cadaver studies. Additionally, data is needed to justify the laser wavelength and energy characteristics being proposed for clinical use. The data must show that the laser device can successfully be used as it is intended (e.g., in a dry/wet field, intraoperatively, percutaneously, with manual guidance, using a foot pedal, or a flushing mechanism for debris) and that the laser at its selected operating parameters will not perforate the vessel or cause excessive tissue damage for each type of tissue to be treated or encountered in the treatment procedure (i.e., thrombotic or fibrotic clot or calcified plaque). The following testing requirements must be fulfilled in order to justify the safe use of the laser in a clinical investigation:
1. Protocols for each prior study must be provided and must give a clear, concise description of the purpose of the study, how the protocol effectively addressed that purpose, and why the results support that purpose.
2. The data must include the animal species, site, type and size of lesion, diameter of blood vessel, method of approach to the lesion, fate of debris, and the conditions of the recanalized vessel in terms of initial state versus post-treatment state. In addition, the data must include the specific laser treatment parameters used such as diameter of laser beam or fiber tip, laser power, treatment procedures followed including exposure times, number of exposures and time between exposures, fiber tip temperature, the dosimetric procedures followed which validate these laser parameters, fiber position in relation to tissue and fiber contact with transmission medium(saline/blood).
3. Data from the work of others may be used if it can be shown that the target tissue, and other operative and output parameters of the laser device used in these studies, are equivalent to those in the proposed study. Careful correlations must be made by extracting the appropriate data from the studies. Simply providing summaries or copies of the publications from these studies is not sufficient.
4. It is helpful if the bibliography includes sufficient documentation to demonstrate the effective use of similar devices. Copies of the cited references must be provided, along with abstracts, personal communications and unpublished reports.
5. In vivo animal data must include sufficient follow-up to demonstrate the healing characteristics of the laser-treated vessel. The work of others may be used here if proper correlations are made.
6. If the laser device has the potential to produce toxic or mutagenic effects on tissue, it is then necessary to evaluate this risk versus the patient risk from atherosclerotic disease. Studies must be initiated to investigate the extent or lack of toxicity or mutagenicity for the wavelength(s) in question and the results of these studies should be submitted to the IDE application prior to FDA granting IDE approval.
7. The method of laser excitation frequency should be specified. Data must be presented to demonstrate that emissions from the laser will not cause interference, or other problems, with pacemakers, electronic circuits used in monitoring, or computer instrumentation. If the laser isradiofrequency(RF)-excited, information must be provided to show that the electromagnetic interference (EMI) from a laser device will not be sensed by a pacemaker's sensing circuitry and thus inhibit the pacemaker, leading to temporary cessation of pacing. FDA's concern in this instance is not one of EMI induced damage to the pacemaker itself, but one of possible adverse effect on a patient, or others exposed, due to pacemaker inhibition cause by the temporal pattern of the laser-burst cycles during the surgical procedure. Results of testing must be submitted with the laser held as close to the equipment as it is likely to be in the surgical suite. Comparisons must be made between the RF emissions from the laser device to those from other RF emitting medical devices commonly used in the surgical suite. The RF emission compliance with American National Standards Institute (ANSI) specifications must describe the means for ensuring that the E-fields reported are actually maximum; estimates of uncertainty and antenna-device distance for the various positions at which the RF data were obtained, must be provided.
8. If a direct viewing capability during lasing is possible, an analysis, data, and information to document that the surgeon will not be exposed to hazardous levels of laser energy must be provided as required by the
Federal Laser Standard (21 CFR Part 1040).
V. INTRAVASCULAR STENTS
Intravascular stents are implantable devices that are placed percutaneously
in stenoses of the peripheral and coronary arteries to maintain vessel patency. These devices are post-amendment Class III devices which require the approval of a PMA application prior to commercial marketing. Clinical data is required to support the determination of the stent's safety and effectiveness. Therefore, an IDE application as a significant risk device study is required to be approved by FDA and the reviewing IRB prior to initiation of a clinical trial. The following sections describe the in vitro and animal study requirements considered to be necessary to support the approval of an IDE application for a clinical investigation and in a subsequent PMA application.
A. IN VITRO TESTING
In vitro studies of intravascular stents includes both bench testing and non-human biologic testing. The data generated during this phase of testing should be conducted according to a consistent and established protocol. The results of these tests should be reported in a statistically meaningful format, i.e., specifications of the number of samples, range of values, mean, standard deviation and lower tolerance limits at a 95 percent probability. For any comparative test, a p-value (or similar measure) indicating statistical significance of the comparison should be provided. Test samples must have undergone sterilization by the process to be used for production purposes and, where appropriate, subjected to the recommended maximum number of re-sterilization cycles using the worst-case method and/or conditions specified. Consideration of worst-case, within tolerance conditions for geometries, blood pressure, etc. must be included.
1. Specification Conformance Testing: The following testing should be conducted on clean and processed material samples, i.e., metal wire:
a. Material analysis - Samples should be chemically analyzed and impurities quantified to ppm accuracy. In addition, scanning electron microscopy (SEM) testing should be performed to detect any evidence of surface contamination or impurities.
b. Mechanical properties - Samples should be measured for tensile strength and elongation. The minimum requirements of any applicable American Society for Testing and Materials (ASTM) specification should be met.
2. Stent Integrity - The following testing should be conducted on finished, sterilized stents after deployment with the proposed delivery system.
a. Stent free-area percentage and dimensional changes - The percentage change in free or open area and decrease in length as a function of stent diameter should be determined and a graphical representation of such submitted. The following testing should be conducted on finished, sterilized stents:
b. Stent uniformity testing - The uniformity of the expanded stent should be determined by quantitative documentation of any deviation from the labeled expanded diameter.
c. Response of the stent to external pressure - The change in stent diameter as a function of circumferential pressure should be determined. The pressure at which deformation is no longer completely reversible should be recorded.
d. Fatigue testing - An in-depth analysis of the stent's fatigue resistance is required to assure that the arterial/venous implant conditions which the stent will be subjected to will not result in fatigue and corrosion despite millions of cycles of stress. The following data is required:
(1) A finite element or other stress analysis that identifies the peak stresses in the stent when subjected to a worst-case physiological load. The amount of residual stress must be determined and accounted for when calculating safety factors. This analysis should demonstrate that fatigue failure of the stent will not occur during the implant life of the stent.
(2) Accelerated in vitro testing of approximately 10 years equivalent real time should be conducted on a statistically significant sample of stents plastically deformed to their largest intended diameter and dynamically cycled over simulated vessel conditions. A complete description of the test protocol and sample preparation used in this study should be provided.
e. Stent recoil - Quantify the amount of elastic recoil (spring-back) for each sized stent and correlate this parameter to the recommended placement (sizing) procedure.
f. Magnetic resonance imaging - Determine whether the stent will cause artifacts with magnetic resonance scans due to distortion of the magnetic field.
g. Stent expansion - Determine whether the plastic deformation experienced by the stent in going from its initial to final position could give rise to crack initiation. An examination of expanded stents, using the proposed delivery system, should be performed under an appropriate magnification. In addition, specify the smallest flow size (length, width and depth) that can be detected by your quality control inspectors on the surface of the stent.
h. Crossing Profile - Determine the crossing profile of the stent/delivery system and discuss its clinical acceptability.
i. Dimensional Verification - Measure and visually inspect the stent to document that all dimensional specifications do not deviate from the design specifications.
3. Stent/Catheter System Testing: Testing is needed to demonstrate that the delivery catheter can safely and reliably deliver the stent to the intended location and that the stent is not adversely affected by the catheter. Unless otherwise noted, all testing should be conducted on complete assemblies with stents mounted.
a. Balloon Burst Strength - Conduct this test on balloons/stents of each balloon and length. The test results must show statistically that, with 95% confidence, 99.9% of the balloons will not burst at or below the maximum recommended pressure, i.e., the pressure required to expand the stent to its labeled diameter.
b. Stent Diameter vs. Balloon Inflation Pressure - Conduct this test on balloons/stents of each diameter and plot/graph the stent diameter versus inflation pressure. This graph, or a tabular representation, should be provided in the Instructions for Use.
c. Bond Strength - Test the bond strength at locations where adhesives are used for bonding between parts of the catheter.
d. Diameter and Profile - Determine the diameter of the catheter shaft, profile of the balloons and inflated diameter of the balloons to ensure that the actual diameter matches the labeled diameters. Stent mounting is not required.
e. Balloon Deflatability - Show that the balloon can be completely deflated by the recommended procedure following stent expansion when it is in an environment simulating a stenosed vessel. Observe and describe any interference with balloon deflation.
f. Balloon Inflation and Deflation Time - Show that inflation and deflation of the balloons using the recommended procedure in the labeling can be accomplished within a specified time.
g. Catheter Body Maximum Pressure - Determine the maximum pressure that the catheter body can withstand when one of the lumens is used for power injection of contrast media.
h. Contrast Media Flow Rate - Determine the contrast media flow rate through the inner lumen at or below the maximum recommended injection pressure. Stent mounting is not required.
i. Pressure Waveform - Determine the natural frequency and damping ratio of the lumen recommended for pressure monitoring. Damping of the pressure waveform must be appropriate and provide accurate measurement; otherwise, the Instructions for Use must clearly state that the catheter is not intended for distal pressure monitoring. Stent mounting is not required.
j. Tip Pulling and Torquing - Show that the force required to break the joints and materials in the distal end of the catheter is sufficiently large to guarantee the integrity of the tip during pulling, pushing or torquing maneuvers.
k. Stent Crimping - If the stent is not provided pre-mounted on the delivery catheter, testing must be conducted to show the functionality of all crimping devices and that the crimping procedure will not damage the stent or catheter.
****It took a few days for me to understand all requirements . I magine implementing would be a formidable task.
Regards,
Sri.... ******TO BE CONTINUED TOMORROW***** |
