I guess we should thank Steve Rash and other folks also for an outstanding Job they have done in continuing to promote the company and its products. My post is split in to two. See for yourselves how difficult it is to build a case for FDA approval. These folks painstakingly have made a lot of effort to do a lot of work with no guarantee of future sales success. ABMI is getting closer to being a mature company.
**************FDA APPROVAL PROCESS GUIDELINES****************
The development of a guidance document for interventional cardiology
devices, including percutaneous transluminal coronary angioplasty (PTCA) balloon catheters, atherectomy catheters, lasers and intravascular stents, is based on the Division of Cardiovascular, Respiratory and Neurology Devices' (DCRND) evaluation of numerous device applications, and the establishment of certain criteria necessary to conduct such evaluations.
Suggestions and recommendations contained in this guidance are not
mandatory requirements, but are nonetheless considered appropriate
requirements to generate valid scientific evidence. In order to phase-in the recommendations, any future investigational device exemptions (IDE) application submitted to FDA must address the recommendations put forth in this guidance as of the date of this guidance document indicted on the cover page,. Any ongoing IDE studies or PMA currently under review will be accountable for the any requirements approved in the IDE application.
Since some clinical studies take many years to complete and be submitted in a PMA application, sponsors should be aware that changes in the clinical trials may be warranted after a clinical trial has been approved to beginif wararnted by the practice of medicine or is generally excepted by the research community. For example, early atherectomy studies were initaited without CPK and CPK-MB isozymes being collected from all patients pre- and postprocedure. Sponsors of the these studies were asked to supply thisinformation, however, upon review of the PMA application as this information is considered an important indicator for monitoring effects of distal emboli generated by the atherectomy procedure. FDA will provide comments and recommendations to the sponsors in the review of IDE applications in order to best facilitate design of a clinical trial that will appropriate for submission of a PMA application.
Furthermore, this is a dynamic document which will be reviewed periodically by the Interventional Cardiology Devices Branch (ICDB), DCRND, by panel members (minimum of 2-year intervals) and industry as devices materials, designs and indications for use change and technology improves. Although assistance in the preparation of this guidance document had been sought from staff members of the ICDB, members of the Circulatory Systems Devices Panel, the National Heart, Lung and Blood Institute (NHLBI), clinical researchers and representative industry, the discussions and recommendation
made during the June 7-8, 1993 Panel Workshop and subsequent comments
submitted from the industry and the research community have been prepared with a great deal of thought and applicability to the determination of a device's safety and effectiveness. This cooperation is truely worthwhile and remarkable since all parties will benefit as the requirements for demonstrating a device's safety and effecitveness are more clearly defined.
All comments have been considered and, where appropriate, incorporated into the guidance document. Any comments that were not considered appropriate will be addressed in specific sections of the guidance. Finally, the ICDB staff want to ackowledge the firms and clinical researchers who have submitted comments on the guidance document.
Advanced Cardiovascular Systems, Inc.
AngeLase, Inc.
Ann Steenkiste, MS, NACI Registry
Devices for Vascular Intervention, Inc.
Eric Topol, MD, Cleveland Clinic Foundation
Heart Technologies, Inc.
Health Industry Manufacturers Association
InterVentional Technologies, Inc.
Johnson & Johnson Interventional Systems, Co.
Katherine Detre, MD, DrPH, University of Pittsburgh
Leocor, Inc.
TABLE OF CONTENTS
NONCLINICAL STUDIES REQUIREMENTS
I. Biocompatibility Testing for All Interventional Cardiology Devices
II. PTCA Balloon Catheter .....................
Physical Testing
Animal Studies
III. Atherectomy Catheters
Physical Testing
Animal Studies
IV. Cardiovascular Lasers: Overall Requirements
V. Intravascular Stents In Vitro Testing
Animals Studies
CLINICAL STUDY REQUIREMENTS
I. Features of Clinical Studies
II. Specific IDE Requirements
III. PMA Application Requirements Specific PMA Requirements
Specific Designs and Device Modifications
ATTACHMENTS
A. Minimum Balloon Burst Strength Testing
B. Original IDE Review Form
C. Definitions for Lesion Characteristics and Data Analysis
D. Format for Report Forms
E. Format for Presenting Study Results
F. Statistical Review Check List for PMA Applications
G. Bibliography
NONCLINICAL STUDIES REQUIREMENTS
Most interventional cardiology devices, including the PTCA balloon
catheter, coronary atherectomy devices, lasers and intravascular stents,are post-amendment class III devices (post-amendment refers to marketing after the enactment of the Medical Device Amendments to the Federal Food, Drug and Cosmetic Act on May 28, 1976). As such, they require approval of a premarket approval (PMA) application, prior to commercial distribution or marketing. Additionally, clinical data is required to support the determination of safety and effectiveness. Thus, an investigational device exemptions (IDE) application as a significant risk device study is required to be approved by FDA and the reviewing institutional review board (IRB) prior to initiation of a clinical trial. This document describes the general framework to be followed in testing interventional cardiology devices and outlines the type of data that is considered necessary and appropriate for submission in an IDE application and in a subsequent PMA application. This document specifically addresses the requirements for material biocompatibility and toxicity, in vitro physical testing, animal
studies and clinical trials, as well as the content and format of the IDE and PMA.
I. BIOCOMPATIBILITY TESTING FOR ALL INTERVENTIONAL CARDIOLOGY DEVICES
The overall safety evaluation of the investigational device begins with an assessment of its biocompatibility. Biocompatibility evaluation depends,in part, on the full characterization of all device materials after sterilization. It is important to identify leachables, by-products, and metabolites using appropriate extraction methods for preparing the sample.
Furthermore, all protocols, test results and the identification of control materials should be provided in order that an independent evaluation of the study conclusions can be made. Protocols do not need to be submitted if standard methods are utilized (e.g., USP methods) and complete references for the methods are provided.
Biocompatibility testing may not be necessary if a material is used in
currently marketed interventional cardiology devices. To ensure identity,however, the material specifications from the manufacturer must be provided. A sponsor may submit information and data available in publications or other legitimate sources which show that the material is non-toxic in tests identical or equivalent to the biological tests for Short Term, Direct Blood Path, Externally Communicating Devices, described in the Tripartite Biocompatibility Guidance for Medical Devices.* While the Tripartite guidance document is comprehensive for testing of polymers, not all these tests are considered necessary for interventional cardiology devices.
ú This guidance document can be obtained from CDRH's Division of Small Manufacturers Assistance by calling (800) 638-2041 or (301) 443-6597.
For PTCA catheters, laser and atherectomy devices, only the first 7 of the 9 tests listed below are considered necessary for the interventional cardiology devices which are not implanted. Furthermore, since intravascular stents are implanted devices, the biocompatibility testing for these devices must also include mutagenicity and carcinogenicity testing.
All new materials must pass these tests to assure their safe use in an
interventional cardiology device. All materials (e.g., polymers, metals,radiopaque material, adhesives, color additives and other leachable (additives) in each component of the device must be non-toxic to human tissues. Color additive petitions are generally not necessary for color additives used in interventional cardiology devices since colors used in these devices are not in contact with the body for a significant period of time. Thus, the routine biocompatibility testing of the color is sufficient to assess its potential toxicity.
The effects of sterilization on device materials and potential leachables,as well as toxic by-products resulting from sterilization, should be considered when conducting biocompatibility tests. Therefore, testing should be performed on the sterilized final product or representative samples. Specific chemical analyses of the sterilized final product and any leachable material from the sterilized final product should be performed before initiating toxicity testing. Furthermore, the tests and analyses for leachable materials must be conducted by choosing appropriate solvent systems which will yield a proper extraction of the leachables.
The following toxicity tests for interventional cardiology devices are considered the necessary and appropriate tests for its use and mode of contact with the body. A manufacturer, however, may substitute or omit tests with adequate justification.
1. Acute Systemic Toxicity - To estimate the harmful effects of either single or multiple exposures to test materials and/or extracts, in an animal model, during a period of less than 24 hours. (Ref. USP Systemic Injection Test)
2. Irritation Tests - To estimate the irritation and sensitization potential of test materials and their extracts, using appropriate site or implant tissue such as skin and mucous membrane in an animal model
and/or human. (Ref. USP Intracutaneous Test)
3. Implantation Tests - To evaluate the local toxic effects on living tissue, at both the gross level and microscopic level, to a sample material that is surgically implanted into appropriate animal implant
site or tissue, e.g., muscle; for 7 - 90 days. (Ref. USP Implantation
Test)
4. Sensitization Assay - To estimate the potential for sensitization of a test material and/or the extracts of a material using an animal and/or human (Ref. Guinea Pig Maximization Test or human patch test).
5. Cytotoxicity - To determine the lysis of cells (cell death), the inhibition of cell growth, and other toxic effects on cells caused by
materials and extracts from the materials using cell culture techniques (Ref. MEM Elution or Agarose Overlay).
6. Hemocompatibility or Hemolysis - To evaluate the effects of blood contacting materials on hemolysis (i.e., the degree of red cell lysis and the separation of hemoglobin caused by test materials and/or in vitro extracts), thrombosis, plasma proteins, enzymes, and the formed elements of the blood using an animal model, with particular attention
to the acceleration of the processes of intravascular thromboses.
7. Pyrogenicity - To evaluate the material mediated pyrogenicity of the test materials and/or extracts (Ref. USP Rabbit Pyrogenicity Test or Limulus Amebocyte Lysate (LAL)).
8. Mutagenicity or Genotoxicity - To determine gene mutations, changes in chromosome structure and number, and other DNA or gene toxicities caused by materials and extracts from the materials using mammalian and non-mammalian cell culture techniques. A battery of tests commonly accepted by the scientific community should be used (Ref. AMES Mutagenicity Test).
9. Carcinogenicity - To assess the material mediated carcinogenicity of the test material and/or extract in an animal model. For this guidance, carcinogenicity is necessary only for stents.
II. PTCA BALLOON CATHETERS
Percutaneous transluminal coronary angioplasty (PTCA) balloon catheters are devices introduced percutaneously into the lumen of the coronary artery where a balloon mounted on the distal end of the catheter shaft is inflated to a specified diameter by injection of mixture of contrast medium and saline to dilate a coronary stenosis. As stated earlier, PTCA balloon catheters are post-amendment class III devices which require approval of a premarket approval (PMA) application prior to commercial distribution or marketing. The following sections describe the general framework to be followed in conducting in vitro physical testing and animal studies using
PTCA catheters. This data, together with complete biocompatibility test data, must be submitted in an IDE application in order to establish the safety of the device and obtain IDE approval to begin a clinical investigation.
A. PHYSICAL TESTING REQUIREMENTS
The PTCA catheter should be tested in vitro to ensure that the design, specifications, integrity, and other physical characteristics of the catheter are sound and suitable for its intended use. The following physical tests should be conducted on catheters, or appropriatesubassemblies, which have been put through a validated sterilization process. Additionally, all testing involving the balloon should be conducted in 37oC saline since temperature and moisture can affect the properties of the balloon polymer. The protocol (including purpose, procedures and equipment setup), test results and conclusions based on clinically-relevant performance specifications should be submitted for an independent evaluation of the study conclusions.
1. Balloon Minimum Burst Strength - Determine the rated burst pressure for each balloon size (i.e., diameter and length of balloon). This test should be conducted on complete catheters, or sub-assemblies of balloons where the balloon is mounted on the catheter shaft, of each diameter and length. The rated burst pressure to be stated in the labeling must be lower (usually by one standard deviation) than the pressure obtained from the in vitro balloon burst testing which shows statistically that, with at least 95% confidence, 99.9% of the balloons will not burst at or below the minimum burst pressure. Attachment 1 describes a method to determine the rated burst pressure. The rated burst pressure should be further substantiated by the results of clinical testing.
2. Balloon Compliance (Distensibility) - Show that the diameter of each size balloon will not be significantly increased beyond its nominal diameter at increasingly higher pressures. This test should be conducted on complete catheters or sub-assemblies of balloons where the balloon is mounted on the catheter shaft. This nominal diameter
inflation pressure is most accurately obtained through bench testing under controlled conditions where the relation of pressure versus diameter can be precisely measured. A balloon compliance chart of the pressure/diameter relation should be provided to illustrate how the balloon diameter increases as the inflation pressure increases. Furthermore, the labeling should include the balloon compliance chart and a statement which cautions that short-term and long-term biological effects at pressures above the nominal diameter inflation pressure are not known.
3. Balloon Inflation/Deflation Performance - Show that the inflation and deflation of each size balloon using conventional techniques can be accomplished within clinically acceptable time limits. This test should be conducted on complete catheters or sub-assemblies of balloons where the balloon is mounted on the catheter shaft. Additionally, ensure that each size balloon can be completely deflated by the procedure recommended in the labeling when in an environment simulating coronary arteries. Observe and describe any interference with balloon deflation.
4. Balloon Fatigue (Repeated Balloon Inflation) - Determine the
repeatability of balloon inflation without failure using the rated burst pressure (not lower than 5 ATM) using a randomly selected group of each size balloon. This test should be conducted on complete catheters, or sub-assemblies of balloons where the balloon is mounted on the catheter shaft. At least 30 balloons of each size should be tested, and there should be no failures after 40 inflations of a given balloon size. According to binomial distribution, 30 successes out of thirty tests would indicate that, with 95% confidence, 90% to 100% of balloons in the same population would pass the test without failure. A description of the failure mode for all failures that may occur during the repeated balloon inflation should be provided.
5. Tip Pulling and Torquing - Show that the force required to break the joints and materials in the distal end of the catheter (e.g., spring tip and nose-cone tip made of metal, plastic or other materials) is sufficiently large to guarantee the physical and mechanical integrity of the tip during pulling, pushing, or torquing maneuvers encountered in angioplasty procedures.
6. Bonding Strength - Test the bonding strength at points where adhesives are used for bonding between parts (such as the proximal end and luer fitting) of the PTCA catheter. The results should be compared with the specifications established by the manufacturer and should be relevant to its clinical use.
7. Catheter Body Maximum Pressure - Determine the maximum pressure that the catheter body can withstand when one of the lumens (usually the inner lumen) is used for the injection of contrast media or perfusion of blood or other fluids. This test should simulate actual use conditions.
8. Contrast Medium Flow Rate - Determine the contrast flow rate through the inner lumen at or below the Catheter Body Maximum Pressure, and at pressures utilized during the actual conditions of clinical use (e.g.,over the range of recommended injection pressures or a pressure used for manual injection using a 10 cc syringe).
9. Diameter and Profile - Determine the outside diameter of the catheter shaft, profile of the balloon, and inflated diameter of the balloon to ensure that the actual diameters match the labeled diameters for each size catheter. The location of the largest balloon profile along the length of the balloon should be identified and used for the inflated and deflated balloon profile. Additionally, identify the method utilized to obtain this measurement.
10.Balloon Preparation - Test the ease of balloon preparation procedures by filling the balloon with contrast medium and expelling the air from the balloon lumen.
11.Over-the Arch Tip Torque - Determine the torque to failure when the catheter tip is not free to rotate for any catheter which is classified as balloon-on-a-wire or fixed-wire technology. The test fixture should consist of a simulated aortic arch and coronary artery through which the catheter is maneuvered. After passing through the artery, the distal catheter tip is firmly held in place while the proximal end of the catheter is rotated in a manner that simulates the conditions of clinical use (e.g., clockwise and/or counter-clockwise rotation). The number of revolutions to failure and the failure mode must be recorded. The performance of the balloon must also be observed and recorded.
Labeling for the device must state the maximum number of rotations
allowed for the catheter based on these test results.
12.Pressure Waveform - Determine the natural waveform frequency and the waveform damping coefficient from the distal port of the catheter for any catheter that is indicated for pressure monitoring. Damping of the waveform must be appropriate to provide an accurate measurement.
B. ANIMAL STUDIES
Animal studies for PTCA balloon catheters are only necessary if the catheter design or mode of angioplasty differ from standard balloon catheters available today and sometimes referred as plain old balloon angioplasty. New balloon catheters designs that would require prior animal studies include, for example, heated balloons or balloons with cutting edges. Clinical investigations of plain old balloon angioplasty catheters do not require animal studies, unless specifically directed by FDA to conduct such studies.
The following studies should be conducted in at least six animals with stenoses in order to perform at least six procedures and compare the results to a control, i.e., compare the balloon segment of the artery with the untreated segment. This can be accomplished in multiple sites in two animals or in single sites in four animals provided comparison can be made to an untreated artery in the same animal. The arteries selected for testing must have diameters similar to those of human coronary arteries.
The test protocol, results and the investigator's comments should be completely described. In addition, the protocol for examining the arteries of animals tested should follow procedures used in the postmortem examination of human coronary arteries.
1. Maneuverability - Test the maneuverability and ease of catheter movement over a guidewire of specific diameter, through arteries with and without acute bends, and during catheter withdrawal from the arteries. The test should ensure the physical integrity of the catheter while in use.
2. Performance - Test the ease and completeness of balloon inflation and deflation, determine the balloon inflation and deflation times and determine the distal flow rate of contrast media with and without a guidewire in place. Also, determine that the radiopaque markers are adequate for fluoroscopic visualization and the distal tip arterial pressure with or without a guidewire in the distal lumen.
3. Histology - Evaluate the acute effects and changes associated with healing relating to angioplasty treatment by detailed gross and histological examination of PTCA-treated arteries 1 day, 6-8 weeks and months posttreatment. Sponsors may justify why this test is not necessary for the particular PTCA catheter in lieu of histology information.
III. CORONARY ATHERECTOMY DEVICES
Atherectomy devices are percutaneous transluminal catheter-type devices that mechanically remove diseased tissue, such as atherosclerotic plaque or thrombus, from coronary arteries by utilizing various cutting methods. Although safety and effectiveness is ultimately determined by the device's performance in the clinical setting, in vitro bench testing of the device assists in determining the reasonable safety of the device. Additionally,it must be shown that the device can be navigated to the target lesion(s) and remove diseased tissue while minimizing damage to the treatment site and all potentially related areas of concern. Since tissue removal can be carried out in many ways through many different device designs, providing specific bench tests are difficult. Therefore, a general overview of the types of concerns that should be addressed are presented. It is the sponsor's responsibility, however, to conduct testing which adequately addresses these concerns as well as any other concerns which may arise due to the unique design of a particular device.
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