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Balloon Valvuloplasty Guidance For The Submission Of an IDE Application and a PMA Application (Text Only)

This guidance was written prior to the February 27, 1997 implementation of FDA’s Good Guidance Practices, GGP’s. It does not create or confer rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. This guidance will be updated in the next revision to include the standard elements of GGP’s.


                  DEPARTMENT OF HEALTH AND HUMAN SERVICES
                           PUBLIC HEALTH SERVICE
                       FOOD AND DRUG ADMINISTRATION
                CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
                        OFFICE OF DEVICE EVALUATION
                    DIVISION OF CARDIOVASCULAR DEVICES  

                      BALLOON VALVULOPLASTY GUIDANCE
                           FOR THE SUBMISSION OF
             AN INVESTIGATIONAL DEVICE EXEMPTIONS APPLICATION
                   AND A PREMARKET APPROVAL APPLICATION
                                                                          
                           Revised January 1989
                                     

                 BALLOON VALVULOPLASTY GUIDANCE DOCUMENT
                                                                
This document describes the general framework to be followed in developing 
and testing a safe and effective percutaneous balloon valvuloplasty 
catheter (PBVC).  The tests are grouped into (A) material biocompatibility 
and toxicity tests, (B) in vitro physical tests, (C) animal tests and (D) 
human clinical tests.

Please note that other elements of an investigational device exemptions 
(IDE) application (21 CFR Part 812) must be included for submission of an 
IDE to FDA.

A.   Material Biocompatility and Toxicity Tests

     For a material which has been tested and used previously in direct 
     blood contacting devices, a sponsor may submit information available 
     in publications or other legitimate sources which show that the 
     material is non-toxic in tests which are identical or equivalent to 
     the tests 1 through 5 listed below.

     All new materials must pass tests 1 through 5 below to insure their 
     safety for use in a PBVC.  All materials (polymers, metals, 
     radiopaques, color dyes and other leachable additives) in each 
     component of the PBVC must be non-toxic to human tissue.

     The effects of sterilization on device materials and potential 
     leachables, as well as toxic by-products resulting from sterilization, 
     should be considered.  Therefore, testing should be performed on the 
     sterilized final product or representative samples therefrom.  
     Specific chemical analyses of the sterilized final product and any 
     leachable material from the sterilized final product must be performed 
     before toxicity testing.  The chemical analyses and toxicity data must 
     be submitted to FDA for review.  The tests and analyses for leachable 
     materials must be conducted by choosing appropriate solvent systems 
     which will yield a proper extraction of the leachables.  Extraction 
     temperature should be 50 C which is one of the three temperatures 
     recommended in the current U.S.P.  The required toxicity tests for a 
     PBVC system are listed below. Additional tests are outlined in the 
     Tripartite Biocompatibility Guidance for Hedical Devices dated 
     September 1986.  Both lists of tests are for guidance purposes.  A 
     manufacturer may substitute or omit tests with adequate justification.

     1.   U.S.P. Biological Tests for Class IV plastics. Extraction by 
          solvents to be done at 50øC.

     2.   Sensitization assay: estimate the potential for sensitization of 
          a material using a test such as the guinea pig maximization test.

     3.   Cytotoxicity test: 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.

     4.   Thrombogenicity test: evaluate whether the blood contacting 
          materials will accelerate the processes of intravascular 
          thromboses. Describe test methodology and identify control 
          materials.

     5.   Hemolysis: determine the degree of red cell lysis and the 
          separation of hemoglobin caused by materials in vitro. Describe 
          test methodology and identify control materials.

     6.   Genotoxicity test: apply the mammalian and non-mammalian cell 
          culture techniques to determine gene mutations, changes in 
          chromosome structure and number, and other DNA or gene toxicities 
          caused by materials and extracts from the materials.  A battery 
          of tests commonly accepted by the scientific community should be 
          used.

B.   In Vitro Physical Tests

     Before the device is tested in vivo, it must be tested in vitro to 
     ensure that the design, specification, integrity, and other physical 
     functions or characteristics of the device are sound and suitable for 
     its intended purpose.  The following physical tests must be done on 
     samples of devices which have been put through the validated 
     sterilization processes, because sterilization may affect the device 
     properties.

     1.   Balloon Minimum Burst Strength Test.  Conduct the test on 
          balloons of each diameter and length.  Test results must show 
          statistically that, with at least 95X confidence, 99.9% of 
          balloons will not burst at or below the maximum recommended burst 
          pressure.

     2.   Balloon Distensibility (Compliance) Test.  Show that the diameter 
          of the balloons will not be significantly increased at 
          increasingly higher pressures.  A plot of balloon diameter 
          against inflation pressure should be submitted.

     3.   Balloon Deflatability Test.   Ensure that the balloons can be 
          completely deflated by the recommended procedure when they are in 
          an environment simulating transvalvular placement.  Observe and 
          describe any interference with balloon deflation.

     4.   Balloon Inflation and Deflation Times Test.  Show that the 
          inflation and deflation of the balloons using conventional 
          techniques can be accomplished within a specified time and supply 
          data.

     5.   Repeated Balloon Inflation (Balloon Fatigue) test. Test a 
          randomly selected group of balloons to determine the 
          repeatability of balloon inflation without failure using the 
          recommended inflation pressure (not lower than 5 atmospheres even 
          if the recommended inflation pressure is lower).  At least 30 
          balloons should be tested, and there should be no failures after 
          forty inflations of a given balloon. 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.

     6.   Tip Pulling and Torquing Test.  Show that the force required to 
          break the joints and materials in the distal end of the catheter 
          (such as spring tip and nose-cone tip made of metal, plastic or 
          other materials) is suffiently large to guarantee the integrity 
          of the tip during pulling, pushing, or torquing maneuvers.

     7.   Catheter Body Maximum Pressure Test.   Determine the maximum 
          pressure that the catheter body can withstand when one of the 
          lumina (usually the inner lumen) is used for the power injection 
          of contrast media.

     8.   Bonding Strength Test.  Test the bonding strength at points where 
          adhesives are used for bonding between parts (such as the 
          proximal end and luer fitting) of the PBVC.  Report the results 
          and compare with specifications.

     9.   Pressure Waveform Test.  Determine the natural frequency of the 
          catheter for pressure measurement from the distal port. Damping 
          of the wave form must be appropriate and provide accurate 
          measurement.

     10.  Diameter and Profile Test.  Determine the diameter of catheter 
          shafts, profile of balloons, and inflated diameter of balloons to 
          ensure that the actual diameters match the labeled diameters.

     11.  Radiopacity Test.  Make sure that the radioopaque markers of the 
          balloon are adequate to show the position of the balloon 
          fluoroscopically.  This can be done during animal testing.

     12.  Balloon Preparation Test.  Test the ease of balloon preparation 
          procedures, e.g., filling the balloon with contrast medium and 
          expelling the air from the balloon lumen.

C.   Animal Tests

     The following tests should be carried out on normal animals, since 
     there is no suitable animal model for valvular stenosis.  Information 
     from the following testing should be described in full in the 
     application.

     1.   The maneuverability or torquing characteristics of the guide wire 
          must be tested to show that it can easily be steered to the valve 
          of interest.

     2.   Test the maneuverability and ease of catheter movement over a 
          guide wire of specific diameter.  Test the ease and completeness 
          of balloon inflation, deflation, and catheter withdrawal.  The 
          test should also ensure the physical integrity of the guide wire 
          and catheter while in use.

     3.   Determine the balloon inflation and deflation times (visualized 
          fluoroscopically), distal flow rate of contrast media with or 
          without the guide wire in place, and the distal tip arterial 
          pressure with or without the guide wire in the distal lumen.

D.   Clinical Testing

     PBVCs for pulmonary valve use are class II devices, and may be 
     approved for marketing by premarket notification (510(k)) application 
     after IDE approval has been obtained and a clinical study of 50 
     patients with two-month follow-up has been completed, FDA has examined 
     the results, and declared the device to be substantially equivalent.

     PBVCs for the aortic and mitral valves are class III devices and 
     require a premarket approval (PMA) application.   Under IDEs for 
     aortic and mitral valvuloplasty, FDA usually grants permission for 20 
     investigators and 250 subjects.

     Balloon valvuloplasty catheters should be evaluated in well organized 
     clinical studies.  Before a clinical study may begin, the sponsor must 
     obtain approval from both FDA (via an IDE application) and an 
     institutional review board (IRB). In addition to the requirements 
     imposed by 21 CFR Part 812, the following items should be addressed in 
     the IDE.

     1.   Patient selection and treatment should reflect the intended use 
          and labeling claims for the device. Appropriate clinical 
          assessment should be performed in order to make proper patient 
          selection for the valvuloplasty procedure and studies should be 
          performed to evaluate the post-procedure results.

     2.   Current FDA policy for premarket approval requires that (a) for 
          aortic valvuloplasty at least 100 patients who have had initially 
          successful results be followed and (b) for mitral valvuloplasty 
          at least 50 patients who have had initially successflul results 
          should be followed. For either type of valvuloplasty, the 
          required number of patients must be followed for a period of six 
          months after the valvuloplasty procedure before a PMA application 
          may be filed.  In order to meet these criteria, the original 
          number of patients entered in the study (including valvuloplasty 
          failures) will need to be considerably larger.  The study shall 
          continue until the PMA is approved by FDA and all patients 
          enrolled in the study shall be followed according to the study 
          protocol while the PMA application is being reviewed.  FDA will 
          request post-approval follow-up to five years.  Follow up studies 
          should include 2D echo and Doppler at 3 months. Catheterization 
          should be perfromed at 6 months unless it is felt inappropriate 
          to the patient's condition. In such cases, ZD echo and Doppler 
          may be substituted. If data from the six month follow-up are to 
          be obtained by ultrasound techniquesl intraoperative ultrasound 
          at the time of valvuloplasty should be performed in order to 
          correlate ultrasound findings with pressure measurements.

     3.   Establish methods or techniques for preparing the balloon 
          catheter, inserting and controlling the guide wire and the 
          valvuloplasty catheter inside vessels, positioning the balloon at 
          the appropriate valve, and dilating the balloon at proper 
          pressures for suitable time periods.

     4.   Current literature indicates that the following list of 
          indications, contraindications and special cautions for the use 
          of the device should be considered.

          Indications for aortic balloon valvuloplasty

          1.   symptomatic patients who represent a high risk for
               valve replacement and
          2.   patients who have refused surgery.

          Contraindications for aortic balloon valvuloplasty
                                     
          1.   aortic regurgitation more than mild,
          2.   non-valvular aortic stenosis,
          3.   aortic valve area of over 1 square centimeter,
          4.   severe coronary artery disease - especially left
               main coronary artery disease, and
          5.   bacterial endocarditis.


     Indications for mitral balloon valvuloplasty

          1.   mitral valve area of 1.3cm2 or less,
          2.   patients with mitral regurgitation 1+ or less,
          3.   symptomatic patients, and
          4.   no age or sex limitations.

     Contraindications for mitral balloon valvuloplasty

          1.   mitral valve area greater than 1.5cm2,
          2.   patients with mitral regurgitation greater 2+,
          3.   asymptomatic patients,
          4.   aortic regurgitation greater than 2+,
          5.   bacterial endocarditis,
          6.   left atrial thrombus,
          7.   patients with severe subvalvular fibrosis
               documented by echocardiography, and
          8.   patients with severe mitral valve calcification.

          (Patients who have severe mitral valve calcification and severe 
          subvalvular fibrosis should be considered candidates for the 
          procedure only if they are non-operative candidates.)
     
     5.   Patient records must include the model, size and length of the 
          guide wires and valvuloplasty catheters, balloon inflation 
          pressure, inflation time, the number of inflation cycles used in 
          each valvuloplasty procedure and any evidence of balloon rupture.

     6.   Records of the study must be completed by each investigator.  The 
          record for each patient receiving valvuloplasty should include 
          the date, ID number, pre-treatment symptons, functional class 
          (NYHA), results of tests performed on the patient, the degree of 
          stenosis, success or failure of the procedure according to 
          predetermined criteria, pre- and postoperative pressure 
          gradients, patient's tolerance of the procedure, post-procedural 
          condition, complications, medications required, and any other 
          pertinent data.  Evaluation criteria must be uniform among all 
          investigators.

     7.   All patient data must be analyzed to determine the reasons for 
          failed procedures and the causes of all complications.

     8.   If a patient dies during the valvuloplasty procedure or prior to 
          hospital discharge, the cause of death must be documented.  An 
          autopsy should be performed where possible, and the findings 
          reported to FDA.  Information should include:  a) at what point 
          in the procedure the patient expired, b) whether another 
          valvuloplasty catheter was used, and  c)whether artificial valve 
          replacement was attempted.  An opinion should be expressed as to 
          whether the death was caused by (1) problems with the 
          investigational catheter, (2) the valvuloplasty procedure, or (3) 
          other factors.  Patients who die during the remainder of the 
          follow-up period should have the circumstances explained as 
          completely as possible, although this documentation will 
          understandably be less complete than deaths occuring under 
          medical surveillance.

     9.   Survival analysis methods should be used to analyze the study 
          results.  Follow-up data at three and six months should be used 
          to construct actuarial life tables to show the estimated 
          probabilities of freedom from each postoperative complication at 
          the end of each follow-up period. A survival analysis should be 
          conducted separately for aortic and mitral valvuloplasty and for 
          fatal and non-fatal events, including both catheter and 
          non-catheter related complications.  The study results should be 
          compared to controls, which may be the results of similar 
          studies.  Statistical methods, such as the Mantel-Haenszel, 
          one-degree of freedom, chi-square test, should be used for any 
          comparisons of life table results.

E.  Clinical Testing Without Intent To Manufacture

     FDA is aware that many physicians are using the Mansfield catheter 
     (presently marketed for pulmonary valvuloplast in children) for 
     valvuloplasty of the aortic and mitral valves, although it has FDA 
     approval for pulmonic valvuloplasty only. FDA has decided to 
     abbreviate requirements for such investigators in order to expedite 
     submission and approval of IDEs in a timely fashion.

     The following items are required for such an IDE;

     1.   Report of Prior Investigations

          a.   copies of all published and unpublished
               adverse information. 

          b.   written permission from Mansfield Scientific
               to reference any appropriate files within
               the agency.

               NOTE: If item b is not obtained, then the
               applicant must submit a report of prior
               clinical, animal and laboratory testing, a
               bibliography of all publications, a summary
               of all obtainable information, and a
               statement whether nonclinical tests comply
               with the GLP regulation.

     2.   Investigational Plan

          Submit the name and intended use of the device, the objectives of 
          the investigation and the duration of the investigation.

     3.   Protocol

          Submit a written protocol describing the methodology and an 
          analysis of the scientific soundness of the protocol.

     4.   Risk Analysis

          A description and analysis of all increased risks to subjects, 
          the manner in which risks will be minimized, a justification for 
          the investigation, and a description of the patient population in 
          terms of number, age, sex, and condition.

     5.   Monitoring procedure

          Provide a written procedure for monitoring, and the name and 
          address of the monitor.

     6.   Investigator Agreement

          Provide an example of investigator agreement, the name and 
          address of investigators who have signed the agreement, a 
          certification that all participating investigators will and have 
          signed the agreement and that no investigator will be added until 
          the agreement is signed.

     7.   IRB Information

          Provide the name, address and chairperson of each IRB, and the 
          action taken by the IRB (i.e., approval-disapproval).

     8.   Sales Information

          Give the amount charged for the device,if sold, and give an 
          explanation of why sale does not constitute commercialization.

     9.   Informed Consent Materials

          Submit all forms and informational materials to be presented to 
          the patient.  The informed consent should not contain exculpatory 
          language and should comply with 21 CFR, Part 50.

     10.  Environmental Impact Assessment

          An environmental impact assessment describing the potential 
          environmental impact of investigatin~ a device, and a claim for a 
          categorical exclusion from this requirement should be submitted.