Medical Devices
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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.
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