Medical Devices
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Tripartite Biocompatibility Guidance - April 24, 1987 (G87-1)
General Program Memorandum #G87-1
April 24, 1987 Tripartite Biocompatibility Guidance [NOTE: THE ORIGINAL ATTACHMENT II, DEVICE CATEGORIES AND SUGGESTED BIOLOGICAL TESTING, IS NOT INCLUDED AT THIS TIME.] Purpose A copy of the Tripartite Biocompatibility Guidance for Medical Devices, dated September 1986, is attached. The purpose of this guidance is to establish an approach for the evaluation of the toxicity of medical devices. This guidance is intended to assist manufacturers and government health authorities to anticipate the information needed for such evaluation. ODE is in the process of developing further guidance that expands on the Tripartite guidance as it applies to the review of submissions made to ODE. Background The Tripartite Subcommittee for Medical Devices is comprised of the senior officials of the medical device authorities of the United States, the United Kingdom, and Canada. During its September 1984 meeting, the Subcommittee decided that development of a common approach to toxicity testing would be highly desirable. The Subcommittee established the Toxicology Subgroup to work this goal. The guidance document produced by the subgroup, Tripartite Biocompatibility Guidance for Medical Devices, has been distributed to each of the three countries with the common understanding that it would be circulated in the respective national communities for comment and use "as appropriate." Our Center's Toxicology Committee will be asked to circulate the guidance among appropriate scientific and industry groups for informal comment. In the interim, ODE will utilize this guidance. Scope and Application of the Guidance The Tripartite guidance enunciates fundamental principles for toxicity evaluation of medical devices and provides a rational framework for their application. The application of these principles envisions the assignment of a given medical device to a category defined by (1) the nature of contact of the device with the body (e.g., external, externally communicating, or internal contact), (2) the time of contact (e.g., transient, short-term, or long-term), and (3) generic material(s) of device manufacture (e.g., polymers). The Tripartite guidance contains a table of suggested tests related to the nature and duration of contact for safety evaluation of medical devices made of polymers. Until such time that the Tripartite Subcommittee or ODE develops additional tables of suggested tests for device materials other than polymers, ODE divisions should use their judgment in adapting the present table to the other materials (e.g., metals, ceramics, biologicals). ODE reviewers should expect the submitter of any IDE or PMA to have considered the relevance and importance of each of the tests suggested for the respective device category, and either to submit the data or to present a sound argument why the information is not needed for the evaluation. In a similar manner, reviewers should consider the suggested tests for their relevance in the determination of substantial equivalence for 510(k) submissions, and require and review data when deemed appropriate. Effective Date: This memorandum is effective immediately. Attachment I
ATTACHMENT I
TRIPARTITE BIOCOMPATIBILITY GUIDANCE FOR MEDICAL DEVICES
Prepared by Toxicology
Sub-group of the
Tripartite Sub-Committee
on Medical Devices
September 1986
TABLE OF CONTENTS
1. Introduction
2. Device Categories: Definitions and Examples
3. Biological Tests
4. Device Categories and Suggested Biological Tests
TRIPARTITE BIOCOMPATIBILITY GUIDANCE FOR MEDICAL DEVICES
I. INTRODUCTION
The purpose of the Tripartite Biocompatibility Guidance is
to offer an approach relevant to Canada, United Kingdom and the United
States for the evaluation of the toxicity of medical devices. This
guidance is intended to assist manufacturers and government health
authorities to anticipate information needed for such evaluation, but
would not be considered as legal requirements. However, all three
countries may impose legal requirements for specific testing for a
medical product depending upon its regulatory status; e.g., in the
United States and Canada, absorbable and biodegradable implant
materials are treated as medical devices, where as in the United
Kingdom these materials are treated as drugs. More specific guidance
and requirements would be requested by the health authorities of the
individual governments. The Tripartite guidance is the outcome of
lengthy discussions by the members of Toxicology Subgroup of the
Tripartite Subcommittee on Medical Devices and is based on the
following fundamental toxicity evaluation principles:
1. The selection of material(s) to be used in device manufacture and
its toxicological evaluation should initially take into account
full characterization of the material, for example, formulation,
known and suspected impurities and processing.
2. The material(s) of manufacture, the final product and possible
leachable chemicals or degradation products should be considered
for their relevance to the overall toxicological evaluation of the
device.
3. Tests to be utilized in the toxicological evaluation should take
into account the bioavailability of the bioactive material, i.e.,
nature, degree, frequency, duration and conditions of exposure of
the device to the body. This principle may lead to the
categorization of devices which would facilitate the selection of
appropriate tests.
Note: A further aspect in deciding on categories of devices
could by the generic nature of the materials of
manufacture.
4. Any in vitro or in vivo experiments or tests must be conducted
according to recognized good laboratory practices followed by
evaluation by competent informed persons.
5. Full experimental data, complete to the extent that an independent
conclusion could be made, should be available to the reviewing
authority, if required.
6. Any change in chemical composition, manufacturing process,
physical configuration or intended use of the device must be
evaluated with respect to possible changes in toxicological
effects and the need for additional toxicity testing.
7. The toxicological evaluation performed in accordance with this
guidance should be considered in conjunction with other
information from other non-clinical tests, clinical studies and
post-market experiences for an overall safety assessment.
II. DEVICE CATEGORIES - Definitions and Examples
A. Non-Contact Devices
Devices that do not contact the patient's body directly or
indirectly; examples include in vitro diagnostic devices.
B. External Devices
1. Intact surfaces
Devices that contact intact external body surfaces
only; examples include electrodes, external prostheses
and monitors of various types.
2. Breached or compromised surfaces
Devices that contact breached or otherwise compromised
external body surfaces; examples include ulcer, burn
and granulation tissue dressings or healing devices
and occlusive patches.
C. Externally Communicating Devices
1. Intact natural channels
Devices communicating with intact natural channels;
examples include contact lenses, urinary catheters,
intravaginal and intraintestinal devices
(sigmoidoscopes, colonoscopes, stomach tubes,
gastroscopes), endotracheal tubes, and bronchoscopes.
2. Blood path, indirect
Devices that contact the blood path at one point and serve
as a conduit for fluid entry into the vascular system;
examples include solution administration sets, extension
sets, transfer sets, and blood administration sets.
3. Blood path, direct
Devices that contact recirculating blood; examples include
intravenous catheters, temporary pacemaker electrodes,
oxygenators, extracorporeal oxygenator tubing and
accessories, and dialyzers, dialysis tubing and
accessories.
D. Internal Devices
1. Bone
Devices principally contacting bone; examples include
orthopedic pins, plates, replacement joints, bone
prostheses and cements.
2. Tissue and tissue fluid
Devices principally contacting tissue and tissue fluid or
mucus membranes where contact is prolonged; examples
include pacemakers, drug supply devices, neuromuscular
sensors and stimulators, replacement tendons, breast
implants, cerebrospinal fluid drains, artificial larynx,
vas deferens valves, ligation clips, tubal occlusion
devices for female sterilization, and intrauterine
devices.
3. Blood
Devices principally contacting blood; examples including
permanent pacemaker electrodes, artificial arteriovenous
fistulae, heart valves, vascular grafts, blood monitors,
internal drug delivery catheters, and ventricular assist
pumps.
III. BIOLOGICAL TESTS*
Sensitization Assay
Estimates the potential for sensitization of a test material
and/or the extracts of a material using in an animal and/or
human.
Irritation Tests
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.
Cytotoxicity
With the use of cell culture techniques, this test determines
the lysis of cells (cell death), the inhibition of cell
growth, and other toxic effects on cells caused by test
materials and/or extracts from the materials.
Acute Systemic Toxicity
Estimates the harmful effects of either single or multiple
exposure to test materials and/or extracts, in an animal
model, during a period of less than 24 hours.
Hemocompatibility
Evaluates any effects of blood contacting materials on
hemolysis, thrombosis, plasma proteins, enzymes, and the
formed elements using an animal model.
Pyrogenicity - Material Mediated
Evaluates the material mediated pyrogenicity of test material
and/or extracts.
Hemolysis
Determines the degree of red blood cell lysis and the
separation of hemoglobin caused by test materials and/or
extracts from the material in vitro.
Implantation Tests
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, bone,; for 7 - 90 days.
Mutagenicity (Genotoxicity)
The application of mammalian or non-mammalian cell culture
techniques for the determination of gene mutations, changes in
chromosome structure and number, and other DNA or gene
toxicities caused by test materials and/or extracts from
materials.
Sub-Chronic Toxicity
The determination of harmful effects from multiple exposures
to test materials and/or extracts during a period of one day
to less than 10% of the total life of the test animal (e.g.,
up to 90 days in rats).
Chronic Toxicity
The determination of harmful effects from multiple exposures
to test materials and/or extracts during a period of 10% to
the total life of the test animal (e.g., over 90 days in
rats).
Carcinogenesis Bioassay
The determination of the tumorogenic potential of test
materials and/or extracts from either a single or multiple
exposures, over a period of the total life (e.g., 2 years for
rat, 18 months for mouse or 7 years for dog).
Pharmacokinetics
To determine the metabolic processes of absorption,
distribution, biotransformation, and elimination of toxic
leachables and degradation products of test materials and/or
extracts.
Reproductive and Developmental Toxicity
The evaluation of the potential effects of test materials
and/or extracts on fertility, reproductive function, and
prenatal and early postnatal development.
*The tests for leachables, such as contaminants, additives
monomers, and degradation products must be conducted by
choosing appropriate solvent systems that will yield a
maximal extraction of leachable materials to conduct
biocompatibility testing.
The effects of sterilization on device materials and
potential leachables, as well as, toxic by-products as a
consequence of sterilization should be considered.
Therefore, testing should be performed on the final
sterilized product or representative samples of the final
sterilized product.
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