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.