A new draft guidance released by US regulators is intended to assist industry with the use of a medical device testing standard developed by the International Standards Organization (ISO) and used to conduct and evaluate biological testing, known as ISO-10993, and in particular to update their understanding of the standard's recommendations in regards to several new areas of technology.
More so than pharmaceutical products, medical devices are often overseen by international non-governmental standards bodies. ISO is a prominent entity in the medical device field, and perhaps its most famous standards are ISO 13485 and ISO 9001, used in the process of declaring conformity to EU medical device standards.
Lesser-known but commonly used is another standard, ISO 10993, Biological Evaluation of Medical Devices - Part 1: Evaluation and Testing. The standard is used in the US and recognized by the US Food and Drug Administration (FDA) to assist in the development of premarket approval (PMA) applications, premarket notifications (510(k)s), de novo request, investigational device applications (IDEs) and humanitarian device exemptions.
Specifically, the standard is geared toward helping device manufacturers answer a question: How does my product affect the human body? That question extends far beyond its intended effects. For example, while a pacemaker may be intended to regulate the heart, the materials used in the construction of that device could potentially have toxicological or other effects on the human body-potentialities that need to be studies and understood before regulators approve a device.
That's where ISO 10993 comes into the regulatory process, FDA explained. Among the standard's many testing considerations are test selection criteria, general testing considerations, specific testing considerations (cytotoxicity, sensitization, hemocompatibility, pyrogenicity, implantation, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and biodegradation), the use of animal safety studies, the assessment of potentially toxic chemicals used in the device, and what data are needed from a biocompatibility test report.
New Draft Guidance
FDA last issued guidance on ISO 10993 in the 1995, and the agency said its new draft guidance contains a number of useful updates for industry, including how to assess potentially toxic chemicals like color additives, prepare samples for nanotechnology components, and test in situ polymerizing and bioabsorbable materials.
And while the agency is quick to note that the standard is a work in progress, and that its guidance will soon be outdated as ISO makes new changes, it maintained that its new recommendations should provide greater insight into how sponsors should bridge the gap between ISO and submitting an application to FDA.
For example, FDA says it encourages sponsors to discuss their testing plans with the Center for Devices and Radiological Health's (CDRH) Officer of Device Evaluation (ODE), especially before initiating long-term testing.
"FDA recommends that full test reports be provided for all tests performed because ISO 10993 includes general methods with multiple options, and in some cases does not include acceptance criteria or address assessment of results," FDA explained. "It is therefore not appropriate to submit a declaration of simple conformity with respect to ISO 10993.3."
At its core, ISO 10993 should provide several basic assurances: That materials used in the manufacture of devices are not carcinogenic, are not genotoxic, and do not cause adverse events, FDA's guidance explains. "Therefore, evaluation of any new device intended for human use requires data from systematic testing to ensure that the benefits provided by the final product will exceed any potential risks produced by device materials," FDA added.
Accordingly, all conducted testing should be appropriate for its given purpose. Sponsors are advised to consider the chemical characteristics of the device's materials, as well as the "nature, degree, frequency and duration of exposure to the body."
"In general, the tests include: in vitro cytotoxicity, acute, sub-chronic and chronic toxicity, irritation, sensitization, hemocompatibility, implantation, genotoxicity, carcinogenicity, and effects on reproduction, including developmental effects," FDA explained. Other tests are to be used as needed, while some tests may not be needed at all provided that use of the material is well-understood by prior testing. Sponsors should be prepared to reference this testing through the use of predicate devices, FDA said.
The guidance, as stated earlier, includes several new considerations for device types that did not exist at the time of the last 1995 guidance. For example, In Situ polymerizing and bioabsorbable materials should be tested using a sample indicative of the finished product, and manufacturers should consider toxicological testing at various stages of the polymerization process (starting, intermediate and final degradation products). In Vivo testing will depend on the polymerization process and the pace at which the polymer degrades.
For nanotechnology or submicron components, FDA says "generally accepted" concerns about aggregation, agglomeration, immunogenicity and toxicity mean that devices incorporating these technologies will be subject to specialized testing requirements. These requirements may exceed the ISO 10993 standard, which is primarily based on chemical testing, which is not necessarily appropriate for nanotechnology.
FDA advises sponsors to "consult relevant literature and standards during the development of test protocols for device specific submicron or nanotechnology component biocompatibility assessments, and contact the respective review division prior to initiation of the test."
The entire guidance may be found here.
FDA: Use of International Standard ISO-10993, "Biological Evaluation of Medical Devices Part 1: Evaluation and Testing"
Federal Register Notice