On June 16, FDA finalized a guideline of broad significance for the medical device industry, Use of International Standard ISO 10993, ‘Biological Evaluation of Medical Devices Part 1: Evaluation and testing within a risk management process’. This guidance was published in draft form in April 2013 and the medical device community has therefore been aware of its main objectives. However, being recognized as a gamechanger in biological safety evaluation, this final guidance is certainly a significant milestone and a good opportunity to reflect on how it is impacting the biological safety evaluation of medical devices.
Overall, this FDA guidance embodies a shift away from biocompatibility testing by rote and a move towards a more thoughtful biological safety evaluation, which is to be conducted under a process of risk management. The requirements for testing in the fundamental areas of biocompatibility, such as genotoxicity, irritation/tissue reactivity, systemic toxicity, hemocompatibility, sensitization, are certainly not going away, in fact, FDA in some cases recommends additional tests for consideration; however, man Chemical characterization of devices and subsequent toxicological risk assessments are evolving from me afterthoughts into having a more important, if not a requisite role in biocompatibility testingufacturers will have to pay more attention to the selection of tests and how to perform these tests for each device.
Chemical characterization, which typically comprises an extractables/leachables (E/L) analysis when the test article is a medical device, together with a toxicological evaluation of the analyses identified, has been a valued part of the biological safety evaluation of a device. However, according to FDA, the chemical/toxicological characterization come much earlier in the process and the resulting data used in the design of a biocompatibility test program under ISO 10993. This is in step with the not-so-new desire to reduce animal use and repetitive testing associated with product safety evaluation.
Whether the more judicious use of traditional animal testing will represent an overall savings, in time and money, for the device industry is not easy to predict. E/L analysis, together with literature-based toxicology assessments can be time-consuming and labor intensive. It is certainly possible that the overall program costs will increase for some device makers.
To appreciate FDA’s final guidance fully, the context set up by ISO 15499, ISO 14971, and ISO 10993-1 itself must be understood, but the common theme shared by all is a greater emphasis on a more holistic safety evaluation, which not only places greater emphasis on the chemical characterization of a device, but also gives greater attention to information on the constituent materials and their history of use, other physical/ mechanical aspects relevant to safety (e.g., aging, degradation), and any other information that may be relevant. patients.
If your device contains previously marketed components, or if the materials are well characterized or have a long track record of safe use, then this information should be considered, where available data may address key questions regarding the safety, or potential risks of a device as used in patients.
Subchronic toxicity be considered, in addition to the 5 test endpoints recommended by the ISO guidance. FDA has suggested that acute systemic toxicity, subchronic toxicity, and implantation endpoints be considered for a broader set of devices and exposures, as compared to ISO, and perhaps even more notable is the recommendation for chronic studies and cancer bioassays for several device categories, where contact is of a permanent (>30 day) duration. The need for testing material-mediated pyrogenicity tests, implantation studies, and basic genotoxicity testing will also be increasing, based on FDA recommendations.
FDA’s recommended endpoints for consideration are just that—recommendations, and device makers can challenge the need for a particular test or propose an alternative means of testing the same endpoint. FDA encourages users to seek other additional data, or provide an assessment of the literature before conducting whole animal studies, especially when chronic toxicity or carcinogenicity studies are being considered.
Many factors related to the nature, degree, frequency, duration, and conditions of exposure during clinical use have already been considered in creating the biocompatibility matrix; however, no agency can write recommendations to cover every device. Even if a test is still necessary, FDA is compelling users to consider all relevant information to ensure that the test will be conducted in a way that will provide the best information possible. Other data may include information from suppliers on the constituent materials and known safety issues, or performance measures that lend assurance to their safe use.
WHAT DEVICE MANUFACTURERS SHOULD BE DOING
Based on these changes, the medical device industry has been taking more time to understand their devices, with respect to the materials used in the manufacturing, chemicals introduced during manufacturing, and the duration, frequency, and conditions of use in a clinical setting. Your breathing circuit is intended to deliver humidified air to a patient, but is it also used to deliver drug products? Could it be? Your device is made from a hard polyurethane plastic which has a very limited and well-known set of leachable substances, none of which are genotoxic. Will you still perform the basic tests of mutagenicity/clastogenicity under ISO 10993? Manufacturers are taking more time to understand the nature of the materials that they use, talking to suppliers when necessary, and seeking out any available test data that may be relevant to the overall safety evaluation. Manufacturers are also spending more time in designing biocompatibility test programs, reaching out to other members of the regulated community or consultants when necessary for help and of course, working to achieve a better understanding of all aspects of the biological safety evaluation as described by FDA.
THE TOXSMART GROUP at TOXIKON is PREPARED TO HELP
With more than 33 years in helping Sponsors comply with Biological Safety Evaluation under Tripartite and now ISO 10993, Toxikon is ready to apply its expertise to your regulatory challenges. As a preclinical contract research facility, Toxikon has an intimate understanding of the technical aspects of bioompatibility testing programs and the detailed aspects of analytical chemistry, in vivo and in vitro studies. This role brings Toxikon into continuous contact with international regulatory agencies, giving Toxikon unique insights into the current thinking at FDA in particular. With biocompatibility testing becoming less of a check-box exercise, Sponsors are relying more and more on Toxikon for our expertise in the review of existing data (and ‘gap analysis’), in toxicological evaluations (for specific constituents), and in the overall biological safety evaluations.
Our risk assessment team has assisted Sponsors with a highly diverse array of medical devices, container closure systems, and drug combination products. Our toxicological evaluations and risk assessments continually meet the scrutiny of regulators and receive high praise among peers in the medical device community.
Toxikon’s chemistry group is accustomed to E/L projects with very specific objectives, but is also adept at balancing the desire to customize analyses with some degree of cost control. Should the need arise, the design of chemical characterization projects will enlist the experience of risk assessors and toxicologists within ToxSmart, which will ensure that the resulting data are usable and relevant for the purpose of a risk assessment that addresses clinical use.
About ToxSMART Team
The ToxSmart team at Toxikon has nearly 60 years of professional experience in toxicology and human health risk assessment within a variety of regulatory frameworks. These projects are principally related to toxicological risk assessment but also include activities under risk management or biological safety assessment as per ISO 14971 and 15499 and Out ToxSMART team assists Sponsors in literature-based toxicological evaluations and in the design of pre-clinical testing programs.
Toxikon Corporation is a preclinical contract research organization (CRO) with ISO/IEC 17025 accreditation that is registered with the US FDA and Japanese MHLW for drug and medical device testing. The company provides in vivo, analytical, and in vitro testing services for the pharmaceutical, biotechnology, and medical device industries. Toxikon currently serves over 1,500 active customers in more than 41 countries.
At DeviceTalks Boston, Tyler Shultz will give attendees an inside look at Theranos and how he was able to sound the alarm after he realized the company was falling apart. Shultz will take attendees behind the story that everyone is talking about: the rise and fall of Elizabeth Holmes and her diagnostic company, Theranos.
Join Shultz and 1,000+ medical device professionals at the 8th annual DeviceTalks Boston.