On October 10, 2019 FDA released the first updated guidance on guidewires since 1995. The guidance can be found here: https://www.fda.gov/media/113959/download. While the guidance covers everything from shelf life to labeling to sterility, here at Biocompatibility Hub, we’re going to focus on the guidance’s details on biocompatibility, predicate comparison and pyrogenicity.
From a biocompatibility standpoint, the identification of a predicate device(s) that contain the same materials, coatings, sterilization method etc. can help determine a path forward. Biocompatibility evaluation itself has moved to be more risk based and the FDA states that if you can find an appropriate predicate device, material safety can be evaluated by a risk assessment. If you can’t find an appropriate predicate then biocompatibility testing will be required. The key words here revolve around the predicate device. If you’re choosing a 510(k) pathway for submission then you have to declare a predicate no matter what, but its utility in risk assessments can vary based on a number of factors. The best way to start, FDA states, is to perform a side by side comparison showing for a number of factors such as flexibility, wire materials, coating materials, sterilization method, and accessories, how similar or different the subject and predicate devices. Speaking of accessories, we’ve been seeing an increasing importance on the evaluation of accessories in test device evaluation and we’ll be releasing a paper on this shortly.
From a biocompatibility standpoint, the identification of a predicate device(s) that contain the same materials, coatings, sterilization method etc. can help determine a path forward. Biocompatibility evaluation itself has moved to be more risk based and the FDA states that if you can find an appropriate predicate device, material safety can be evaluated by a risk assessment. If you can’t find an appropriate predicate then biocompatibility testing will be required. The key words here revolve around the predicate device. If you’re choosing a 510(k) pathway for submission then you have to declare a predicate no matter what, but its utility in risk assessments can vary based on a number of factors. The best way to start, FDA states, is to perform a side by side comparison showing for a number of factors such as flexibility, wire materials, coating materials, sterilization method, and accessories, how similar or different the subject and predicate devices. Speaking of accessories, we’ve been seeing an increasing importance on the evaluation of accessories in test device evaluation and we’ll be releasing a paper on this shortly.
In any material risk assessment, the concentration of a component in a predicate device vs. the subject device is important. When it comes to alloy or polymer mixtures in devices like guidewires, it should be kept in mind that the predicate concentration of a material should be the same or greater than the subject device. For vascular devices such as catheters and guidewires, additionally, if a coating is present on 5 cm of the predicate and 15 cm of length of the subject device what’s the effect? How do surface properties, both macro and micro, compare? If the diameters are different, how will this affect performance and vascular occlusion in the target vessels if they’re the same?
Beyond the risk assessment, if it’s identified that biocompatibility testing will be required, the predicate still fits in to certain required endpoints for evaluation including hemocompatibility testing of in-vivo thrombogenicity, complement activiation and hemolysis. The totality of biocompatibility endpoints for evaluation should come from FDA’s 2016 Use of ISO 10993-1 guidance. Based on a contact type and duration of externally communicating devices with limited (<24 hour) duration direct contact with the circulating blood, the endpoints include:
Beyond the risk assessment, if it’s identified that biocompatibility testing will be required, the predicate still fits in to certain required endpoints for evaluation including hemocompatibility testing of in-vivo thrombogenicity, complement activiation and hemolysis. The totality of biocompatibility endpoints for evaluation should come from FDA’s 2016 Use of ISO 10993-1 guidance. Based on a contact type and duration of externally communicating devices with limited (<24 hour) duration direct contact with the circulating blood, the endpoints include:
· cytotoxicity
· sensitization
· irritation/intracutaneous reactivity
· acute systemic toxicity
· material-mediated pyrogenicity
· complement activation (SC5b-9 pathway is recommended and C3a pathway optional)
· in vivo thrombogenicity
· direct and indirect hemolysis
The specifics on the performance of each test can be found in the corresponding ISO 10993 standards.
When it comes to pyrogenicity, there are two basic things which can cause the febrile response the rabbit pyrogen test is designed to measure. The first are gram-negative bacteria and the second are chemicals, but both of which can pose patient risk. The material mediated rabbit test is able to measure both types whereas the LAL endotoxin test can only measure the bacterial pyrogens. The FDA has a number of guidance documents regarding bacterial and chemical pyrogens that should be considered and these are detailed in the guidewire guidance.
While it’s specifically called out, guidewires are increasingly being made of new novel materials to increase their utility and because of this, genotoxicity should be assessed if necessary. In terms of which device size/configuration to use for testing, FDA says to use the largest surface area device model with the worst case exposure and should represent the final finished product including sterilization.
For the manufacturers, be sure read the entire guidance and for all of your biocompatibility questions, you can find us at www.biocompatibilityhub.com
· sensitization
· irritation/intracutaneous reactivity
· acute systemic toxicity
· material-mediated pyrogenicity
· complement activation (SC5b-9 pathway is recommended and C3a pathway optional)
· in vivo thrombogenicity
· direct and indirect hemolysis
The specifics on the performance of each test can be found in the corresponding ISO 10993 standards.
When it comes to pyrogenicity, there are two basic things which can cause the febrile response the rabbit pyrogen test is designed to measure. The first are gram-negative bacteria and the second are chemicals, but both of which can pose patient risk. The material mediated rabbit test is able to measure both types whereas the LAL endotoxin test can only measure the bacterial pyrogens. The FDA has a number of guidance documents regarding bacterial and chemical pyrogens that should be considered and these are detailed in the guidewire guidance.
While it’s specifically called out, guidewires are increasingly being made of new novel materials to increase their utility and because of this, genotoxicity should be assessed if necessary. In terms of which device size/configuration to use for testing, FDA says to use the largest surface area device model with the worst case exposure and should represent the final finished product including sterilization.
For the manufacturers, be sure read the entire guidance and for all of your biocompatibility questions, you can find us at www.biocompatibilityhub.com
