After our original post on biocompatibility deficiency letters, we received a couple of questions about some specific cases that have been asked of the manufacturers. Here we’ll cover a few of these most common cases we’ve seen and the best way to address them.
It definitely pays to work with a consultant or lab who has been working on 10993, MHLW or compendial (USP, EP, JP etc.) testing for a long time since in many cases, they’ve seen the same questions you’ve been sent and know how to address them in a somewhat cut and paste fashion. When the questions are ones which may be misguided, biocompatibility labs and sponsors should try to respond to the deficiency letters in a manner that not only address the specific questions, but also educate the reviewer.
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It should be noted that while most of the major US biocompatibility labs belong to the associated AAMI/ISO 10993 committees, just because it’s in an ISO document doesn’t mean that FDA is fully acceptant of the changes proposed. Always keep an eye on the FDA’s recognized consensus standards. In other cases, FDA takes a new direction in how a study should be performed or reported, but the only way that labs find out about the new direction is from an increase in deficiencies coming from manufacturers and then the labs adjust accordingly.
Each biocompatibility test is designed to evaluate a specific reaction that may happen when the device is introduced to a patient. For instance, hemocompatibility evaluates blood interactions, the intracutaneous injection irritation test evaluates the irritation potential and the toxicity tests (acute, subacute, subchronic) evaluate the toxicity of a product. Essentially, they evaluate what the test names indicate. Many times, the reviewer may have a question about a clinical observation, score or other event within the test and puts the question in the deficiency letter without considering the observation in the context of the rest of the battery of biocompatibility tests. For instance, the reviewer may ask how a test article unrelated skin wound or alopecia seen on one or more test animals in the guinea pig maximization test isn’t indicative of a safety concern of the test article. Remember the guinea pig tests look for sensitization as the end point. These wounds or the alopecia may have been caused by cagemates or the dosing procedure and if possible the report and data should support this and can be indicated as such in the response. In addition though, the intracutaneous injection test (which looks for skin reactions) and the acute systemic which looks for a toxicologic response, can be used to support the response. The acute systemic is dosed at a much higher dose than the guinea pig tests and the intracutaneous injection test would indicate if the dosing of the test article causes a skin irritation reaction.
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Each biocompatibility test is designed to evaluate a specific reaction that may happen when the device is introduced to a patient. For instance, hemocompatibility evaluates blood interactions, the intracutaneous injection irritation test evaluates the irritation potential and the toxicity tests (acute, subacute, subchronic) evaluate the toxicity of a product. Essentially, they evaluate what the test names indicate. Many times, the reviewer may have a question about a clinical observation, score or other event within the test and puts the question in the deficiency letter without considering the observation in the context of the rest of the battery of biocompatibility tests. For instance, the reviewer may ask how a test article unrelated skin wound or alopecia seen on one or more test animals in the guinea pig maximization test isn’t indicative of a safety concern of the test article. Remember the guinea pig tests look for sensitization as the end point. These wounds or the alopecia may have been caused by cagemates or the dosing procedure and if possible the report and data should support this and can be indicated as such in the response. In addition though, the intracutaneous injection test (which looks for skin reactions) and the acute systemic which looks for a toxicologic response, can be used to support the response. The acute systemic is dosed at a much higher dose than the guinea pig tests and the intracutaneous injection test would indicate if the dosing of the test article causes a skin irritation reaction.
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Aside from the actual technical in-life conduct of biocompatibility studies, the sample preparation phase is the other critical step. In a way, it’s the most critical because if the extraction isn’t performed properly then the rest of the study may be called into question. The most common deficiencies for extracts predominantly only need clarification and aren’t necessarily problems with the studies. Examples of clarifications for extraction include the extraction ratio used, what components were included/excluded in the extract, choice of extraction conditions (time and temperature), how quickly the extracts were used after being removed from the oven and finally if the extracts were filtered, pH adjusted, centrifuged or otherwise manipulated in any way. These are easy replies and if they’re not in the report already, just need a simple signed letter from the lab with the requested information.
Where things can get stickier for the manufacturer are if the test article is changed during extraction. The three major items we see are when colorants leach out of the test articles (big no no), the test article degrades/deforms or melts (another no no unless the test article is designed to do so clinically) and if the extracts have particulates in them (rusting, extracted compounds etc.). When these types of events happen with the associated FDA questions, the lab may be able to help from their experience in similar situations, but the primary crux of the response will need to be from the manufacturer. In most cases, unless otherwise already working with consultants, the manufacturer knows their device well enough to answer the questions and they may need to explore further physical or chemical testing.
Stay tuned for Deficiency Letters: Part 3 as we explore other common deficiencies and some ideas on how to tackle them. For the manufacturers in the crowd, as you read these, consider them in your biological and toxicologic evaluation plans/assessments and hopefully you can mitigate or prevent them. If you work in a biocompatibility CRO and have common deficiencies that you see, you’re welcome to write them up and provide them to us at biocompatibilityhub@gmail.com, or just drop us a line through our contact page and you can just line item the deficiencies and we can write it up. Remember that we’re here for the community and welcome any and all feedback and contributions. If you wish to stay anonymous or take credit for your work, we’re happy to support in both cases.
Where things can get stickier for the manufacturer are if the test article is changed during extraction. The three major items we see are when colorants leach out of the test articles (big no no), the test article degrades/deforms or melts (another no no unless the test article is designed to do so clinically) and if the extracts have particulates in them (rusting, extracted compounds etc.). When these types of events happen with the associated FDA questions, the lab may be able to help from their experience in similar situations, but the primary crux of the response will need to be from the manufacturer. In most cases, unless otherwise already working with consultants, the manufacturer knows their device well enough to answer the questions and they may need to explore further physical or chemical testing.
Stay tuned for Deficiency Letters: Part 3 as we explore other common deficiencies and some ideas on how to tackle them. For the manufacturers in the crowd, as you read these, consider them in your biological and toxicologic evaluation plans/assessments and hopefully you can mitigate or prevent them. If you work in a biocompatibility CRO and have common deficiencies that you see, you’re welcome to write them up and provide them to us at biocompatibilityhub@gmail.com, or just drop us a line through our contact page and you can just line item the deficiencies and we can write it up. Remember that we’re here for the community and welcome any and all feedback and contributions. If you wish to stay anonymous or take credit for your work, we’re happy to support in both cases.
