In the entirety of ISO 10993 biocompatibility, the in-vivo thrombogenicity test also known as the non-anticoagulated venous implant (NAVI) can easily be considered one of the most finicky and sensitive tests of them all.   It is best to implant a predicate control as a comparison device in the contralateral vein.  There are many factors which go into the test which is typically performed in dogs or sheep, but seemingly sometimes the outcomes are variable at best.  The most common contributing factors to thrombus forming during the test are sample geometry (both 3D and micro surface features), coatings, device to implanted vessel diameter ratios and intrinsic animal blood factors (variant susceptibility to clotting).  No matter how perfect your device in terms of design and manufacturing, you may still find that one of your implants has significant clotting on it at the end of the study.  The test is performed with two or three animals and you may find that significant scoring may be observed in one or more animals.  Unfortunately, if the same device is placed in three different animals, you may get three different results under the same testing conditions.  Where it becomes tricky, and unfortunately difficult in justification, is when one implant performs well and the others do not.  If you're lucky, both the predicate and the test implants will score highly together in the animal indicating a potential that the clotting was induced by an animal that was more prone to clotting than the population.

​Continue reading below

​While there is some comfort that the test device matched the scoring observed on the predicate device, FDA and other regulatory bodies may still require justification that the significant clotting observed in the test implant isn't an issue.  The test is performed using no anticoagulants, for four hours in a canine (more prone to clotting than humans) most commonly and all three of these conditions are often extreme uses that won't be seen clinically.  There are some devices that fit these clinical requirements, but others are used in heparinized patients for 15 minutes.  The FDA may ask for assurances of device surface analysis to show no geometrical anomalies or other issues (see the most recent Use of 10993 FDA document for commentary) but it can be an uphill battle still.  You may be required to add labeling in the device to declare the results of the preclinical study but not all hope is lost.  Your CRO or regulatory professional who has had to submit thrombogenicity results to regulatory bodies in the last few years will be able to help guide you and provide plenty of input on how to proceed.  

If you have been asked for justification of results for a thrombogenicity test you have already performed or are looking for ways to set yourself up for success before testing, reach out to us and we can help you as we also offer consulting assistance since we're biocompatibility professionals who are here to help out.