The following are common biocompatibility issues that should be considered when conducting biocompatibility testing for a Drug delivery and Drug Eluting Systems.

*It is important to understand how the test samples compare to the final sterilized product (including the drug substance). The test article certification (the stand alone document) could be used to detail how any differences may or may not affect biocompatibility of the final product. If a coated coupon is to be used as the test sample, data should be provided to demonstrate that the drug, carrier, and substrate materials elute drug and chemical leachants (from both the carrier and substrate materials) of the same type and quantity using exhaustive extraction techniques.

*Sponsors should consider whether carrier-only samples should be tested (e.g., if the drug has the potential to mask a toxic response to the drug-eluted carrier system).

* For bioabsorbable materials, test sample preparation should take into consideration starting, intermediate, and final degradation products so that the toxicity of all can be assessed.

*For extraction testing, sponsors should consider the following.

*t is important to conduct short-term extraction tests on the stent and the delivery system separately. If the delivery system and the stent are combined into a single test sample, this will dilute the amount of implanted stent materials being presented to the test system and may not identify potentially toxic agents that would have been found if the stent was tested separately from the delivery system. We think this is especially important to consider as a Drug Eluting Systems is a permanent implant that typically incorporates novel polymer/drug combinations where biocompatibility should be assessed carefully. The extensive vascular implantation testing that is conducted for these types of products is either unable to determine some of the toxicity issues assessed by these extraction screening tests or is not as sensitive as some of the extraction screening tests. The Drug Eluting Systems and delivery system should be evaluated separately in the following tests, if performed:
* cytotoxicity
* sensitization
* intracutaneous reactivity
* acute systemic toxicity
* material mediated pyrogenicity
* hemolysis (extract test only; the direct contact test may be performed on the stent alone)
* complement activation
* subchronic and chronic toxicity (Device alone)
* traditional muscle implant (Device alone)
* genotoxicity (device alone; delivery system should be tested separately if new materials are included that have never been previously used in blood-contacting devices or implants)
*carcinogenicity (device alone)

*Final, sterilized stents that include any coating and/or carrier materials and the drug should be used for extraction testing.

*Surface area to extract volume, according to ISO 10993-12, should be used to calculate the amount of product being sampled. Weight per extract volume calculations should only be used in the event that the surface area cannot be calculated (which likely will not be the case for the stent). Where there are concerns about numbers of samples needed for extractions, one can consider using concentrated extraction techniques to meet surface area recommendations.

*Both polar and nonpolar extracts should be used.

*If extraction samples are not used immediately, they should be stored according to ISO 10993-12.

*Test reports should include information on the condition of the extraction vehicle (e.g., color, presence of any particles) and any changes in the postextraction vehicle from pre-extraction should be explained. Details regarding storage conditions should be described. If the samples are stored prior to use, the sponsor should discuss why storage would not affect the test results.

*For cytotoxicity testing, extraction vehicles should include MEM and 5 percent serum as these materials will allow for extraction of both polar and nonpolar constituents from the test sample.

*For material-mediated pyrogenicity testing, methods such as those outlined in the current USP 151 Rabbit Pyrogen Test can be used, except that traditional biocompatibility extraction methods should be used, (e.g., 50°C for 72 hours; 70°C for 24 hours; or 120°C for 2 hours) or an equivalent method.

*If overlapping stents could be used clinically, should be explained why biocompatibility testing will provide information on toxicity at the overlapped stent segment.

* For cytotoxicity testing, both direct contact and elution methods should be considered.

*For guinea pig maximization sensitization testing, historical positive control testing is not sufficient to determine whether the animal model continues to be capable of detecting a positive sensitization response. We recommend running either concurrent controls, or periodic test laboratory controls within 3 months of the evaluation of the test samples. Protocols and results from positive control testing with a minimum of 5 animals should be provided with the application to confirm that the same methods were used for both the positive control testing and the test samples.

*For guinea pig maximization sensitization testing, test reports should confirm that none of the female animals used in the testing is pregnant, as pregnancy can reduce the ability of a female animal to detect a sensitization response.

* For sensitization testing, FDA also accepts local lymph node assay (LLNA) testing as an alternative to guinea pig maximization testing, if appropriate methods are used.

* For hemocompatibility testing, hemolysis, complement activation, and in vivo thromboresistance should be considered. Complement activation should be addressed either by testing with both C3a and SC5b-9, or with a scientific justification for the omission of testing. Sponsors may also assess in vivo thrombogenicity in the vascular animal implantation testing in lieu of a separate canine in vivo thrombogenicity test.

*Muscle implant studies should be performed even when vascular implant studies are performed. When new materials/chemicals are used in a medical device, it is required both the muscle implant study as well as studies of the device implanted at the proposed anatomical site. The muscle implant study is used as a screening test to look at local toxicities. Because the muscle implants tend to form a fibrous capsule around the implant, any materials eluted over time from the test article will be contained within the capsule, and therefore might result in an exaggerated response that might not necessarily be observed in the vascular implant study. We believe that both tests are informative to the overall toxicity assessment of both the material components of the product and the final product when used in its intended anatomical location.

* For implantation testing of products including biodegradable materials, tests should be conducted to determine the length of degradation and/or absorption time (i.e., until the material has completely disappeared) and to assess whether tissue healing occurs once the material is gone.

* For materials that have not been used previously as implant materials (e.g., new base materials and/or materials with altered formulations), additional toxicity testing (e.g., reproductive toxicity, additional immunotoxicity) not normally performed for products in contact with cardiovascular tissue and circulating blood may be called for.

* A risk assessment should be conducted to determine the necessity of carcinogenicity testing. This assessment should include the following elements:

* The complete chemical formulations for all components of the Drug Eluting Systems (drug, coating materials, metals, additives, and processing agents). The sponsor should identify how much would theoretically be present in an individual stent (assume worst case, i.e., largest stent) as well as per patient (assume a worst case situation where a patient might receive multiple stents).

*The potential breakdown products and descriptions of the mechanism by which the breakdown products, drug, and/or other compounds of concern are formed during the degradation process should be evaluated. Because certain constituents may be present upon degradation that were not included as original materials or processing agents, these constituents should be evaluated as well. Assessments should also include the effects of all processing agents (e.g., adhesives, mold cleaning agents, mold releasing agents, sterilization chemicals) that come into contact with the stent and delivery system materials during processing (including contact with other material components of the final product).

*A thorough literature review should be provided to include search terms and an analysis of the toxicity of the materials and breakdown products. If potential carcinogens exist in the materials and/or in the intermediate or breakdown products, the sponsor should identify and quantify these components and determine how much of the potential carcinogen would be available in a single product (i.e., assume all breakdown product precursors are converted into the potential chemical of concern, and that all of this material is available to the tissue environment). A risk assessment should also be provided with literature evidence to demonstrate that the amount of the potential carcinogen available in one stent does not pose a carcinogenic risk. This analysis should also be provided assuming a maximum number of stents likely to be implanted in a single patient (worst case analysis). This overall carcinogenicity risk assessment should be considered in conjunction with genotoxicity testing on the final product.

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