Biocompatibility-UHMWPE

[srinu]

Dear Friends,
I got one question from FDA 510(K),it's Total knee system file,we did all the Biocopatibility tests except Chronic toxicity and carcinogenecity and we provided the predicate device data like same material and manufacturing/processing comparision .
The question is that only sterilization process for UHMWPE parts are different ,Ours is with Eo gas sterilization and the predicate device with gamma stsreilization.
Eo gas sterilization is superior than Gamma sterilizationfor UHMWEP parts , however FDA agency asked us to provide rationale to show Eto gas is good than gamma for biocopatibility safety.
We did all the biocopatibility tests except 2 as i mentioned ,then any idea or information to provide rationale to show Eo gas sterilization is good for Biocompatibility than Gamma stsreilization.

Thanks in advance.

 

[srinu]

Any Ideas or suggestions please...

 

[planB]

Would you be in a position to share the exact wording of the FDA deficiency/request?

At first glance, I would not try to argue with EO sterilisation being "superior" to gamma irradiation, but rely on your already performed material characterization in conjunction with the endpoint testing you performed on the new final device sterilised with EO. It is very typical - and generally accepted world-wide - to justify omission of tests for chronic toxicity and carcinogenicity, based on a risk assessment of your already accumulated test data.

FDA says in their guidance, p. 43 ff

[...]Therefore, the following elements should be considered in conjunction with genotoxicity information to evaluate carcinogenic risk of the medical device in its final finished form:
• Include the complete chemical formulations and manufacturing residuals for all components of the device with the potential for tissue contact. [...]
• Quantify the total amount of extractables and leachables [...]
• Evaluate how much of each chemical would be present in an individual worst-case patient exposure situation. [...]
• Evaluate the genotoxicity and carcinogenicity potential of the chemicals, [...]

Prior to conducting carcinogenicity testing, the sponsor is advised to discuss proposed testing with FDA [...]

HTH,

 

[srinu]

Hello PlanB,
Thanks for your response.
Exactly what FDA asked like below.
"You have Done all Biological End points as per ISO 10993-1 except Chronic toxicity and Carcinogenicity hence please provide the rationale for omitting those endpoints or provide any supporting data to support / do the test".

So my question is that we have done all the other end points and all are good results.
1. For chronic toxicity - Can i state like that there is no evidence of toxicity from the performed tests (Subchronic toxicity) hence no need of doing chronic toxicity additionally to prove the safety?
2. Carcinigenicity- Can i state like that there is no evidence of DNA damage from the performed tests (Genotoxicity test) hence no need of doing carcinogenicity additionally to prove the safety?

Can you put some light on this and advice me how to depend or provide rationale for omitting those 2 end points.

Thank you.

 

[planB]

Your rationale should preferably be based on an evaluation of the items the FDA put forward in their guidance, p. 43 ff, as I pointed out previously, "documented by knowledgeable and experienced professionals" (quote from ISO 10993-1:2018, section 4.1). Providing you with a wording for your response is beyond this forum, just this:

ad (1): Chronic toxicity: you would have to elaborate your rationale, just stating will probably not be sufficient; The FDA guidance gives you one example to use on p 13: "For example, NOAELs and LOAELs from a systemic toxicity study can often be used to waive acute, subchronic, or chronic system toxicity testing [...]". In addition, ISO 10993-1:2018, section B.4.3.2 provides you with a list of criteria that might be useful to address in your rationale.

ad(2) Carcinogenicity: arguing with the result of genotoxicity tests is not sufficient because "there are carcinogens that are not genotoxins and carcinogenesis is multifactorial" (quote from the FDA guidance, p. 43)

HTH,

 

[srinu]

our rationale should preferably be based on an evaluation of the items the FDA put forward in their guidance, p. 43 ff, as I pointed out previously, "documented by knowledgeable and experienced professionals" (quote from ISO 10993-1:2018, section 4.1). Providing you with a wording for your response is beyond this forum, just this:

ad (1): Chronic toxicity: you would have to elaborate your rationale, just stating will probably not be sufficient; The FDA guidance gives you one example to use on p 13: "For example, NOAELs and LOAELs from a systemic toxicity study can often be used to waive acute, subchronic, or chronic system toxicity testing [...]". In addition, ISO 10993-1:2018, section B.4.3.2 provides you with a list of criteria that might be useful to address in your rationale.

ad(2) Carcinogenicity: arguing with the result of genotoxicity tests is not sufficient because "there are carcinogens that are not genotoxins and carcinogenesis is multifactorial" (quote from the FDA guidance, p. 43)

HTH,

Thanks for your valuble points. We will try to do it as per your points.