Biocompatibility omission justification for FDA 510(k)

[arakis369]

Hello all,

We are preparing our biocompatibility testing for our medical device which is a surface device in contact with a mucosal membrane for more than 24 hours but less than 30 days. As per ISO10993, we need to conduct cytotoxicity, sensitization and irritation tests. However the FDA requires additional tests including systemic toxicity, subchronic toxicity and implantation.

There is a footnote on the ISO10993 standard which states:

These additional evaluation tests should be addressed in the submission, either by inclusion of the testing or a rationale for its omission.

I am happy to conduct these additional tests however the subchronic test costs more than double all the remaining tests and takes 50% longer as well. Does anyone have any experience with providing a rationale for not including this test? Our product is made from polycarbonate (Makrolon from Bayer).

Thank you

 

[SuperGirl]

If the FDA requires the extra test, they are going to have to be addressed in some way, shape or form- otherwise you won't get past the RTA (refuse to accept) screening.

As far as a rational for not performing the testing, has your supplier completed the test or a similar test on the material that you could say something along the lines of "this was tested on the raw material by the supplier (testing included, attachment XXX) and no significant reprocesses in completed to change the material" or something...

although, imo, if the FDA requires it, it makes the 510(k) review process go much smoother if you can just get the testing done.

 

[planB]

Hello all,

We are preparing our biocompatibility testing for our medical device which is a surface device in contact with a mucosal membrane for more than 24 hours but less than 30 days. As per ISO10993, we need to conduct cytotoxicity, sensitization and irritation tests. However the FDA requires additional tests including systemic toxicity, subchronic toxicity and implantation.

There is a footnote on the ISO10993 standard which states:

These additional evaluation tests should be addressed in the submission, either by inclusion of the testing or a rationale for its omission.

I am happy to conduct these additional tests however the subchronic test costs more than double all the remaining tests and takes 50% longer as well. Does anyone have any experience with providing a rationale for not including this test? Our product is made from polycarbonate (Makrolon from Bayer).

Thank you

Hi,

some clarification:
ISO 10993-1, Table A.1 is called "Evaluation tests for consideration", which means that you have to evaluate based on the data you know whether you have to test for the listed biological risk, or whether you have enough data at hand to justify its ommission. You may also come to the conclusion that you have additional risks to consider - Annex A specifically says in the beginning that this matrix is not(!) a checklist.

As per the Agency's Blue book memorandum and the more-up-to date draft guidance, this ISO evaluation matrix is extended by Systemic toxicity (acute), subchronic toxicity (subacute tox.) and Implanatation with FDA's notiong in the draft guidance:

"O = These additional evaluation tests should be addressed in the submission, either by inclusion of the testing or a rationale for its omission."

So the Agency is open for scientifically sound rationales.

Usually, you built your rationales on available data you retrieved from literature and data you generated as part of your biocompatibility evaluation report.

What you need for your rationales:
(1) Solid material characterization of your final product, i.e. leachables ore even better (ehaustive) extractables, supported by data about your used materials (MDS and other data sheets) and in-depth knowledge of all manufacturing proccesses these materials undergio until ending up as final products, including any processing aids, cleaning steps, ...
(2) you did a cytotoxicity test and have already demonstrated that your device is neither senitizing nor irritating?
(3) do you have post-market experience about comparable predicate devices?

In case you can demonstrate from your material characterization that you have no leachables/extractables present that might lead to an acute systemic /subchronic toxicity reaction or any local effects after implantation, beefed up by test data done for (2) above and (3) actual clinical post-market data on equivalent predicate device, you may built a strong argument to conclude that you do not have to address these additional risks by dedicated tests.

HTH,

Gerhard

 

[Ronen E]

Additionally, the big bio test houses might offer the service of an expert toxicologist who would create the rationale for you and issue a formal letter (for a few $), possibly subject to some other required testing. The overall $ figure and timeline might be significantly reduced compared to the original test you are trying to avoid.

When you say "FDA requires", are you referring to a guidance or pre-submission advice, or to an actual submission examiner's response? If it is the latter, I wouldn't hold my expectations too high. If he/she required it, most likely the least painful way is to run the test as required. You might just have to bite the bullet.

Cheers,
Ronen.

 

[arakis369]

Hello everyone,

Thank you for your valuable responses. We have not received advice from the FDA that they require any of the additional tests, it is based on the information as per Gerhard's response. My line of thought is exactly as Gerhard's last paragraph states, especially considering that our material is polycarbonate which has been used in medical devices for decades. I am hoping that by conducting the sensitization, irritation, cytotoxicty, subacute toxicity and implantation tests as well as a strong rationale for not conducting the subchronic toxicity we should be able to satisfy the FDA.

Thank you all.

 

[MIREGMGR]

...has your supplier completed the test or a similar test on the material that you could say something along the lines of "this was tested on the raw material by the supplier (testing included, attachment XXX) and no significant reprocesses in completed to change the material"

My past experience has been that FDA used to be open to rationales and particularly to an explanation that the raw materials all had been tested (data provided) and similar material combinations and processing were used in other devices for which biocompatibility was established (data provided).

My recent experience has been that FDA will accept nothing less than every designated test performed on the entire finished-design, actual-production-process device--not just the patient contact parts/elements--with no allowance for any alternate approach.

I'd discuss your approach with the examiner before submitting. Speaking from experience, going through the RTA process is no fun and wastes a huge amount of time.

 

[arakis369]

Hello MIREGMGR,

Thank you for that.

We will be conducting the biocomp testing on the final, packaged, sterilised product so we tick the box on that part.

I have read through the FDA's guidance document on using ISO10993 and the last paragraph of 3. A. states:

If literature is used to support omission of certain biocompatibility tests, the submission should include information on the applicability of the dose, route, and frequency of exposure from the literature report(s) as compared to the proposed device use. In addition, while literature may be appropriate to support the omission of certain toxicity tests, it may not be appropriate to justify omission of all biocompatibility studies. For example, No Observed Adverse Event Level (NOAEL) and Low Observed Adverse Event Level (LOAEL) data could be used to justify omission of acute, subchronic, or chronic system toxicity assessments, but would not be relevant for genotoxicity, local and systemic carcinogenicity, sensitization, or reproductive toxicity assessments.

It is this paragraph in particular that I am hoping will provide justification for not conducting the subchronic tests. What are your thoughts on this?

Thanks

 

[MIREGMGR]

My thought would be: you should be calling the examiner and discussing it with him/her.

The examiner however may refuse to talk about it directly, and instead tell you to prepare a pre-sub submission per the new Qsub guidance, in which you lay out your argument in advance of the actual 510(k), and they get to hash it out internally off the submission clock.

That's happened to me once so far, and on a 510(k) that was submitted a long time before the Qsub guidance was released so it wasn't even a pre-sub.

 

[planB]

Hello MIREGMGR,

Thank you for that.


It is this paragraph in particular that I am hoping will provide justification for not conducting the subchronic tests. What are your thoughts on this?

The route you are considering, is layed out in ISO 10993-17:2002
Biological evaluation of medical devices -- Part 17: Establishment of allowable limits for leachable substances. Be aware that this standard is _not_ a recognized consensus standard.

In order to make use of published NOAEL data for your purposes, you may want to proceed the following way:

1) Do a thorough material characterization on the final product. Demonstrate, that the leachables/extractables you are quantifying from your studies are actually either really exhaustive or reflect the the clinically relevant amount. To this end, you have to employ adeaute polar and apolar extraction vehicles at suitable temperatures and time periods (refer to ISO 10993-18)

2) Search for relevant and reliable literature of NOAEL data derived for biological endpoints relevant for the intended use of your device. Have a look in the appendix of ISO 10993-7 as a working model how this can be done. You may require expert toxicological experience to reach at a defendable MOS (margin of safety). TOXNET is a good and free starting point for your literature search. For some ubiquitous chemicals, you might find tons of literature (e.g. plasticizers like DEHP or BPA) and even suitable review publication summing up available perr-reviewed literature. For some more obscure chemicals you might find nothing. You may then further relay to the TTC (Threshold of toxicological concern) concept, but at his point you really may want to rethink your choice of materials and manufacturing processes.

3) If you find not only a handful of potentially toxic leachables/extractables in your final product material characterization, but a cocktail the route for calculation MOS will quickly amount to a thesis. It might be more feasible then to either demonstrate safety through in-vivo testing or investigate your materials and manufacturing processes if you could improve there.

HTH,

Gerhard