Biocompatibility - why are animal studies necessary?

[Mark Meer]

Just a thread for discussion here.
...Note: I'm no expert so am just thinking out-loud...

I'm wondering: with all the technologies for material analysis available, why are animal studies still the main way to provide evidence of biocompatibility?

I would think that at this point, we'd have enough data as to the types of compounds/chemicals (and their concentrations) that raise biocompatibility concerns, that material analysis would be sufficient in most cases to demonstrate biocompatibility (i.e. by demonstrating the absence of such compounds, or that they are at sufficiently low concentrations).

Any material or biocompatibility experts out there enlighten me?

 

[MIREGMGR]

1. Cytotoxicity...the starting point for ISO 10993 device compatibility...is in vitro.

2. Many scientists believe that while gross cellular toxicity is relatively well understood as to biological mechanism, irritation, sensitization, and a range of other biological interactions that may be manifested as inflammation or immune system response either are not so well understood, or occur at levels for which existing in vitro tests are insufficiently sensitive or selective.

 

[Mark Meer]

But surely it all comes down to chemical composition, no?

I'd be curious: of all the materials that fail biocompatibility testing, how many are in the category "scientists don't know why", and how many can be traced to the presence of a particular compound (or set of compounds), at given concentration thresholds.

To me, anything falling in to former category is suspect. If there is no explanation for why a material passes or fails an animal test, then how on earth can we reliably extrapolate the findings to humans?

1. Cytotoxicity...the starting point for ISO 10993 device compatibility...is in vitro

Correct me if I'm wrong, but isn't this the only test in the 10993 series that doesn't involve animals?
Also, I don't think there's a category for which cytotoxicity testing alone is sufficient to demonstrate biocompatibility. Likely at minimum, you'd be required to to the sensitization and irritation tests: both which involves animals...the former needing a lot of them.

 

[pkost]

Biocompatibility is not just restricted to compounds and their concentration. Other factors affect how cells react; even the surface structure can have an impact i.e. polished instead of rough; random or patterned etc.

There are many factors that play there part and we do not fully understand how all of them affect the system; until we do we cannot simulate it in vitro

 

[somashekar]

From the FDA Transparency >> FDA basics about "Why are animals used for testing medical products?"

For medical devices, the focus of animal testing is on the device’s ability to function with living tissue without harming the tissue (biocompatibility). Most devices use materials, such as stainless steel or ceramic, that we know are biocompatible with human tissues. In these cases, no animal testing is required. However, some devices with new materials require biocompatibility testing in animals.

There are still many areas where animal testing is necessary and non-animal testing is not yet a scientifically valid and available option. However, FDA has supported efforts to reduce animal testing. In addition, FDA has research and development efforts underway to reduce the need for animal testing and to work toward replacement of animal testing.

 

[Mark Meer]

...even the surface structure can have an impact i.e. polished instead of rough; random or patterned etc.

True, but such factors are moot once you start taking extracts (which is the basis for a lot (all?) of the animal testing).

Most devices use materials, such as stainless steel or ceramic, that we know are biocompatible with human tissues. In these cases, no animal testing is required. However, some devices with new materials require biocompatibility testing in animals.

I can't help but be a bit cynical about such FDA public goodwill statements, only because in practice getting a 510k through by simply claiming use of material that "we know are biocompatible...[so] no animal testing is required" typically doesn't go over so well...

"Most devices use materials...no animal testing is required."
"...some devices with new materials require biocompatibility testing in animals."

Ya, right. More like "few" and "all".

 

[Julie O]

I can't help but be a bit cynical about such FDA public goodwill statements, only because in practice getting a 510k through by simply claiming use of material that "we know are biocompatible...[so] no animal testing is required" typically doesn't go over so well...

I am not sure why it is a statement of FDA public goodwill, but I would also have to disagree with it. Materials per se are not biocompatible. One type of material may be biocompatible for use in surgical gloves, but not for use as an implant. A material may be biocompatible for short-term contact, but not long term. Another may be biocompatible with the ophthalmic system, but not with the cardiovascular system. The biocompatibility of the material can also be affected by the manufacturing process, contact with packaging materials, and storage conditions.

Maybe it varies from NB to NB, but I haven't found the Europeans to be noticeably more lax on this than FDA. At least, not for Class III devices, which get reviewed for safety by the NBs. The testing that only gets reviewed by ISO 13485 auditors may be a different matter.

 

[J0anne]

If the materials are well established, such as SS 304 (Stainless Steel 304) and you have material data certification that it is in fact SS 304, you don't need to test on animals for most of the world. I don't have a copy of the standard to hand, but there is a flow chart that tells you to take a risk based approach where such things as SS 304 are used.

Japan still insist on animal testing regardless.

 

[Julie O]

I think 10993:1 is essentially a description of the risk-based approach, and the rest of the sections are details on specific aspects of the testing. I also endorse the risk-based approach, which is a process to be worked through as an alternative to just "knowing" that a material is biocompatible.

I came on board just as the silicone breast implant controversy was breaking, and I've never forgotten this response to a question about it at a regulatory conference:

"I think a year ago FDA would have said they know everything there is to know about silicone. I think right now they aren't sure they know anything at all."

So I tend to cringe when people talk about knowing a material is biocompatible. And I'm of the firm opinion that anyone who uses the term "FDA-approved material" should be permanently disbarred. As the biocompatibility bar has continued to rise over the years, I keep thinking that I've finally heard the last of this one, but, sometimes, no matter how hard you beat a dead horse, it just won't stay dead.

 

[Randy]

Good question and good answers, sometimes material has to be tested with living tissue...However people could be substituted for animals to make PETA and others happy....If they would volunteer to be 1st that would be OK as well (Of course using people has been tried and that argument lost as well)