Medical devices
In the case of medical devices, the most egregious submissions, ironically, failed for reasons other than genotoxic exposures. Thus, rarely if ever was a product denied approval or clearance solely as a result of a positive genotoxicity assay. But a positive result often led to investigations and further processing of the product to remove the genotoxin. Drugs with positive genotoxicity tests have this property added to the label, but in my experience, that is not the case for medical devices, even though I requested it at least once. Some medical devices contain bovine or porcine collagen or other material preserved with glutaraldehyde. These invariably tested positive in the Mouse Lymphoma Assay (MLA) but not Ames bacterial assays, even in some cases where the device was rinsed to remove glutaraldehyde. In cases where we were not aware of the presence of an animal product, or such presence was denied, a positive MLA led me to query about this and generally I was right. Genotoxicity test results were thus sometimes informative in unexpected ways. I never could understand why an unstable and reactive glutaraldehyde could still be genotoxic after incubation at 37° for 3 days. Maybe it reacted and produced another genotoxic product or there was an artifact related to this specific assay. This issue is still outstanding.
The requirement for genotoxicity tests in product submissions FDA-wide aided in general safety assessment, since product development always focused on assuring a non-genotoxic effect if feasible. However, in the medical device center there is a new policy of assaying for genotoxins via chemical characterization of medical device extracts instead of in vitro biological testing. Besides requiring identification of hundreds of constituents, [at the time I left] the analytical method didn’t generally include a step that would detect aldehydes like glutaraldehyde, formaldehyde, or nanoparticle effects. For this and other reasons, this seems problematic.
The FDA-wide harmonization of genotoxicity assessments no longer exists, as each center is operating independently and differently.