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.