The real world of regulatory genotoxicity
It’s generally the case that most products exhibiting overt genotoxicity are not submitted to FDA for approval at all, unless for life threatening conditions or those indications where there are no reasonable alternatives. Regulatory genotoxicity reviews may characterize weak or inconsistently mutagenic test articles. These tests are not easy to perform or to review. Thus, I want to call out and note the efforts of colleagues at FDA and in the regulated industry for this difficult work. In a sense, however, we are doing the same thing we have done for the last 40 years, presently just doing it a little better. Instead of detecting mutants in bacteria and mammalian cells, we can specify which mutations and where, via ecNGS and in different cells and systems. There is a focus on quantitative assessments, a linear extrapolation in a 4-dimensional world. This is useful in certain contexts, but current assessments are not likely to enlighten human risk of a specific FDA product under review. We need a new paradigm or new approaches to better address human risk. This may be more likely with the advent of big data analysis, but it won’t happen unless we admit that the present offerings aren’t sufficient.