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FDA warns of common deficiencies in nitrosamine safety submissions
Summary
FDA reviewers commonly find submissions with inadequate enhanced AMES assays, proposals that rely only on negative AMES results to set alternate AI limits, and improper surrogate selection for read-across, the presenter said.
The presenter listed three top pitfalls FDA pharmacology/toxicology reviewers encounter when assessing nitrosamine submissions: (1) inadequate enhanced AMES assays, (2) proposals that set alternate AI limits solely on a negative enhanced AMES result, and (3) improper use of surrogate read-across.
"This slide is listed a top 3 PDE files we identified," the official said, identifying inadequate enhanced AMES testing (including failure to test at recommended high doses), solvent interference, missing positive controls, and insufficient metabolic activation conditions as frequent problems. The presenter emphasized that a negative enhanced AMES alone is not sufficient to justify an alternate AI limit and that FDA recommends a suite of assays (enhanced AMES, in vitro mammalian mutation assays and in vitro metabolism studies) to support AI limits up to 1,500 ng/day.
The official urged applicants to provide robust assay design, appropriate controls, and structural justification when using surrogate data for read-across, and to avoid approaches the agency currently does not accept without sufficient supporting evidence.
