Regulatory Forum Commentary* Counterpoint: Dose Selection for rasH2 Mouse Carcinogenicity Studies

Area of Science:

• Toxicology
• Preclinical drug development
• Carcinogenicity studies

Background:

• Dose selection for long-term carcinogenicity studies is critical for preclinical drug safety assessment.
• RasH2 mouse models are utilized for carcinogenicity testing.
• Maximum tolerated dose (MTD) from range-finding studies informs high-dose selection.

Purpose of the Study:

• To retrospectively evaluate the adequacy of MTD determination from 1-month range-finding studies for selecting high doses in 6-month rasH2 mouse carcinogenicity studies.
• To assess the reliability of MTD criteria (body weight gain, mortality, organ toxicity) in dose selection.

Main Methods:

• Retrospective analysis of 11 compounds with completed range-finding and 6-month rasH2 mouse carcinogenicity studies.
• Evaluation of MTD criteria including at least 10% body weight gain decrease, mortality, and target organ toxicity.
• Comparison of sponsor-proposed high doses with doses suggested by regulatory bodies.

Main Results:

• MTD from range-finding studies appropriately identified high doses for pivotal studies in 8 out of 11 compounds.
• High doses were based on decreased body weight gain (2 compounds) or mortality (7 compounds).
• One study used the maximum feasible dose; regulatory agencies sometimes suggested different doses.

Conclusions:

• The MTD approach using range-finding studies is generally effective for selecting high doses in rasH2 mouse carcinogenicity studies.
• Criteria for MTD, particularly mortality and body weight changes, are key indicators for dose selection.
• Regulatory input may influence dose selection, and high mortality in pivotal studies may necessitate dose adjustments.