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

Area of Science:

• Toxicology
• Pharmacology
• Genetics

Background:

• Pharmaceutical development relies on carcinogenicity studies in Tg.rasH2-transgenic mice.
• High-dose selection is critical for these 6-month studies, influencing data reliability.
• Current methods include maximum tolerated dose (MTD) estimation, maximum feasible dose (MFD), exposure plateau, and limit doses.

Purpose of the Study:

• To review Merck's Tg.rasH2 carcinogenicity studies and assess high-dose selection strategies.
• To evaluate the predictive accuracy of 1-month range-finding studies for 6-month study tolerability.
• To determine optimal approaches for setting minimally toxic high doses in carcinogenicity assessments.

Main Methods:

• Review of eleven 6-month Tg.rasH2 carcinogenicity studies and their 1-month range-finding studies.
• Analysis of high-dose selection criteria: MTD estimation, MFD, or exposure plateau.
• Comparison of predicted tolerability from 1-month studies with observed tolerability in 6-month studies.

Main Results:

• High doses were selected based on MTD estimation (6 studies), exposure plateau (3 studies), and MFD (2 studies).
• One-month MTD estimation accurately predicted 6-month tolerability in 4 out of 6 studies.
• Two studies showed poorer-than-expected tolerability when MTD was used for high-dose selection.

Conclusions:

• The accuracy of MTD estimation from 1-month studies for predicting 6-month carcinogenicity study tolerability is variable.
• Using three or more dose levels is beneficial for ensuring adequate carcinogenicity evaluation, especially if the high dose approaches or exceeds the MTD.
• Refined strategies for high-dose selection are needed to improve the reliability of Tg.rasH2 carcinogenicity studies.