Regulatory Forum commentary: alternative mouse models for future cancer risk assessment

Area of Science:

• Pharmaceutical sciences
• Toxicology
• Regulatory affairs

Background:

• Current International Council for Harmonisation (ICH) S1 guidance mandates extensive rodent carcinogenicity studies for pharmaceuticals.
• There is a growing need to optimize drug development timelines and reduce animal testing.
• Advancements in predictive toxicology offer alternative approaches to traditional long-term studies.

Purpose of the Study:

• To discuss proposed revisions to ICH S1 guidance regarding rodent carcinogenicity assessment for small molecule pharmaceuticals.
• To introduce a weight-of-evidence approach for determining the necessity of carcinogenicity studies.
• To evaluate the utility of alternative models like the rasH2 mouse in cancer risk assessment.

Main Methods:

• Discussion and proposal of a weight-of-evidence framework for carcinogenicity study decisions.
• Consideration of specific scenarios based on human cancer risk levels.
• Evaluation of 6-month transgenic mouse models (rasH2, p53+/-) and 2-year mouse/rat studies.
• Planning for a prospective evaluation of the proposed approach.

Main Results:

• A weight-of-evidence approach could streamline carcinogenicity assessment, potentially reducing the number of required studies.
• Compounds with high or minimal human cancer risk may bypass certain traditional rodent studies.
• The rasH2 mouse model shows promise for predicting relevant neoplastic findings with fewer irrelevant outcomes compared to 2-year rodent models.

Conclusions:

• The proposed revisions aim to make carcinogenicity testing more efficient and relevant.
• Alternative mouse models may offer valuable insights into human cancer risk assessment.
• A prospective evaluation is crucial to validate the proposed weight-of-evidence approach before revising ICH S1 guidance.