High dose selection in general toxicity studies for drug development: A pharmaceutical industry perspective

Area of Science:

• Pharmaceutical toxicology
• Drug safety assessment
• Nonclinical study design

Background:

• The selection of high doses in nonclinical toxicology studies is a complex and debated topic.
• Current terms like Maximum Tolerated Dose (MTD) and Maximum Feasible Dose (MFD) lack precise definition in study design.
• Existing principles for toxicology study design are applicable across regulatory, academic, and industrial settings.

Purpose of the Study:

• To provide a pharmaceutical industry perspective on selecting appropriate high doses for nonclinical toxicology studies.
• To emphasize the importance of demonstrating the full dose-response continuum in safety assessments.
• To highlight the need for relevance to human therapeutic doses and clinical context.

Main Methods:

• Discussion of dose selection strategies for nonclinical safety assessment.
• Consideration of the dose-response continuum, including No Observed Adverse Effect Level (NOAEL).
• Incorporation of clinical indication and phase-specific factors into dose selection.

Main Results:

• High dose selection requires balancing the demonstration of toxic effects with human relevance.
• Dose selection should encompass the range from NOAEL to toxic doses.
• Clinical context, including indication and study phase, must inform dose selection.

Conclusions:

• Appropriate high dose selection is critical for robust nonclinical safety assessment of new drugs.
• A comprehensive approach considering dose-response, human relevance, and clinical context is necessary.
• Standardized principles for dose selection benefit regulatory, academic, and industrial toxicology.