Dose Selection Task Force

 

Terms of Reference

Provide guidance for dose-setting in repeated-dose toxicity studies. In the development of the guidance, the following elements will be included:

• Critical review of the basis for using a maximally tolerated dose
• Discussion of the dilemma of identifying hazard versus identifying artefact
• A response to the RAC’s thoughts on the utility of range-finding studies
• Examination of pharmacokinetic and physiological considerations in dose-setting
• Discussion on the question of accuracy versus sensitivity for hazard identification
• Recommendations for dose setting

Objectives

The objective of the Task Force is to provide guidance on dose-setting to support appropriate design and interpretation of toxicity studies. Recent opinions published by MSC-RAC on low top dose selection in animal toxicity studies have indicated an apparent intent of increasing dosages systematically in view of the criteria used for classification and labelling and ED assessment. Moreover, there has been an attempt to limit or stop the use of kinetics-based dose level selection by at least one EU member state. This raises the question of inappropriate dose-setting potentially leading to unjustified CMR classification and the need for science-based guidance.

While regulators and policy makers need to promote chemical safety, they should take all aspects in the process of safety assessment of chemicals into account. These include, risk assessment, C&L requirements as well as animal welfare. The Task Force represents an opportunity to help provide the best information to achieve such balance as well as to help support the appropriate design and interpretation of toxicity studies.

 

Timeline and deliverables

• The Task Force was active between 2019 and 2022 and produced TR 138 and Sewell et al 2022.
• The focus of the Task Force work, and above two publications, was dose setting in repeat dose studies.
• A dedicated subgroup of the Task Force was reactivated in 2023 to work on dose setting in DART studies and published the result of their work in early 2024.