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
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 TF output will be a report and a peer-reviewed paper providing guidance on dose-setting.
- It is foreseen that the Task Force will complete its work within 8 months, with a subsequent period of dissemination activities anticipated.
- The Task Force kick-off meeting is anticipated to take place in Q3 2019.