Toward implementing virtual control groups in nonclinical safety studies: Workshop report and roadmap to implementation

Historical data from control groups in animal toxicity studies is currently mainly used for comparative purposes to assess validity and robustness of study results. Due to the highly controlled environment in which the studies are performed and the homogeneity of the animal collectives it has been proposed to use the historical data for building so-called virtual control groups, which could replace partly or entirely the concurrent control. This would constitute a substantial contribution to the reduction of animal use in safety studies. Before the concept can be implemented, the prerequisites regarding data collection, curation and statistical evaluation together with a validation strategy need to be identified to avoid any impairment of the study outcome and subsequent consequences for human risk assessment. To further assess and develop the concept of virtual control groups the transatlantic think tank for toxicology (t4) sponsored a workshop with stakeholders from the pharmaceutical and chemical industry, academia, FDA, pharmaceutical, contract research organizations (CROs), and non-governmental organizations in Washington, which took place in March 2023. This report summarizes the current efforts of a European initiative to share, collect and curate animal control data in a centralized database and the first approaches to identify optimal matching criteria between virtual controls and the treatment arms of a study as well as first reflections about strategies for a qualification procedure and potential pitfalls of the concept.
Plain language summaryAnimal safety studies are usually performed with three groups of animals where increasing amounts of the test chemical are given to the animals and one control group where the animals do not receive the test chemical. The design of such studies, the characteristics of the animals, and the measured parameters are often very similar from study to study. Therefore, it has been suggested that measurement data from the control groups could be reused from study to study to lower the total number of animals per study. This could reduce animal use by up to 25% for such standardized studies. A workshop was held to discuss the pros and cons of such a concept and what would have to be done to implement it without threatening the reliability of the study outcome or the resulting human risk assessment.