Nonclinical Safety Testing with Virtual Control Groups

Virtual Control Groups are set to reduce animal use in medicines development. The European Medicines Agency (EMA) has released a draft Qualification Opinion endorsing the use of Virtual Control Groups to replace or reduce concurrent control groups in non-GLP rat dose-range finding studies.

Equivalent Safety Conclusions Without Extra Animals

Reanalyses of eight legacy rat studies showed that replacing concurrent control groups with Virtual Control Groups produced the same overall study conclusions. Key endpoints including No Observed Adverse Effect Level (NOAEL), Highest Non-Severely Toxic Dose (HNSTD), target organ identification, and relevant biomarkers remained unchanged. This approach directly supports the 3Rs principles by significantly cutting the number of animals required in early safety testing.

High Replicability Across Legacy Studies

When Virtual Control Groups were constructed using predefined matching criteria, the primary objectives of dose-range finding studies were consistently preserved. Matching factors included test facility, strain, sex, supplier, route of administration, vehicle, and initial body weight within a five-year window. Even in cases with minor numerical differences in certain clinical pathology parameters, the overall toxicological interpretation and dose selection decisions stayed identical.

Curated Database Powers Reliable Matching

The methodology depends on a well-curated historical control database developed by the Innovative Health Initiative VICT3R consortium. Data from previous studies were standardised using the CDISC SEND format and enriched with key demographic details. A detailed Standard Operating Procedure guides the construction of Virtual Control Groups, allowing limited, justified flexibility in matching criteria when supported by statistical verification.

Regulatory and Economic Benefits of 3Rs Innovation

This EMA endorsement of Virtual Control Groups marks an important step toward embedding New Approach Methodologies in regulatory toxicology. By reducing control animals that traditionally make up to 25% of study cohorts, the approach lowers both animal use and associated costs while shortening early development timelines.

The draft opinion is open for public consultation until 12 May 2026. For the full details, read the EMA’s announcement on virtual control groups.