Toxicologic Pathology· 2026Q2
Scientific and Regulatory Policy Committee Points to Consider: Virtual Control Groups and Their Implications for Anatomic and Clinical Pathology Evaluation During Nonclinical Toxicity Studies
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- Q2SCImago
- 2026year
Short summary
Virtual control groups (VCGs) are unlikely to fully replace concurrent control groups (CCGs) in nonclinical toxicity studies due to VCGs' inability to account for all study-specific variables, leading to potential distortion of clinical pathology endpoints (31-49% interpretation error rates).
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Key points
- Concurrent control groups (CCGs) remain the gold standard for controlling study variables in toxicity testing.
- Pure virtual control groups (VCGs) are unlikely to replicate CCG discernment due to differences in biological, environmental, and procedural attributes.
- Clinical pathology endpoints show high vulnerability to VCG distortion, with reported nonreproducibility rates of 31-49%.
- Hybrid control groups (reduced CCG + VCG) offer a balanced approach to reduce animal use while maintaining scientific rigor.
- Major upgrades to historical control data (HCD) are needed, including comprehensive metadata and access to archived tissue images.
AI-generated from the title and abstract; the full text is not read.
Abstract
Replacement of concurrent control groups (CCG) with virtual control groups (VCG) has been advocated as a strategy to reduce animal use in nonclinical toxicity testing. This "Points to Consider" paper examines VCG utility as it impacts toxicologic pathology endpoints and identifies the following points. (1) The CCG remains the gold standard, as it best controls for extrinsic and intrinsic study variables in discriminating subtle effects. (2) Pure VCG are unlikely to provide the same discernment since historical control data (HCD) from which VCG are assembled do not share all biological, environmental, husbandry, and procedural attributes of animals in the current study. (3) Clinical pathology endpoints are particularly vulnerable to VCG distortion given their dynamic range and sensitivity to preanalytical variables, with proof-of-concept studies demonstrating nonreproducibility rates for data interpretation of 31% to 49%. (4) Hybrid control groups combining reduced CCG with VCG are the most rational implementation strategy, balancing 3Rs (reduction, refinement, replacement) goals with scientific rigor and ongoing HCD refreshment. (5) The HCD pools require major upgrades, including comprehensive individual animal metadata, particularly for preanalytical and analytical variables, and (6) access to archived tissues as whole-slide scanned images, permitting reevaluation by the study pathologist using consistent nomenclature and grading criteria. (7) No major regulatory authority currently accepts VCG as a replacement for CCG in Good Laboratory Practice studies, and (8) proprietary data and data-sharing barriers to building sufficiently large multi-institutional HCD databases remain unresolved. (9) The VCG feasibility is highly species-dependent. (10) Multiple other new approach methodologies and modified study designs can support reduced animal use when VCG are not an optimal approach.
The authors' abstract, as published at the source. Toxicologic Pathology, 2026 · DOI ↗
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