The virtual control group (VCG) concept provides a potential opportunity to reduce animal use in drug development by replacing concurrent control groups (CCGs) in nonclinical toxicity studies. This work investigated the feasibility and reliability of using VCGs in place of CCGs. A historical control database (HCD), constructed from Genentech Inc. rat toxicity study data, was reviewed to understand trends and sources of variability in control animals over time, and to identify data curation requirements for assembling VCGs, e.g., alignment of units of measurement. Several endpoints were investigated and stratified against different study design parameters. Sex, route of administration, fasting status, and body weight at study initiation were among the parameters that were indicated as key matching criteria. With a high-level understanding of potential sources of variability, a retrospective proof-of-concept (POC) study was designed, evaluating a historical rat pilot toxicity study for test article-related changes. A masked interpretation of the study was conducted using its CCG and two unique VCGs that were constructed from individual animal data pulled from our HCD. While the results of the microscopic pathology assessment and most endpoints were similar across the different control groups, the POC revealed the risk of using VCGs to interpret subtle test article-related changes in clinical pathology parameters. Within the context of our POC, it appears the use of a VCG is not completely equivalent to the CCG, especially with clinical pathology parameters. Additional work is needed to understand the potential utility, and thus, viability of VCGs in other contexts.
Keywords: clinical pathology; historical control data; nonclinical toxicity studies; pathology; reduction of animal use.
This study explored the potential of virtual control groups (VCGs) to reduce the number of living control animals in drug development. The process involves using historical control animal data instead of live control animals in toxicity studies. Several parameters were identified as crucial factors that must be aligned in assembling VCGs. The VCG concept was tested using a historical rat toxicity study by comparing results against the conventional control group as well as two different VCGs. Although results were similar in most cases, interpreting subtle changes in clinical pathology parameters was almost impossible when using the VCGs. Further work is needed to fully optimize and assess the potential of VCGs. The significance of this work lies in the possibility of reducing the number of animals used in testing, in support of the 3Rs (replace, reduce, and refine).