The road to virtual control groups and the importance of proper body-weight selection.

Abstract

Virtual control groups (VCGs) created from historical control data (HCD) can reduce the number of concurrent control group animals needed in regulatory toxicity studies by up to 25%. This study investigates the performance of VCGs on statistical outcomes of body weight development between treatment and control groups in legacy studies. The objective is to reproduce the statistical outcomes of 28-day sub-chronic studies (legacy studies) after replacing the concurrent control group with virtual ones. In rodent toxicity studies initial body weight is used as surrogate for the age of animals. For the assessment of VCG-sampling methods three different approaches are explored: (i) sampling VCGs from the entire HCD ignoring initial body weight information of the legacy study, (ii) sampling from HCD matching the legacy study's initial body weights, and (iii) sampling from HCD with assigned statistical weights derived from legacy study initial body weight information. It is shown that the ability to reproduce statistical outcomes by virtual controls is mainly determined by the congruence between the legacy study and the HCD weight distribution: regardless of the chosen approach, the ability to reproduce statistical outcomes was well for VCGs when the legacy study's initial-body-weight distribution was similar to the HCD's. When the initial body weight range of the legacy study was at the extreme ends of the HCD's distribution, the weighted-sampling approach was superior. This article highlights the importance of proper HCD-matching by the legacy study's initial body weight and discusses required conditions to accurately reproduce body weight development.