Retrospective analysis of the potential use of virtual control groups in preclinical toxicity assessment using the eTOX database

Wright, Peter S R; Smith, G. F.; Briggs, Katharine; Thomas, Robert F.; Maglennon, Gareth; Mikulskis, Paulius; Chapman, Melissa; Greene, Nigel; Phillips, Benjamin U.; Bender, Andreas

doi:10.1016/j.yrtph.2022.105309

Cited by 9 publications

(8 citation statements)

References 59 publications

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“…To understand how replacing concurrent controls with VCGs influences the outcome of a study with respect to the so-called “treatment-relatedness” ( Wright et al, 2023 ), a study with a reported treatment-related change in calcium in male rats was selected. This study is denoted as “legacy study” in this article.…”

Section: Methodsmentioning

confidence: 99%

“…To avoid misleading impact of those lurking variables, adequately matching of HCD for generation of VCGs is key. The importance has recently been shown for clinical pathology parameters ( Wright et al, 2023 ) where the error rate in the recognition of treatment-related findings increased while loosening the selection criteria for HCD. In certain study types, such as carcinogenicity bioassays or the rat bone marrow micronucleus assays, requirements for the selection process of HCD are defined ( Greim et al, 2003 ; Keenan et al, 2009 ; Igl et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…In the non-clinical settings, several methods for generating virtual control groups were proposed and include Bayesian approaches to either replace concurrent controls with inclusion of historical data ( Kramer and Font, 2017 ; Wright et al, 2023 )—which is the goal of the VCG approach—or to increase the statistical power of studies ( Bonapersona et al, 2021 ). In regulatory toxicology the studies are conducted according to standardized guidelines ( FDA, 2000 ; OECD, 2008 ; EMA, 2010 ), which provide general recommendations for group sizes for each study type.…”

Section: Introductionmentioning

confidence: 99%

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Hurdles and signposts on the road to virtual control groups—A case study illustrating the influence of anesthesia protocols on electrolyte levels in rats

et al. 2023

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Introduction: Virtual Control Groups (VCGs) represent the concept of using historical control data from legacy animal studies to replace concurrent control group (CCG) animals. Based on the data curation and sharing activities of the Innovative Medicine Initiatives project eTRANSAFE (enhancing TRANSlational SAFEty Assessment through Integrative Knowledge Management) the ViCoG working group was established with the objectives of i) collecting suitable historical control data sets from preclinical toxicity studies, ii) evaluating statistical methodologies for building adequate and regulatory acceptable VCGs from historical control data, and iii) sharing those control-group data across multiple pharmaceutical companies. During the qualification process of VCGs a particular focus was put on the identification of hidden confounders in the data sets, which might impair the adequate matching of VCGs with the CCG.Methods: During our analyses we identified such a hidden confounder, namely, the choice of the anesthetic procedure used in animal experiments before blood withdrawal. Anesthesia using CO2 may elevate the levels of some electrolytes such as calcium in blood, while the use of isoflurane is known to lower these values. Identification of such hidden confounders is particularly important if the underlying experimental information (e.g., on the anesthetic procedure) is not routinely recorded in the standard raw data files, such as SEND (Standard for Exchange of Non-clinical Data). We therefore analyzed how the replacement of CCGs with VCGs would affect the reproducibility of treatment-related findings regarding electrolyte values (potassium, calcium, sodium, and phosphate). The analyses were performed using a legacy rat systemic toxicity study consisting of a control and three treatment groups conducted according to pertinent OECD guidelines. In the report of this study treatment-related hypercalcemia was reported. The rats in this study were anesthetized with isoflurane.Results: Replacing the CCGs with VCGs derived from studies comprising both anesthetics resulted in a shift of control electrolyte parameters. Instead of the originally reported hypercalcemia the use of VCG led to fallacious conclusions of no observed effect or hypocalcemia.Discussion: Our study highlights the importance of a rigorous statistical analysis including the detection and elimination of hidden confounders prior to the implementation of the VCG concept.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hurdles and signposts on the road to virtual control groups—A case study illustrating the influence of anesthesia protocols on electrolyte levels in rats

et al. 2023

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“…Replacement of control animals by synthetic control or VCs, leveraging the large volume of HCD available from legacy studies (internally or at Contract Research Organizations [CROs]) has recently been proposed by both individuals and groups. 3,8,11,14 This proposal presumes reporting of background findings in control databases occurs with fidelity equal to reporting of test article-effects.…”

Section: Overview Of the Initial Vcg's Conceptmentioning

confidence: 99%

“…In this context and taking advantage of the previous curation and analysis work from the eTOX initiative, 10 the concept of Virtual Control Groups (VCGs or ViCoGs) was introduced and discussed in recent papers. 3,11,14 The advent of digital technology offers the possibility of using curated digital data, including whole slide images (WSIs), to act as VCGs and potentially replace living animals (CCs) in toxicology studies. Despite significant challenges that will need to be overcome, implementation of VCGs does not seem out of reach and industry partners are more than ever committed to synergize efforts in anticipation of the tremendous positive impact on the ethical use of animals, cost savings, and animal availability for critical studies (especially dogs and nonhuman primates [NHPs]).…”

Section: Introductionmentioning

confidence: 99%

Toxicologic Pathology Forum Opinion Piece: Use of Virtual Control Groups in Nonclinical Toxicity Studies: The Anatomic Pathology Perspective

Grevot,

Boisclair,

Guffroy

et al. 2023

Toxicol Pathol

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In the last decade, numerous initiatives have emerged worldwide to reduce the use of animals in drug development, including more recently the introduction of Virtual Control Groups (VCGs) concept for nonclinical toxicity studies. Although replacement of concurrent controls (CCs) by virtual controls (VCs) represents an exciting opportunity, there are associated challenges that will be discussed in this paper with a more specific focus on anatomic pathology. Coordinated efforts will be needed from toxicologists, clinical and anatomic pathologists, and regulators to support approaches that will facilitate a staggered implementation of VCGs in nonclinical toxicity studies. Notably, the authors believe that a validated database for VC animals will need to include histopathology (digital) slides for microscopic assessment. Ultimately, the most important step lies in the validation of the concept by performing VCG and the full control group in parallel for studies of varying duration over a reasonable timespan to confirm there are no differences in outcomes (dual study design). The authors also discuss a hybrid approach, whereby control groups comprised both concurrent and VCs to demonstrate proof-of-concept. Once confidence is established by sponsors and regulators, VCs have the potential to replace some or all CC animals.

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“Appraisal of state-of-the-art” The 2021 Distinguished Service Award of the Safety Pharmacology Society: Reflecting on the past to tackle challenges ahead

Valentin

Sibony

Rosseels

et al. 2023

Journal of Pharmacological and Toxicological Methods

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Retrospective analysis of the potential use of virtual control groups in preclinical toxicity assessment using the eTOX database

Cited by 9 publications

References 59 publications

Hurdles and signposts on the road to virtual control groups—A case study illustrating the influence of anesthesia protocols on electrolyte levels in rats

Hurdles and signposts on the road to virtual control groups—A case study illustrating the influence of anesthesia protocols on electrolyte levels in rats

Toxicologic Pathology Forum Opinion Piece: Use of Virtual Control Groups in Nonclinical Toxicity Studies: The Anatomic Pathology Perspective

“Appraisal of state-of-the-art” The 2021 Distinguished Service Award of the Safety Pharmacology Society: Reflecting on the past to tackle challenges ahead

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