Can you trust your animal study data?

Peers, Ian; South, Marie C.; Ceuppens, Peter R.; Bright, Jonathan; Pilling, Elizabeth A.

doi:10.1038/nrd4090-c1

Cited by 29 publications

(25 citation statements)

References 6 publications

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“…6 However, continued occurrences of clinical safety terminations calls into question the value of nonclinical testing in predicting human risk. 7,8 Nonetheless, when confidence in nonclinical safety data is high compounds are more likely to be safe in humans. 9 Uncertainty regarding safety predictions occurs at three major transition points in biopharmaceutical testing: (1) the transition inherent in using simple in vitro models to predict in vivo nonclinical (animal) results early in discovery; (2) the transition from nonclinical testing to human clinical trials; and (3) the transition from testing in well-controlled clinical trials to the larger diverse patient population post approval.…”

Section: Introductionmentioning

confidence: 99%

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

et al. 2017

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Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP'). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses complement traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.

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Section: Introductionmentioning

confidence: 99%

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

et al. 2017

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“…In general, it is believed that expert statistical input is currently under-utilized and can help address issues of robustness and quality in preclinical research (Peers et al 2012(Peers et al , 2014.…”

Section: What Are the Issues At Hand?mentioning

confidence: 99%

Preclinical data reproducibility for R&D—the challenge for neuroscience

Steckler

2015

Psychopharmacology

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“…Group sizes were based on the AstraZeneca good statistical practice review applied to the study. 24 At the start of the study, animals in the first group (group 1) were between 25 and 30 months of age, while those in the second group (group 2) were at least 31 months of age, with the oldest being 37 months. Dogs in both groups were sham dosed by insertion of an oral gavage tube once daily for 3 days.…”

Section: Methodsmentioning

confidence: 99%

Spontaneous Pathology and Routine Clinical Pathology Parameters in Aging Beagle Dogs

et al. 2015

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AstraZeneca ran a bespoke study to generate age-matched clinical pathology and histopathology data from a cohort of Beagle dogs aged between 25 and 37 months to support the use of these older animals in routine preclinical toxicology studies. As the upper age range of Beagle dogs routinely used in toxicology studies does not normally exceed 24 months, there is an absence of appropriate age-matched historical control data. The generation of such data was crucial to understand whether age-related differences in spontaneous findings might confound the interpretation of toxicology study data. While the majority of the histopathology findings in all the older dogs occurred at a similar prevalence as those expected in young adult dogs (<24 months), a number of differences were observed in the thymus (involution), bone marrow (increased adiposity), testes (degenerative changes), and lung (fibrosis, pigment and alveolar hyperplasia) that could be misinterpreted as a test article effect. Minor differences in some clinical pathology values (hemoglobin, alkaline phosphatase, absolute reticulocytes) were of a small magnitude and considered unlikely to affect the interpretation of study data.Keywords aging, background lesions, beagle, dog, clinical pathology, incidental findings, histopathology, toxicology studies While Beagle dogs were originally developed for hunting, they have been extensively used as a species for the toxicity testing of agrochemicals and pharmaceuticals. 2,4,22 Olson 21 provided data that supported the use of nonrodents in safety testing by comparing human toxicities with those identified in animals. The results showed the true positive concordance rate of 71% for rodent and nonrodent species combined, with nonrodents alone being predictive for 63% of human toxicities.Chronic toxicity testing in dogs is normally confined to studies with a maximum duration of 1 year, with animals typically being 6 to 12 months old at study start. As a result, publications detailing the incidence of spontaneous pathology findings in Beagles are confined to animals no older than 2 years. 12,[16][17][18]28 While chronic lifetime studies in Beagle dogs have been undertaken at the Lovelace Respiratory Research Institute (LLRI), 19 published data from these studies does not include detailed observations of the spontaneous pathology noted in dogs aged between 2 and 5 years.AstraZeneca had a cohort of older beagle dogs available for use on routine toxicity studies, with the age of all animals exceeding the upper age limit of Beagles routinely used in toxicity testing (>24 months), raising concerns about a lack of suitable age-and strain-matched historical control data and potential impact on the interpretation of histopathology findings.AstraZeneca has a commitment to fully implement the principles of replacement, reduction, and refinement (3 Rs) for the use of animals in research; therefore, the aim of the study described here was to generate a complete ''guideline compliant'' set of hematology, clinical chemistry, and ...

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Can you trust your animal study data?

Cited by 29 publications

References 6 publications

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

Preclinical data reproducibility for R&D—the challenge for neuroscience

Spontaneous Pathology and Routine Clinical Pathology Parameters in Aging Beagle Dogs

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