Assessing the predictive value of safety pharmacology studies

The potential of a novel pharmaceutical compound to cause an unexpected or adverse event (AE) in humans is currently assessed in safety pharmacology studies in animals. Testing for potential safety concerns in the central nervous system is carried out in a group of behavioural tests in rats or mice named the Functional Observational Battery or Irwin Test – neurobehavioral assessment is used here as a catch-all term).

Animal Models Framework analysis

To assess the concordance of data from animal studies with human outcomes, five pharmaceutical companies collaborated to provide data on 141 candidate compounds under development. The NC3Rs, acting as an honest broker, anonymised and analysed the data to assess the predictive nature of the FOB/Irwin test batteries. By comparing the occurrence of AEs in the rodent and human data for each compound, the ability of the animal model to predict pain, fatigue/somnolence, dizziness and nausea was assessed. The results of this analysis demonstrated that, within this dataset, the FOB/Irwin tests do not predict these common side effects.

This study demonstrates that animal models do not predict AEs for which there may not be a direct equivalent (nausea, dizziness). It was perhaps more surprising that the tests did not predict when a drug would cause fatigue in the human, as the animal tests included measures of locomotor activity and other relevant outcome measures. Within the confines of the dataset (as described in Mead et al 2016), this study demonstrates that current models do not adequately predict many CNS safety liabilities. Further work is required to identify the most human-relevant preclinical tests.

The NC3Rs is also investigating how the application of human tissue- and cell-based models may improve the predictive ability in safety pharmacology.

Survey on the Use and Impact of the Neurofunctional Assessment

A survey was carried out to ascertain how the neurofunctional assessments are used during drug development and their perceived impact. The survey was formulated and tested by an international expert working group and disseminated by email. Respondents indicated that both rodent and non-rodents are used as standard for CNS non-clinical safety assessment. Events recorded in the neurofunctional assessment were often predicted by a prior study, e.g. repeat toxicology study. Respondents were asked to score the perceived impact of each measure in the test batteries, and the measures were ranked. This indicated that some measures were perceived to have high impact on the downstream drug development process, whereas a significant number had little or no perceived value. Several areas were identified where changes could reduce the number of animals used, including the study of both sexes and the practice of ordering spare animals.

The streamlining of CNS safety pharmacology studies to include parameters which impact drug development could refine the use of animals in this area, but data is required on the use of individual measures from companies. This data could be used to assess how often individual measures a) produce an observed outcome and b) contribute to downstream decision making. This work has been published in the Journal of Pharmacological and Toxicological Methods.

Mead AN, Amouzadeh HR, Chapman K et al. (2016) Assessing the predictive value of the rodent neurofunctional assessment for commonly reported adverse events in phase I clinical trials; Regul Toxicol Pharmacol 80:348-357 doi: 10.1016/j.yrtph.2016.05.002

Jackson SJ, Authier S, Brohmann H et al. (2019) Neurofunctional test batteries in safety pharmacology – Current and emerging considerations for the drug development process; J Pharm Tox Meth; In Press; doi: 10.1016/j.vascn.2019.106602

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