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Regul Toxicol Pharmacol. 2016 Oct;80:348-57. doi: 10.1016/j.yrtph.2016.05.002. Epub 2016 May 4.

Assessing the predictive value of the rodent neurofunctional assessment for commonly reported adverse events in phase I clinical trials.

Author information

1
Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
2
Amgen Inc., Global Patient Safety & Labeling, Thousand Oaks CA 91320, USA.
3
National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), Gibbs Building, 215 Euston Road, London, NW1 2BE, UK.
4
AstraZeneca R&D, da Vinci Building, Melbourn Science Park, Cambridge Road, Melbourn, Royston, Hertfordshire, SG8 6HB, UK.
5
GlaxoSmithKline, Safety Assessment Department, Park Road, Ware, UK.
6
National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), Gibbs Building, 215 Euston Road, London, NW1 2BE, UK. Electronic address: sam.jackson@nc3rs.org.uk.
7
Novartis DS&E and Oncology OGD, Postfach, CH-4002, Basel, Switzerland.
8
AstraZeneca R&D, Drug Safety & Metabolism, Cambridge, CB22 3AT, UK.
9
Novartis Institutes of Biomedical Research, Safety Pharmacology, CH-4057, Basel, Switzerland.
10
AstraZeneca R&D, Drug Safety & Metabolism, Alderley Park, SK10-4TG, Macclesfield, UK.

Abstract

Central Nervous System (CNS)-related safety concerns are major contributors to delays and failure during the development of new candidate drugs (CDs). CNS-related safety data on 141 small molecule CDs from five pharmaceutical companies were analyzed to identify the concordance between rodent multi-parameter neurofunctional assessments (Functional Observational Battery: FOB, or Irwin test: IT) and the five most common adverse events (AEs) in Phase I clinical trials, namely headache, nausea, dizziness, fatigue/somnolence and pain. In the context of this analysis, the FOB/IT did not predict the occurrence of these particular AEs in man. For AEs such as headache, nausea, dizziness and pain the results are perhaps unsurprising, as the FOB/IT were not originally designed to predict these AEs. More unexpected was that the FOB/IT are not adequate for predicting 'somnolence/fatigue' nonclinically. In drug development, these five most prevalent AEs are rarely responsible for delaying or stopping further progression of CDs. More serious AEs that might stop CD development occurred at too low an incidence rate in our clinical dataset to enable translational analysis.

KEYWORDS:

Adverse events; Central nervous system; First-in-human; Functional observational battery; Methods; Neurobehavioural assessment; Predictive value; Translation

PMID:
27155597
DOI:
10.1016/j.yrtph.2016.05.002
[Indexed for MEDLINE]
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