title: Assessing the predictive value of the rodent neurofunctional assessment for commonly reported adverse events in phase I clinical trials.
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.
authors.affiliation: Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Andy N
authors.initials: AN
authors.lastname: Mead
authors.affiliation: Amgen Inc., Global Patient Safety & Labeling, Thousand Oaks CA 91320, USA.
authors.forename: Hamid R
authors.initials: HR
authors.lastname: Amouzadeh
authors.affiliation: National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), Gibbs Building, 215 Euston Road, London, NW1 2BE, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chapman
authors.affiliation: AstraZeneca R&D, da Vinci Building, Melbourn Science Park, Cambridge Road, Melbourn, Royston, Hertfordshire, SG8 6HB, UK.
authors.forename: Lorna
authors.initials: L
authors.lastname: Ewart
authors.affiliation: GlaxoSmithKline, Safety Assessment Department, Park Road, Ware, UK.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Giarola
authors.affiliation: 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.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Jackson
authors.affiliation: Novartis DS&E and Oncology OGD, Postfach, CH-4002, Basel, Switzerland.
authors.forename: Philip
authors.initials: P
authors.lastname: Jarvis
authors.affiliation: Novartis DS&E and Oncology OGD, Postfach, CH-4002, Basel, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Jordaan
authors.affiliation: AstraZeneca R&D, Drug Safety & Metabolism, Cambridge, CB22 3AT, UK.
authors.forename: Will
authors.initials: W
authors.lastname: Redfern
authors.affiliation: Novartis Institutes of Biomedical Research, Safety Pharmacology, CH-4057, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Traebert
authors.affiliation: AstraZeneca R&D, Drug Safety & Metabolism, Alderley Park, SK10-4TG, Macclesfield, UK.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Valentin
authors.affiliation: Amgen Inc., Global Patient Safety & Labeling, Thousand Oaks CA 91320, USA.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002490:Central Nervous System / Q000187:drug effects* / Q000503:physiopathology; D002493:Central Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D051381:Rats; D015203:Reproducibility of Results; D018570:Risk Assessment; D013045:Species Specificity; D018675:Toxicity Tests / Q000379:methods*
keywords: Adverse events; Central nervous system; First-in-human; Functional observational battery; Methods; Neurobehavioural assessment; Predictive value; Translation