PMID- 27155597
OWN - NLM
STAT- MEDLINE
DCOM- 20170309
LR  - 20170309
IS  - 1096-0295 (Electronic)
IS  - 0273-2300 (Linking)
VI  - 80
DP  - 2016 Oct
TI  - Assessing the predictive value of the rodent neurofunctional assessment for 
      commonly reported adverse events in phase I clinical trials.
PG  - 348-57
LID - S0273-2300(16)30105-2 [pii]
LID - 10.1016/j.yrtph.2016.05.002 [doi]
AB  - 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.
CI  - Copyright (c) 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Mead, Andy N
AU  - Mead AN
AD  - Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
FAU - Amouzadeh, Hamid R
AU  - Amouzadeh HR
AD  - Amgen Inc., Global Patient Safety & Labeling, Thousand Oaks CA 91320, USA.
FAU - Chapman, Kathryn
AU  - Chapman K
AD  - National Centre for the Replacement, Refinement and Reduction of Animals in 
      Research (NC3Rs), Gibbs Building, 215 Euston Road, London, NW1 2BE, UK.
FAU - Ewart, Lorna
AU  - Ewart L
AD  - AstraZeneca R&D, da Vinci Building, Melbourn Science Park, Cambridge Road, 
      Melbourn, Royston, Hertfordshire, SG8 6HB, UK.
FAU - Giarola, Alessandra
AU  - Giarola A
AD  - GlaxoSmithKline, Safety Assessment Department, Park Road, Ware, UK.
FAU - Jackson, Samuel J
AU  - Jackson SJ
AD  - 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.
FAU - Jarvis, Philip
AU  - Jarvis P
AD  - Novartis DS&E and Oncology OGD, Postfach, CH-4002, Basel, Switzerland.
FAU - Jordaan, Pierre
AU  - Jordaan P
AD  - Novartis DS&E and Oncology OGD, Postfach, CH-4002, Basel, Switzerland.
FAU - Redfern, Will
AU  - Redfern W
AD  - AstraZeneca R&D, Drug Safety & Metabolism, Cambridge, CB22 3AT, UK.
FAU - Traebert, Martin
AU  - Traebert M
AD  - Novartis Institutes of Biomedical Research, Safety Pharmacology, CH-4057, Basel, 
      Switzerland.
FAU - Valentin, Jean-Pierre
AU  - Valentin JP
AD  - AstraZeneca R&D, Drug Safety & Metabolism, Alderley Park, SK10-4TG, Macclesfield, 
      UK.
FAU - Vargas, Hugo M
AU  - Vargas HM
AD  - Amgen Inc., Global Patient Safety & Labeling, Thousand Oaks CA 91320, USA.
LA  - eng
PT  - Journal Article
DEP - 20160504
PL  - Netherlands
TA  - Regul Toxicol Pharmacol
JT  - Regulatory toxicology and pharmacology : RTP
JID - 8214983
SB  - IM
MH  - Animals
MH  - Behavior, Animal/*drug effects
MH  - Central Nervous System/*drug effects/physiopathology
MH  - Central Nervous System Diseases/*chemically induced/physiopathology
MH  - *Clinical Trials, Phase I as Topic
MH  - Dose-Response Relationship, Drug
MH  - Drug-Related Side Effects and Adverse Reactions/*etiology/physiopathology
MH  - Humans
MH  - Mice
MH  - Rats
MH  - Reproducibility of Results
MH  - Risk Assessment
MH  - Species Specificity
MH  - Toxicity Tests/*methods
OTO - NOTNLM
OT  - Adverse events
OT  - Central nervous system
OT  - First-in-human
OT  - Functional observational battery
OT  - Methods
OT  - Neurobehavioural assessment
OT  - Predictive value
OT  - Translation
EDAT- 2016/05/08 06:00
MHDA- 2017/03/10 06:00
CRDT- 2016/05/08 06:00
PHST- 2016/01/04 00:00 [received]
PHST- 2016/04/20 00:00 [revised]
PHST- 2016/05/02 00:00 [accepted]
PHST- 2016/05/08 06:00 [entrez]
PHST- 2016/05/08 06:00 [pubmed]
PHST- 2017/03/10 06:00 [medline]
AID - S0273-2300(16)30105-2 [pii]
AID - 10.1016/j.yrtph.2016.05.002 [doi]
PST - ppublish
SO  - Regul Toxicol Pharmacol. 2016 Oct;80:348-57. doi: 10.1016/j.yrtph.2016.05.002. 
      Epub 2016 May 4.