title: A multi-site comparison of in vivo safety pharmacology studies conducted to support ICH S7A & B regulatory submissions.
abstract: BACKGROUND
  Parts A and B of the ICH S7 guidelines on safety pharmacology describe the in vivo studies that must be conducted prior to first time in man administration of any new pharmaceutical. ICH S7A requires a consideration of the sensitivity and reproducibility of the test systems used. This could encompass maintaining a dataset of historical pre-dose values, power analyses, as well as a demonstration of acceptable model sensitivity and robust pharmacological validation. During the process of outsourcing safety pharmacology studies to Charles River Laboratories, AstraZeneca set out to ensure that models were performed identically in each facility and saw this as an opportunity to review the inter-laboratory variability of these essential models.
  
  
  METHODS
  The five in vivo studies outsourced were the conscious dog telemetry model for cardiovascular assessment, the rat whole body plethysmography model for respiratory assessment, the rat modified Irwin screen for central nervous system assessment, the rat charcoal meal study for gastrointestinal assessment and the rat metabolic cage study for assessment of renal function. Each study was validated with known reference compounds and data were compared across facilities. Statistical power was also calculated for each model.
  
  
  RESULTS
  The results obtained indicated that each of the studies could be performed with comparable statistical power and could achieve a similar outcome, independent of facility.
  
  
  CONCLUSIONS
  The consistency of results obtained from these models across multiple facilities was high thus providing confidence that the models can be run in different facilities and maintain compliance with ICH S7A and B.
authors.affiliation: Global Safety Pharmacology, Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. lorna.ewart@astrazeneca.com
authors.forename: Lorna
authors.initials: L
authors.lastname: Ewart
authors.forename: Aileen
authors.initials: A
authors.lastname: Milne
authors.forename: Debbie
authors.initials: D
authors.lastname: Adkins
authors.forename: Amanda
authors.initials: A
authors.lastname: Benjamin
authors.forename: Russell
authors.initials: R
authors.lastname: Bialecki
authors.forename: Yafei
authors.initials: Y
authors.lastname: Chen
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Ericsson
authors.forename: Stacey
authors.initials: S
authors.lastname: Gardner
authors.forename: Claire
authors.initials: C
authors.lastname: Grant
authors.forename: David
authors.initials: D
authors.lastname: Lengel
authors.forename: Silvana
authors.initials: S
authors.lastname: Lindgren
authors.forename: Sarah
authors.initials: S
authors.lastname: Lowing
authors.forename: Louise
authors.initials: L
authors.lastname: Marks
authors.forename: Jackie
authors.initials: J
authors.lastname: Moors
authors.forename: Karen
authors.initials: K
authors.lastname: Oldman
authors.forename: Mark
authors.initials: M
authors.lastname: Pietras
authors.forename: Helen
authors.initials: H
authors.lastname: Prior
authors.forename: James
authors.initials: J
authors.lastname: Punton
authors.forename: Will S
authors.initials: WS
authors.lastname: Redfern
authors.forename: Ross
authors.initials: R
authors.lastname: Salmond
authors.forename: Matt
authors.initials: M
authors.lastname: Skinner
authors.forename: Margareta
authors.initials: M
authors.lastname: Some
authors.forename: Andrea
authors.initials: A
authors.lastname: Stanton
authors.forename: Michael
authors.initials: M
authors.lastname: Swedberg
authors.forename: John
authors.initials: J
authors.lastname: Finch
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Valentin
mesh_terms: D000818:Animals; D004285:Dogs; D015195:Drug Design; D004335:Drug and Narcotic Control; D064420:Drug-Related Side Effects and Adverse Reactions; D017408:Guidelines as Topic; D006801:Humans; D007391:International Cooperation; D008297:Male; D008954:Models, Biological; D010993:Plethysmography, Whole Body / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013686:Telemetry / Q000379:methods; D018675:Toxicity Tests / Q000379:methods* / Q000592:standards
keywords: ANCOVA; ANOVA; AZ; AZGBR; AZSWE; AZUSA; Analysis of Covariance; Analysis of Variance; AstraZeneca; AstraZeneca Sweden; AstraZeneca United Kingdom; AstraZeneca United States of America; CNS; CR; Cardiovascular system; Central Nervous System; Central nervous system; Charles River Laboratories; ECG; Electrocardiogram; Gastrointestinal system; HR; HRM; Heart Rate; Heart Rate Mean; ICH; ICH S7A and B; Inter-laboratory variability; International Conference on Harmonisation; Intraperitoneal; MABP; Mean Arterial Blood Pressure; RR; Regulatory acceptance criteria; Renal system; Respiratory Rate; Respiratory system; S.E.M.; Safety pharmacology; Scientific validation criteria; Standard Error of the Mean; TV; Tidal Volume; WBP; Whole Body Plethysmography; beats per minute; bpm; breaths per minute; brpm; i.p.; s.c.; subcutaneous