title: Repeated "Day 1" FOB testing in ICH S7A safety assessment protocols: The influence of within- and between-session learning.
abstract: A large number of CNS safety assessment studies using the standard Functional Observational Battery (FOB) are conducted each year at Contract Research Organizations throughout the globe. Study design characteristics are as varied as the Sponsors for whom they are contracted. Gender inclusion, sample sizes, and timing of the FOBs are generally negotiated during protocol development. The ICH S7A guidelines describe a dose-effect study design for CNS safety assessment to be conducted prior to the first dose administration in man. Additionally, some Sponsors attempt to use the CNS safety FOB to establish both time- and dose-related acute behavioral effects of their compound in this single critical safety study. In this review, we highlight the confounding influences of multiple postdose FOBs (Day 1) versus the more standard, single FOB scheduled near systemic Cmaxof the compound. Within- and between-session learning, combined with changes in vigilance/alertness/fatigue in both the animals and raters, can limit the generalizability of the FOB to accurately assess CNS effects under the current guidelines. Rationale is provided as to the tenuous nature of conducting simultaneous time- and dose-effect behavioral assessments as part of the core safety pharmacology programs.
authors.affiliation: Departments of Neurobehavioral Sciences, MPI Research, 54943 North Main Street, Mattawan, MI 49071, USA. Electronic address: david.gauvin@mpiresearch.com.
authors.forename: David V
authors.initials: DV
authors.lastname: Gauvin
authors.affiliation: Departments of Neurobehavioral Sciences, MPI Research, 54943 North Main Street, Mattawan, MI 49071, USA; Department of Psychology, Western Michigan University, Kalamazoo, MI, USA.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Zimmermann
authors.affiliation: Safety Pharmacology, and Drug Safety Evaluation, MPI Research, 54943 North Main Street, Mattawan, MI 49071, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Dalton
authors.affiliation: MPI Research, 54943 North Main Street, Mattawan, MI 49071, USA.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Baird
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods* / Q000592:standards*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000517:prevention & control; D006801:Humans; D000071220:Pharmaceutical Research / Q000379:methods* / Q000592:standards*
keywords: Contract research organization; Experimental confounds; Functional observational battery; Methodology; Practice effects; Rat