title: An example of optimal phase II design for exposure response modelling.
abstract: This paper presents an example of how optimal design methodology was used to help design a phase II clinical study. The planned analysis would relate the clinical endpoint to exposure (measured via the area under the curve (AUC)), rather than dose. Optimal design methodology was used to compare a number of candidate phase II designs, and an algorithm for finding optimal designs was employed. The sigmoidal E(max) with baseline (E₀) model was used to relate the clinical endpoint to individual subject AUCs, and the primary metrics were D optimality and the standard error (SE) of the AUC required to yield a clinically relevant change in the clinical endpoint. The performance of the candidate designs were compared across four different 'true' exposure response relationships (determined from the analysis of an earlier proof of concept (PoC) study). The results suggested the total sample size should be increased from the planned 540 individuals, and that the optimal design with 700 individuals would be equivalent to 812 individuals with the reference design (a 16% gain). The performance with this design was considered acceptable, although all designs performed poorly if the true exposure response relationship was very flat. This work allowed a prospective assessment of the likely performance and precision from the exposure response modelling prior to the start of the phase II study, and hence allowed the design to be revised to ensure the subsequent analysis would be of most value.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. al.maloney@exprimo.com
authors.forename: Alan
authors.initials: A
authors.lastname: Maloney
authors.forename: Marloes
authors.initials: M
authors.lastname: Schaddelee
authors.forename: Jan
authors.initials: J
authors.lastname: Freijer
authors.forename: Walter
authors.initials: W
authors.lastname: Krauwinkel
authors.forename: Marcel
authors.initials: M
authors.lastname: van Gelderen
authors.forename: Philippe
authors.initials: P
authors.lastname: Jacqmin
authors.forename: Ulrika S H
authors.initials: US
authors.lastname: Simonsson
mesh_terms: D000465:Algorithms; D019540:Area Under Curve; D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D006801:Humans; D008954:Models, Biological; D012107:Research Design; D018401:Sample Size