An example of optimal phase II design for exposure response modelling
2010 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 37, no 5, 475-491 p.Article in journal (Refereed) Published
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 (E-0) 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.
Place, publisher, year, edition, pages
2010. Vol. 37, no 5, 475-491 p.
Exposure response, Optimal design, E-max model, Phase II clinical trial
IdentifiersURN: urn:nbn:se:uu:diva-134140DOI: 10.1007/s10928-010-9168-yISI: 000282873500002PubMedID: 20872056OAI: oai:DiVA.org:uu-134140DiVA: diva2:372167