title: Seamless Phase IIa/IIb and enhanced dose-finding adaptive design.
abstract: In drug development, when the drug class has a relatively well-defined path to regulatory approval and the enrollment is slow with certain patient populations, one may want to consider combining studies of different phases. This article considers combining a proof of concept (POC) study and a dose-finding (DF) study with a control treatment. Conventional DF study designs sometimes are not efficient, or do not have a high probability to find the optimal dose(s) for Phase III trials. This article seeks more efficient DF strategies that allow the economical testing of more doses. Hypothetical examples are simulated to compare the proposed adaptive design vs. the conventional design based on different models of the overall quantitative representation of efficacy, safety, and tolerability. The results show that the proposed adaptive design tests more active doses with higher power and comparable or smaller sample size in a shorter overall study duration for POC and DF, compared with a conventional design.
authors.affiliation: a Clinical Statistics US, Bayer HealthCare Pharmaceuticals Inc ., Whippany , New Jersey , USA.
authors.forename: Jiacheng
authors.initials: J
authors.lastname: Yuan
authors.affiliation: b Department of Biostatistics and Bioinformatics , Duke School of Medicine , Durham , North Carolina , USA.|c School of Public Health, Li Ka Shing Faculty of Medicine , University of Hong Kong , Hong Kong , China.
authors.forename: Herbert
authors.initials: H
authors.lastname: Pang
authors.affiliation: d Department of Mathematics , Hong Kong Baptist University , Hong Kong , China.
authors.forename: Tiejun
authors.initials: T
authors.lastname: Tong
authors.affiliation: e Novartis Pharmaceuticals Corporation , East Hanover , New Jersey , USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Xi
authors.affiliation: e Novartis Pharmaceuticals Corporation , East Hanover , New Jersey , USA.
authors.forename: Wenzhao
authors.initials: W
authors.lastname: Guo
authors.affiliation: e Novartis Pharmaceuticals Corporation , East Hanover , New Jersey , USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Mesenbrink
mesh_terms: D017322:Clinical Trials, Phase II as Topic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D011336:Probability; D012107:Research Design; D018401:Sample Size
keywords: Adaptive design; dose finding; proof of concept; seamless design; utility