Zhaoling Meng, Tao Sheng, Lei Ma, Qiang Lu, Dimple Patel and Hui Quan
sanofi
Objectives: Dose selection for confirmative Phase 3 studies is always considered as one of the most difficult tasks in drug development. When the endpoint is of event type, the difficulty for dose selection could increase due to the relatively small Phase 2 study sample size and lack of sufficient data to appropriately quantify the dose-response relationship. We explored the utilization of plasma concentration data for a more informative dose justification through the exposure-response relationship modeling.
Methods: A negative binomial PK/PD model for accounting over-dispersion is applied to establish the relationship between exposure and a recurrent event endpoint. Baseline covariates which potentially can impact treatment effect are included. Through the PK/PD model, treatment effects of different doses can be predicted for dose justification. Clinical trial simulations (CTS) were utilized to incorporate the PK/PD modeling results and Phase 2 knowledge, assist the selection of Phase 3 patient population and trial design options, assess the impact of the design assumption uncertainty and predict Phase 3 probability of success.
Results: The annualized exacerbation event rate in asthma was fitted with the above models. The approach provided satisfactory results for dose justification. Also, trial simulation provided further useful information for dose selection in achieving the desired probability of success.
Conclusions: PK/PD modeling on a recurrent event endpoint combined with CTS can ensue in a more informative decision making for the Phase 3 dose selection.
Reference: PAGE 24 (2015) Abstr 3420 [www.page-meeting.org/?abstract=3420]
Poster: Methodology - Study Design