Session 9: Dose Finding and Selection in Clinical Phase
Organizers: Qiqi Deng (Boehringer-Ingelheim) and Joshua Betcher (Quintiles)
Chair: Susan Wang (Boehringer-Ingelheim)
Rebhi Bsharat (Quintiles) “Using utility index to evaluate risk-benefit of several doses to help in dose selection”
In early phase studies where the sample size is small and several endpoints are used for evaluation to choose candidate doses for latter stage of drug development, the challenge is choosing the best doses that have maximum efficacy and the best safety profile. Treatment arms including active control and/or placebo could give conflicting messages when evaluated based on different endpoints. A technique is presented to summarize overall utility of each dose and compare different doses to placebo or active control using a clinical utility index which is a multivariate utility function that summarizes the utility for each subject across all endpoints. Active doses are compared to placebo or active control using bootstrap confidence intervals. The technique supports informed-decision making based on evaluation of different scenarios using simulation.
Li Wang (Abbvie) “Enhanced understanding of MCPMod in Dose-ranging Studies”
MCPMod (Bretz et al, 2005 and Pinheiro et al. 2014) is the approach to provide additional insights for the selection of the “best” underlying dose-response model and controls FWER at the POC stage for model selection. The target dose is selected from the final model and is not bounded in the candidate set of the doses evaluated in the trial. They enable the more informative Phase II trial study design to provide a more solid basis for all subsequent dose selection strategies and decisions. Specifically, MCPMod approach receives regulatory supportive opinion, e.g. EMA – CHMP qualification opinion on 10/01/2013. In this research, we further evaluated the performance of MCPMod on MED estimation using weighted and unweighted AIC criteria and the impact of number of doses and different prior assumptions on model selection and restricted MED estimation.
Qiqi Deng (Boehringer-Ingelheim) “A robust method using ordinal linear contrast test to design dose ranging study”
Nowadays, many sponsors are working to speed up the clinical development process. A commonly used strategy is to combine the Proof of Concept (PoC) and the dose-ranging clinical studies into a single trial at the early Phase II development. In such trials, the primary objective is to establish the POC and make go-no go decision. And the important secondary objective is to identify a range of doses to move into phase III. We propose to use ordinal linear contrast test (also referred to as trend test) to design such a trial, which is easy to communicate to non-statisticians, simple to implement, and provides robust performance for different dose response curves under monotonic assumption. We will also discusses the implication of different ways of allocating patients to each treatment group, under a given total sample size – which is often limited by budget and ethical concerns.
Yaning Wang (FDA) “Regulatory Application of Exposure-Response Analyses in Dose Selection”
Exposure-response analyses are routinely conducted by Pharmacometric reviewers at FDA to address the key question: is the dose/dosing regimen selected consistent with the exposure-response relationships for both efficacy and safety? Such analyses are used to support the approved dose/dosing regimen and justify additional studies such as post-marketing requirement (PMR) or post-marketing commitment (PMC) studies to further optimize the dose/dosing regimen. Case studies will be shared to demonstrate the application of exposure-response analyses in regulatory decision making process.
