Comparing Strategies for Trials with High Placebo Response

August 27, 2012

Placebo lead-in design is a design option to lower the impact of high placebo response rates on the success of a clinical trial. In placebo lead-in design all subjects receive placebo first, after which subjects who have not responded to placebo are randomized to placebo versus drug and the efficiency analysis commences. The goal of placebo lead-in trial is to increase the treatment difference in a trial compared to a standard single stage parallel design. Both placebo lead-in and a parallel design can be viewed as special cases of a two-stage design where only placebo non-responders continue in the second stage. Using the framework of the two-stage design we compute the optimal allocation ratio between drug and placebo in stage 1 to determine whether a single stage design, a placebo-lead-in design, or a two-stage design is the best design for a given set of response rates. Robustness of various designs is discussed.

Impact of Phase 2 Dose-finding Study Design on Phase 3 Probability of Success and Net Present Value

Martch 29, 2012

Traditionally, sample size considerations for phase 2 trials are based on the desired properties of the design and response information from the previous trials. In this presentation, we propose to design phase 2 trials based on program-level optimization. We present a framework to evaluate the impact that several phase 2 design features have on the probability of phase 3 success (PoS) and the expected net present value (NPV) of the product. These factors include the phase 2 sample size, decision rules to select a dose for phase 3 trials, and the sample size for phase 3 trials. Using neuropathic pain as an example, we use simulations to illustrate the framework and show the benefit of including these factors in the overall phase 2 design process. Among the findings are that while increased phase 2 sample size yields increased PoS uniformly, it can decrease NPV after achieving an optimum.