The unblinded sample size re-assessment (ubSSR) has been categorized as a "less-well understood" type of adaptive design in the CDER/CBER draft guidance on adaptive design. There has been, however, an increase in application of this type of design since the publication of this guidance. In this talk we will present selected case studies of trials using the uSSR. The presentation will address trial designs, regulatory interactions and operational challenges.

Methods for controlling the type-1 error of an adaptive group sequential trial were developed in seminal papers by Cui, Hung and Wang, Lehmacher and Wassmer, and Muller and Schafer. However, corresponding solutions for the equally important and related problem of parameter estimation at the end of the adaptive trial have not so far been completely satisfactory. In this paper a method is provided for computing a two sided confidence interval having exact coverage, along with a point estimate that is median unbiased, for the primary efficacy parameter in a two arm adaptive group sequential design. The possible adaptations are not confined to sample size alterations but also include data dependent changes in the number and spacing of interim looks and changes in the error spending function. The procedure is based on mapping the final test statistic obtained in the modified trial into a corresponding backward image in the original trial.

The accelerated use of adaptive design in clinical trials has provided drug research and development a more flexible and effective approach to better distribute resources and fitting patients' needs. Nevertheless, the extensive adaptive design research mainly focuses on the logistics of the trial itself lacking the global view which should incorporate both drug innovation and finance considerations. In this paper, we compare the adaptive design to the traditional fixed sample size design for phase 2 dose finding trials to optimize Net Present Value (NPV) for a drug via simulations of a single Phase 2 trial followed by 2 phase 3 trials. Results demonstrate that the adaptive design not only requires smaller sample size with higher probability of success in a phase 3 study, but also produces higher expected NPV than the fixed design in the long run.

In past work we have shown the value of program level optimization of Phase 2 and Phase 3 clinical trial designs for neuropathic pain (Patel N et.al. 'Designing Phase 2 Trials Based on Program-Level Considerations: A Case Study for Neuropathic Pain', Drug Information Journal, 2012, 46 (4) 439-454). The objective in that publication was to maximize Expected Net Present Value (ENPV) of the program while taking into account both efficacy and safety considerations. In this talk we will discuss extensions of that work to carrying two doses into Phase 3 when Phase 2 results indicate sufficient separation in efficacy between them in addition to meeting efficacy and safety targets. We consider situations where results may require additional Phase 3 programs for regulatory approval to enable taking two doses to market. In addition to the objective of maximizing ENPV we examine optimization with the objective of maximizing clinical utility.