1 adaptive design working group PhRMA adaptive design working group on behalf of Keaven Anderson Suman Bhattacharya Alun Bedding Don Berry Christy Chuang-Stein Sylva Collins David DeBrota Vlad Dragalin Richard Entsuah Paul Gallo Brenda Gaydos Andy Grieve David Henry Tony Ho Rod Humerickhouse Michael Krams Gary Littman Jeff Maca Cyrus Mehta Binh Nguyen Alan Pallay Inna Perevozskaya Jose Pinheiro Michael Poole Judith Quinlan Jerry Schindler Gernot Wassmer

2 adaptive design working group problem statement challenges with current drug development models –increased clinical development cost and duration –reduced yield of successful NDAs –high attrition rate in late stages of development (phase II/III)

3 adaptive design working group opportunities facilitate understanding & implementation of adaptive designs ……and by doing so………..……………………… improve quality, speed and efficiency of decision making in clinical drug development –bring more winners onto market quickly –discard losers early –shift towards a more seamless integrated approach to clinical R&D optimize patient treatment within a given trial –maximize patient exposure to doses/drugs that work –minimize patient exposure to doses/drugs that dont work

4 adaptive design working group adapting in the light of accumulating data adaptations can include –sample size (stopping early, increasing sample size) –treatment allocation ratios –dose / treatment arms (dropping, adding arms) –adapting hypothesis (primary objective, primary endpoint) –patient population (entry criteria) –observational scheme –test statistics –stages of the experiment (e.g. seamless phase II/III) –dynamic randomization based on baseline covariates

5 adaptive design working group challenge adaptive designs not yet routinely used –perception that there might be regulatory concerns –extra time&resource required to design/implement non-standard designs –lack of internal/external buy-in to concept –lack of infrastructure for timely data collection and data analysis –lack of training/experience in best practices for adaptive design methods

6 adaptive design working group working streams outline (JS) rationale – when to adapt (MK) definition and classification of adaptive designs (VD) dose-response finding trials (BG) seamless phase II/III (JM) Implementation (SC) sample size re-estimation (CCS) regulatory issues (PG) case studies (SB)

7 adaptive design working group objective develop and communicate recommendations –integrating perspectives from industry, academia, health authorities

8 adaptive design working group questions? comments?