Panel Discussion 1 George Williams Amgen

Barbara Tilley - Sample Size Estimation… Key point – considering both short term benefit of symptomatic treatment and long term course of disease – statistical model Design challenge – choice of baseline – relative to course of disease (e.g. on state for Parkinson's disease, duration of symptomatic treatment, de novo patients, length of wash-out periods) -what question being addressed – short or long term effects Model – assume speed of initial symptomatic effect is identical across patients Questions Impact of subsequent other therapies Impact of subsequent on and off states in Parkinson example Arbitrary six month time interval in Parkinson example Importance of long term duration and relationship to dropouts/lost to follow-up

Chris Coffey - Adaptive Designs… Continuing challenges in the wide adoption of adaptive designs in clinical trials Recognize the wide variety of adaptive designs Statistical and logistical Quinlan et al (2010) Clinical Trials Technical – timely data capture, drug supply management, information flow Regulatory – perception/official positions Change management – comfort level with traditional approaches Importance of simulations of such designs – statistical properties of the design Challenges for industry as well – project plans must allow enough time to thoroughly do the necessary planning and conduct the simulations / scenario analyses

Xiaoxi Zhang - Prediction of Patient Accrual… Very important practical problem in the execution of clinical trials Realistic targets for sample size rather than sample size that cannot be achieved in time and on budget Aid in monitoring of accrual to take action to enhance accrual Sophisticated models for accrual prediction Incorporates uncertainty versus ad hoc approaches Recognize early projections will inherently have wide CIs

Xiaoxi Zhang - Prediction of Patient Accrual… Challenges include: Constancy of assumptions Varying start times by site – IRBs Seasonal variation/holidays Protocol changes – amendments Impact of external events – results of other trials, evolution of the science Recruitment strategies change during course of the trial Increasingly geographically disperse enrollment Models need to handle reality of multi-site trials and allow monitoring of accrual by site

Xiaoxi Zhang - Prediction of Patient Accrual… Importance of careful feasibility assessment Physicians typically overestimate ability to accrue Importance of retention Prediction of outcome events for event based trials Lag of reporting/impact of adjudication processes

Steve Kimmel and Andrea Troxel - Adherence… Importance of improving adherence In practice of medicine Low adherence can lead to underestimation of effects in clinical trials Lottery incentive has potential Impact of other covariates (e.g., age) Value of randomized trials to assess intervention Protocol design impact adherence Appropriate patient selection Protocol simplicity Importance of visit adherence as well Reduce missing data