Introduction to Adaptive Design

1. Economic and Statistical Analysis of Healthcare Technology Teresa Nelson, MS Principal Statistician ©Technomics Research 2009

10. SSR – Efficient Use of Resources Feature Conservative Fixed SSR GSD Size Likely over-powered “ Right-sized” with respect to variability “ Right-sized” with respect to variability and effect size Use of resources Least efficient Moderately efficient Most efficient Type I error spent NA None Yes

14. Continuum of Options for Looking BROAD ACCESS Broad Sponsor access to interim comparative endpoint results AND dissemination into the public domain or to personnel conducting the trial NO ACCESS Independent DSMB with NO sponsor access to interim comparative endpoint results LIMITED ACCESS Charter instructs DSMB to unblind sponsor only if futility may be an issue or access to interim power FIREWALL ACCESS Small group within Sponsor has access to all interim comparative endpoint results

15. Continuum of Options for Looking Broad Firewall Limited No Access Feasibility Market Approval Unblinded Unblinded or Blinded Public dissemination OK NO public dissemination or sharing with personnel involved in trial conduct No FDA issue Acceptable to FDA Looking for endpoints for market approval trial Endpoint change due to external changes unlikely to be okay Endpoint change due to external changes more okay Endpoint change due to external changes okay

16. Continuum of Options for Looking Broad Firewall Limited No Access Feasibility Market Approval Unblinded Unblinded or Blinded Public dissemination OK NO public dissemination or sharing with personnel involved in trial conduct No FDA issue Acceptable to FDA Looking for endpoints for market approval trial Endpoint change due to external changes unlikely to be okay Endpoint change due to external changes more okay Endpoint change due to external changes okay

17. Continuum of Options for Looking Broad Firewall Limited No Access Feasibility Market Approval Unblinded Unblinded or Blinded Public dissemination OK NO public dissemination or sharing with personnel involved in trial conduct No FDA issue Acceptable to FDA Looking for endpoints for market approval trial Endpoint change due to external changes unlikely to be okay Endpoint change due to external changes more okay Endpoint change due to external changes okay

18. Dr. Burns, are you sure this is what statisticians call a double blind experiment?

26. Adaptive Randomization Conventional Covariate Response Fixed vs. modified Fixed Modified based on ongoing trial results Modification none Baseline covariates and trt assignment Response of the previous patients, e.g. ‘play the winner’ Goal Balance trt and control groups Reduce covariate imbalance Most ethical, pts receive better trt based on “up to the patient” results

27. Adaptive Randomization Conventional Covariate Response Fixed vs. modified Fixed Modified based on ongoing trial results Modification none Baseline covariates and trt assignment Response of the previous patients, e.g. ‘play the winner’ Goal Balance trt and control groups Reduce covariate imbalance Most ethical, pts receive better trt based on “up to the patient” results

34. CS #1: Trial Design *If already at highest (lowest) dose, repeat current dose Assign 1 st block to middle dose Assign next block to nearest lower dose* Assign next block to nearest higher dose* Evaluate Response Response in less than 60% of patients Response in greater than 60% of patients Stopping criteria met? NO Stopping criteria met? NO Yes Yes

44. CS #1: Efficient Sample size cut in half, even if continued to max of 200, sample size reduced by 120 patients!!!!! Fixed sample size parallel group design CS #1 Sample Size 40 pts at each dose + placebo = 320 patients 41 placebo, 85 drug (32 at optimal dose)= 126 patients

47. Seamless Phase II/III designs TRT A TRT C TRT B Control Learning Phase Confirmatory Phase TRT A TRT B TRT C Control Period of analysis and decision making

53. Thank you! Teresa Nelson, MS 218-463-5627 [email_address] www.technomicsresearch.com Ryan Wilson 612-234-8498 [email_address] www.symbiosclinical.com

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