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Economic and Statistical Analysis of  Healthcare Technology Teresa Nelson, MS Principal Statistician  ©Technomics Research 2009
[object Object],[object Object],Ryan Wilson Symbios Clinical, Inc. Adaptive Trial Design
Agenda  ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Outline/Goals ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Adaptive Designs are ,[object Object],[object Object],[object Object]
Adaptive Designs include ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Why use adaptive design? ,[object Object],[object Object],[object Object]
Sample Size Re-Estimation (SSR) ,[object Object],[object Object],[object Object]
What should be done? Option 1:   Plan a  fixed trial  using a  conservative sample size , i.e. highest variability estimate and the lowest effect size.  Option 2:   ,[object Object],[object Object],[object Object],[object Object],Option 3: Use a group sequential design (GSD)
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
SSR – Regulatory Acceptance ,[object Object],[object Object]
Access to What?  ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
What to consider when looking  ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
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
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
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
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
Dr. Burns, are you sure this is what statisticians call a double blind experiment?
Under-utilized tool - CP and PD ,[object Object],[object Object],[object Object],[object Object]
CP and PD - Uses ,[object Object],[object Object],[object Object]
Group Sequential Designs (GSD) ,[object Object],[object Object],[object Object],Note:  Last look can be set based on practical limitations, e.g. available budget First Look Last Look Variability Smallest Largest Effect Size Biggest Smallest Power 80% Higher?
GSD – Potential Operational Bias ,[object Object],[object Object],[object Object],[object Object]
Call for Further Adaptations   ,[object Object],[object Object],[object Object],[object Object]
Where are the new designs used?   ,[object Object],[object Object],[object Object],[object Object]
Call for Further Adaptations   ,[object Object],[object Object],[object Object],[object Object]
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
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
Adaptive Randomization Summary ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Adaptive Dose Escalation (ADE) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Case Study #1: Migraine Headaches ,[object Object],[object Object],[object Object]
CS #1:  Motivation ,[object Object],[object Object],[object Object]
CS #1:  Trial Design ,[object Object],[object Object],[object Object],[object Object]
CS #1:  Trial Design ,[object Object],[object Object]
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
 
CS #1:  Stopping Rule ,[object Object],[object Object],[object Object],[object Object],[object Object]
CS #1: Determining Maximum Size ,[object Object],[object Object],[object Object]
CS #1: Additional Sampling ,[object Object],[object Object]
CS #1: Changes for Practical Implementation ,[object Object],[object Object],[object Object]
 
CS #1:  Simulation Used to…  ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Rate Median Trial Size, 95%  Type I Error < 5% 120 – 130,  135 – 200 Power > 80% 125 – 150 , 145 – 200
CS #1: Results ,[object Object],[object Object],[object Object],[object Object],[object Object],2.5 mg dose Placebo P-value 66%  27% 0.0001
CS #1: Ethical ,[object Object],[object Object],[object Object],[object Object],[object Object]
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
Other ADE Trial Types  ,[object Object],[object Object],[object Object],[object Object]
Seamless Phase II/III designs  ,[object Object],[object Object],[object Object],[object Object]
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
Seamless Phase II/III Implementation ,[object Object],[object Object],[object Object]
Seamless Phase II/III Implementation ,[object Object],[object Object],[object Object],[object Object]
Best fit for newer adaptations ,[object Object],[object Object],[object Object],[object Object],[object Object]
Good fit for Medical Device Trials ,[object Object],[object Object],[object Object],[object Object]
Resources ,[object Object],[object Object],[object Object],[object Object]
Thank you! Teresa Nelson, MS 218-463-5627 [email_address] www.technomicsresearch.com   Ryan Wilson 612-234-8498 [email_address] www.symbiosclinical.com
If interested in contracting our services please contact: Kim Martinson Vice President-Business Development Email:  [email_address] Ph: 218-331-2272 www.TechnomicsResearch.com

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Intro To Adaptive Design

  • 1. Economic and Statistical Analysis of Healthcare Technology Teresa Nelson, MS Principal Statistician ©Technomics Research 2009
  • 2.
  • 3.
  • 4.
  • 5.
  • 6.
  • 7.
  • 8.
  • 9.
  • 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
  • 11.
  • 12.
  • 13.
  • 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?
  • 19.
  • 20.
  • 21.
  • 22.
  • 23.
  • 24.
  • 25.
  • 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
  • 28.
  • 29.
  • 30.
  • 31.
  • 32.
  • 33.
  • 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
  • 35.  
  • 36.
  • 37.
  • 38.
  • 39.
  • 40.  
  • 41.
  • 42.
  • 43.
  • 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
  • 45.
  • 46.
  • 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
  • 48.
  • 49.
  • 50.
  • 51.
  • 52.
  • 53. Thank you! Teresa Nelson, MS 218-463-5627 [email_address] www.technomicsresearch.com Ryan Wilson 612-234-8498 [email_address] www.symbiosclinical.com
  • 54. If interested in contracting our services please contact: Kim Martinson Vice President-Business Development Email: [email_address] Ph: 218-331-2272 www.TechnomicsResearch.com