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The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
The Role of Data Monitoring Committees 
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The Role of Data Monitoring Committees 

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During this presentation, Ron Kershner, Ph.D. discussed the responsibilities of DMCs from the perspective of protecting patient safety and providing critical, independent oversight to key study …

During this presentation, Ron Kershner, Ph.D. discussed the responsibilities of DMCs from the perspective of protecting patient safety and providing critical, independent oversight to key study objectives. Drawing on past clinical trials to illustrate key points, Ron addressed DMC operational considerations, such as meeting frequency and content, control of information, data cleaning issues and scope/format of data tabulations.

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  • 1. 2 0 11 FA L L B I O M E T R I C S W E B I N A R S E R I E S The Role of Data Monitoring CommitteesSept. 20, 2011 Presented by Ronald Kershner, Ph.D.
  • 2. Ronald Kershner, Ph.D.  Vice President, Biostatistics and Data Operations  25+ years of clinical research experience – Includes over 24 NDAs in various therapeutic areas – Served on over 20 data monitoring committees  Authored more than 30 publications and presentations with a recent focus on eClinical technologies and independent data monitoring committees  Ph.D. in Statistics from Cornell University2011 FALL BIOMETRICS WEBINAR SERIES
  • 3. Today’s Topics3 1) Reasons for DMCs 2) Roles, objectives and set-up for DMCs 3) Operational considerations 4) Statistical considerations: p-value adjustments 5) Where companies get it wrong 2011 FALL BIOMETRICS WEBINAR SERIES
  • 4. Reasons for DMCs  Ethics  Insurance2011 FALL BIOMETRICS WEBINAR SERIES
  • 5. Reasons for DMCs: Ethics5  Oversight function to insure patient safety  Monitor and be able to quickly react to any untoward safety events 2011 FALL BIOMETRICS WEBINAR SERIES
  • 6. Reasons for DMCs: Insurance6 Operational Issue  Provide oversight function of study progress  Insure study will have reasonable likelihood of achieving basic objectives – Futility probability  Early warning system for operational issues – Critical design parameters – Sample size considerations may warrant adaptive design  Stop early – No efficacy or unacceptable safety – Early, compelling, untoward, unexpected efficacy 2011 FALL BIOMETRICS WEBINAR SERIES
  • 7. Roles, Objectives and Set-up for DMCs  DMC  Executive Committee  Data Analysis Center2011 FALL BIOMETRICS WEBINAR SERIES
  • 8. DMC Charter8  Define roles and responsibilities of DMC members  Communication with Executive Committee  Scope of data reviews  Structure and timing of meetings 2011 FALL BIOMETRICS WEBINAR SERIES
  • 9. Committee Roles9 DMC Executive Committee  Review data tabulations  Responsible for study from ongoing clinical trial oversight and conduct  Deliberations are  Membership: company, confidential investigators  Make recommendations to  Decision makers Executive Committee 2011 FALL BIOMETRICS WEBINAR SERIES
  • 10. DMC Members10 Who to include: Who NOT to include:  Independent clinical members  Company/sponsor/client – Therapeutic area experts  Study investigators – No vested interest in  Investigator’s company company or outcome of contact trial  Individuals who can change or  Independent statistician influence patient recruitment  Individuals with data classification responsibilities  Individuals who could control or change study design, objectives or planned analyses 2011 FALL BIOMETRICS WEBINAR SERIES
  • 11. Key Points Comparing the Committees11 DMC Executive Committee  Independent  Company representation  Access to data  Investigator representation  No decisions, (optional) recommendations to  NO access to data Executive Committee  Decision makers, based on recommendations from DMC 2011 FALL BIOMETRICS WEBINAR SERIES
  • 12. Number of Meetings12  Function of – Recruitment rate – Size of study  Can be more frequent for AEs  Conference calls, web conferences, or face-to face 2011 FALL BIOMETRICS WEBINAR SERIES
  • 13. DMC Meetings13 Open Sessions Closed Sessions Minutes  Executive  DMC Only  Document Committee  Unblinded data deliberations  DMC review  Confidentiality is  No unblinded data key 2011 FALL BIOMETRICS WEBINAR SERIES
  • 14. Assure Confidentiality of Interim Results14 Case Study: Sepsis  Potential blockbuster with estimated $1B/year market potential  NYT: 12 Feb 1993  Centoxin – Efficacy endpoint in pivotal study changed based on knowledge of interim results – NDA terminated 2011 FALL BIOMETRICS WEBINAR SERIES
  • 15. Data for DMC Member Review15 What information needs to be provided to the DMC members for meetings? ✓ Patient accounting a) ✓ Demographics/medical history b) ALL OF ✓ Enrollment summaries c) THESE ✓ AEs/SAEs – coded summaries d) ✓ Basic efficacy summaries e) 2011 FALL BIOMETRICS WEBINAR SERIES
  • 16. Operational Considerations  Keep review scope focused – “Interim analysis” is not final analysis  Emphasize simple tables and graphics, not listings  Information needs to be current – Current is more important than clean2011 FALL BIOMETRICS WEBINAR SERIES
  • 17. Example: Lab Data17  Hematology, LFTs  2-year study  Lab panels every month  6 LFTs X 24 visits = 144 displays  Don’t use: Normal range shift tables? Change from baseline?  Consider: Use 1 table to display any value outside a biologically significant boundary at any time – Biologically significant = 3 or 4X upper limit or CDC toxicity level 2011 FALL BIOMETRICS WEBINAR SERIES
  • 18. Plan for Rapid Retrieval of Outcomes18 Important to minimize time lag between CRF at site versus in- house EDC Paper CRFs  Very helpful alternative to  Short forms, worksheets paper  Phone calls  Make sure data is entered  Working/temporary at the sites databases  Help Desk support 2011 FALL BIOMETRICS WEBINAR SERIES
  • 19. Other Considerations19  Resource intensive process, particularly for paper CRFs – Monitoring – Programming – Data Management  Additional analysis requests based on DMC input and reviews – More tables, ad hoc requests Should company be made aware? 2011 FALL BIOMETRICS WEBINAR SERIES
  • 20. Statistical Considerations: p-value Adjustments  When DMC looks at interim data, p-value adjustments are necessary – Avoid over reaction to early trends – Maintain nominal alpha level of 0.05 for the final analysis2011 FALL BIOMETRICS WEBINAR SERIES
  • 21. P-value adjustments21  Multiple looks require an adjustment to the p- value  Need to control overall Type I error rate  Type I error = 0.05 for one look = 0.14 for 5 looks = 0.20 for 10 looks 2011 FALL BIOMETRICS WEBINAR SERIES
  • 22. Control type I error and maintain nominal 0.05 alpha for final analysis22 Interim analyses utilize p-values at levels of approx. 0.0001 at each look versus 0.05 at each look e.g., 6 interim analyses (6 looks): Final alpha = 0.05 – 6*0.0001 = 0.0494 2011 FALL BIOMETRICS WEBINAR SERIES
  • 23. Z Values for Clofibrate-Placebo Differences in Proportion of Deaths by Month23 2011 FALL BIOMETRICS WEBINAR SERIES
  • 24. Key Points24  There are sound reasons to have a DMC monitor ongoing data  P-value adjustments need to be made  P-value adjustments for interim looks can be very small and final alpha can be maintained very near 0.05 2011 FALL BIOMETRICS WEBINAR SERIES
  • 25. Where Companies Get it Wrong  Administrative analyses  DMC for safety only  Blinding the DMC2011 FALL BIOMETRICS WEBINAR SERIES
  • 26. Administrative Analyses26  Look at data with no intent to modify study  Look at data for operational (“insurance”) issues  Since no intent to change, no adjustment of p- values should be necessary  If efficacy data are involved, adjustment is needed – Always a potential to overreact to early trends – Major red flag 2011 FALL BIOMETRICS WEBINAR SERIES
  • 27. Safety Only?27 Should DMCs be used for review of safety only? ✗ Yes a) DMC needs access both efficacy and safety ✓ No b) to assess risk and benefit 2011 FALL BIOMETRICS WEBINAR SERIES
  • 28. Restrict Monitoring for Safety Only28 Case Study: AMD  Limited Phase II dosing information  First major entry into patients was two large Phase III studies – Limited safety data  Efficacy endpoint: mean difference of > 2 lines between treatment and placebo after two years of therapy 2011 FALL BIOMETRICS WEBINAR SERIES
  • 29. Restrict Monitoring for Safety Only29 Case Study: AMD 2011 FALL BIOMETRICS WEBINAR SERIES
  • 30. Restrict Monitoring for Safety Only30 Case Study: AMD  Results: only 1 of 2 studies showed significance  Reason: high placebo response rate 2011 FALL BIOMETRICS WEBINAR SERIES
  • 31. Blinding of Data31 Does the data need to be blinded for the DMC review? ✗ Yes a)  Not an FDA or ICH requirement  Imposed by companies to: – “Prevent bias” ✓ No b) – “Avoid over reaction to early trends” 2011 FALL BIOMETRICS WEBINAR SERIES
  • 32. ICH E932 Interim analysis requires unblinded access to treatment group assignments - 4.1 Interim analysis …involves access to … unblinded data and results - 4.5 2011 FALL BIOMETRICS WEBINAR SERIES
  • 33. Controlling Bias…Overreaction33  The DMC does not make decisions  DMC has no vested interest (unlike company)  Monitoring boundaries are in place  Degree of empowerment of DMC comes from Executive Committee and is described in the Charter 2011 FALL BIOMETRICS WEBINAR SERIES
  • 34. Summary  Patient safety is key  DMC is an independent group  Charter describes roles and responsibilities  Monitoring boundaries are needed  DMC needs to be unblinded and needs to assess both benefit and risk2011 FALL BIOMETRICS WEBINAR SERIES
  • 35. Upcoming Webinars35 Register at www.premier-research.com/webinars ▪ IVR/IWR…More than just Randomization 11 October at 11:00 am EDT Speakers: Bruce Bailey and Ryan Michaud ▪ Streamlining Data Management Start-up 15 November at 11:00 am EST Speaker: Cheryl Silva ▪ Strategies for Implementing CDISC 13 December at11:00 am EST Speaker: Thomas Kalfas 2011 FALL BIOMETRICS WEBINAR SERIES
  • 36. Questions? Ronald Kershner, Ph.D. Vice President, Biostatistics and Data Operations Centre Square West 1500 Market Street, Suite 3500 Philadelphia, PA 19102 Telephone: 215.282.5444 ron.kershner@premier-research.com2011 FALL BIOMETRICS WEBINAR SERIES

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