Statistical Issues In Medical Device Trials


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George Koustenis,
David Breiter,
Boston Scientific
Roseann White,
Abbott Vascular
George Woodworth, Univ. of Iowa

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Statistical Issues In Medical Device Trials

  1. 1. FDA/INDUSTRY STATISTICS WORKSHOP: Washington, D.C. Sept. 29, 2006 Statistical Issues in Medical Device Trials George Koustenis, FDA-CDRH David Breiter, Boston Scientific Roseann White, Abbott Vascular George Woodworth, Univ. of Iowa 2008/2/27 1
  2. 2. The Use of Objective Performance Criteria (OPC) in Medical Device Evaluation FDA/Industry Statistics Workshop September 29, 2006 Washington, D.C. George Koustenis Division of Biostatistics Office of Surveillance and Biometrics 2008/2/27 Center for Devices and Radiological Health 2 U.S. Food and Drug Administration
  3. 3. OBJECTIVE The purpose of this presentation is to provide a brief introduction to the possible use of Objective Performance Criteria (OPC) in the evaluation of medical devices during the regulatory approval process. 2008/2/27 3
  4. 4. DEFINITION OF OPC Fixed Target(s) Objective and Meaningful Standard Provides Comparison in Evaluating Safety and Effectiveness Usually a Rate Surrogate for Control Group Benchmark for Minimally Acceptable Values Not a Control Group 2008/2/27 4
  5. 5. CONTROLS Standard Comparison for an Experimental Treatment Group of Patients with Same Condition, Demographics, & Prognostic Values By Controlling for as Many Variables as Possible – Any Differences are Presumed Due to New Intervention 2008/2/27 5
  6. 6. TYPES OF CONTROLS Concurrent Randomized Controlled Trial (RCT) The Gold Standard Effectively Minimizes Bias Effectively Balances Demographics & Unknowns Supports Basic Assumptions of Standard Statistical Methodology 2008/2/27 6
  7. 7. Historical Controls Compares Current Therapy & Patients Against Others Studied in Previous Investigations Not Randomized to Current Conditions May Be Too Far Removed in Time Very Difficult to Validate the Data from Historical Trials Tend to Produce More Positive Results 2008/2/27 7
  8. 8. ESTIMATES OF OPC’S Necessarily Driven by Historical Data Requires Appropriate Pooling of Different Investigations OPC’s Inherit All of Problems Seen with Historical Controls Even Sophisticated Pooling/Analytical Techniques Cannot Eliminate Basic Problems 2008/2/27 8
  9. 9. USE OF OPC’s In CDRH Some Current Use of OPC’s Cardiac Ablation Catheters Replacement Heart Valves Ophthalmics Hip Replacement Systems 2008/2/27 9
  10. 10. USE OF OPC’s In DEVICE TRIALS Given that the use of OPC represents a significant departure from the standard scientific approach to the design and analysis of medical device clinical trials, the question now becomes: when might it be appropriate to use this type of non- control comparison in the medical device approval process? 2008/2/27 10
  11. 11. CITED ADVANTAGES Of OPC’s Smaller Sample Size Standard Value for All Sponsors Save Time and Money Easier to Execute I.E. – “Least Burdensome” 2008/2/27 11
  12. 12. DISADVANTAGES Of OPC’s All the Problems Associated with Historical Controls Problems with Validity of Data & Analysis Problems with Advances in Practice of Medicine May be Disagreement on Final OPC Value Problems with Single Arm Trials Selection Bias May Not See Pre-Post Benefits 2008/2/27 12
  13. 13. DISADVANTAGES Of OPC’s May Not Be Least Burdensome Smaller Sample Size? N=100 or 150? Time and Resource Intensive to Develop Sets a Minimum Standard Superiority? Older and Older Data Protect and Promote the Public Health? 2008/2/27 13
  14. 14. WHEN MIGHT OPC’s Be USED? History of OPC’s in Medical Devices Non-Experimental or Quasi- Experimental Designs May be Valid in Certain Situations 2008/2/27 14
  15. 15. MINIMUM REQUIREMENTS WHEN OPC’s MIGHT Be USED Great Deal is Known About the Natural History of the Disease or Condition Underlying Patient Population is Well Described & Relatively Stable Extensive Clinical History & Experience with This Device 2008/2/27 15
  16. 16. MINIMUM REQUIREMENTS WHEN OPC’s MIGHT Be USED (cont.) Stable and Well Known Standard of Care Appropriate Ancillary Technology is Relatively Stable No Significant New Questions of Safety or Effectiveness Consensus Among FDA, Industry, Clinical, Academic and Patient Communities Expectation of Significantly Positive Treatment Effect 2008/2/27 16
  17. 17. HOW SHOULD OPC’s BE DERIVED? Data Driven Rigorous And Scientifically Valid Methodologies Valid Databases Appropriate Statistical Modeling Appropriately Designed and Powered Pivotal Trial Periodical Re-Evaluation and Updating the OPC’s 2008/2/27 17
  18. 18. OTHER IMPORTANT OPC ISSUES All Parties Must Have a Clear Understanding of the OPC in Medical Device Trials – Success and Failure OPC’s Already in Limited Use in Device Trials No Current General Policy of OPC Use in CDRH Need for Comprehensive, Coherent, and Consistent OPC Policy for Device Trials 2008/2/27 18
  19. 19. WHAT SHOULD THIS POLICY CONTAIN? Clear Definitions of All Appropriate Terms Established Guidance on Minimum Standards for a Device or Device Class Specific Roles Played by FDA, Industry, Clinical Community, Academia and Other Interested Parties Provisions for Periodic Updating of OPC Specific Guidance on Methodology to Derive an OPC Unambiguous Policy Regarding Failure to Meet OPC 2008/2/27 19
  20. 20. SUMMARY An introduction to the history and use of Objective Performance Criteria (OPC) in medical device evaluation Advantages and disadvantages of OPC’s When and how OPC might be used & developed Discussed the need for developing a CDRH policy regarding use of OPC in medical device trials General outline of this policy is presented in an effort to begin dialogue between CDRH, industry, clinical community & other interested parties 2008/2/27 20
  21. 21. REFERENCES Please see accompanying brief commentary Request electronic copy from 2008/2/27 21
  22. 22. Q&A 2008/2/27 22