DMC Issues from a Pharmaceutical Industry Perspective

1. DMC Issues from a Pharmaceutical Industry Perspective Steven Snapinn Amgen FDA-Industry Workshop September 15, 2005

2. Outline • Assessing the Need for a DMC • Independence of the DMC • Scope of the DMC’s Responsibilities • Issues in Setting the Stopping Boundaries • How Are Decisions Made? • Case Study 1: PRISM-PLUS • Stopping for Futility • Case Study 2: CONSENSUS II

3. Assessing the Need for a DMC • Considerations • Seriousness of the Medical Condition • Uncertainty of Efficacy and Safety • Size of the Trial • Duration of the Trial • Benefits of Having a DMC • Credibility • Experience • Neutrality

4. Internal vs. External DMCs • Early Development • Safety Monitoring by Study Team • Dose Escalation Decisions • Efficacy Monitoring by Internal DMC • Independent of Study Team • Phase III • External DMC Typical

5. Independence of the DMC • Committee Membership • DMC Independent of Sponsor • No Sponsor Participation in Closed Session • Preparation of Interim Reports • Regulatory Guidance Frowns on This Being a Sponsor Responsibility • Sponsors Typically Contract Independent Group

6. The Case for an Unblinded Sponsor Statistician • “Firewall” • Familiarity with the Study • Control of the Allocation Schedule and Interim Results • Sponsor’s Risk • Quality Assurance • Data Leaks • What Constitutes “Independence”?

7. Scope of the DMC’s Responsibilities • Safety Monitoring • Efficacy Monitoring • Timeliness and Accuracy of the Database • Protocol Adherence? • Sample Size Re-estimation? • Requests for ad hoc Analyses

8. Issues in Setting the Stopping Boundaries • Stopping Boundaries for Safety • Stopping Boundaries for Efficacy: Protect Patients in the Trial or Protect All Patients? • Require Overwhelming Evidence or Moderate Evidence? • Are Patients Fully Informed?

9. Issues in Setting the Stopping Boundaries (continued) • Review of Efficacy Data for Risk/Benefit Assessment Only • Set Extreme Efficacy Criterion (eg, 0.0005) • Protection for Sponsor • Group Sequential vs. Conditional Probability

10. Other Issues • Partial vs. Full Unblinding • Information Sharing Across DMCs • Monitoring Noninferiority Trials

11. How Are Decisions Made? • Decision-Making Authority • Independent Steering Committee • Sponsor • Sponsor’s Awkward Position • Reclaiming Type I Error • Efficacy Boundary Crossed But Trial Continues • Futility Boundaries

12. Case Study: PRISM-PLUS • Patients with Acute Coronary Syndrome • Non-Q-Wave Myocardial Infarction • Unstable Angina Pectoris • Evaluation of Tirofiban, an Inhibitor of Platelet Aggregation

13. PRISM-PLUS Study Design • Three Treatment Arms • Control Arm: Heparin Alone • Monotherapy Arm: Tirofiban Alone • Combination Arm: Heparin+Tirofiban • Composite Endpoint • Refractory Ischemia/Readmission for UAP • Myocardial Infarction • Death

14. Study Organization • Oversight by an Independent Steering Committee • Sponsor Representatives Attend SC Meetings • Makes Decisions on DMC Recommendations • Data Monitored by an Independent DMC • No Sponsor Representative (Other than Unblinded Statistician) • Recommendations on Trial Modification to SC

15. Interim Results of PRISM-PLUSComposite Endpoint

16. Interim Results of PRISM-PLUSDeath

17. Summary of Results • Composite Endpoint Rates Similar in Heparin and Tirofiban Groups • Death Rate Higher in the Tirofiban Group • 7-Day Mortality • 16/345 vs. 4/351 - p-value = 0.006 • Pooling Heparin and Combo Groups • 16/345 vs. 9/687 - p-value = 0.001 • Is This Sufficient Evidence?

18. The Pharmaceutical Sponsor’s Dilemma • DSMB Recommended Discontinuation of the Tirofiban Arm • Steering Committee Felt That the Evidence Was Insufficient • Representatives of the Sponsor Were Present at the Meeting • Can the Sponsor Allow Randomization to Continue when the DMC Believes That Patients Will Die Unnecessarily?

19. Final Results of PRISMDeath

20. Stopping for Futility • Inability of a Trial to Meet Its Objectives • Operational vs. Statistical • Goal Is to Preserve Resources • No Ethical Imperative • Group Sequential vs. Conditional Probability • Frequentist vs. Bayesian Methods

21. Stopping for Futility (continued) • One-Sided vs. Two-Sided Boundaries • Can Alpha Be “Reclaimed”? • Cost in Power and Secondary Objectives • Need for Prior Agreement

22. Case Study: CONSENSUS II • 9000 Patients with Acute Myocardial Infarction • Comparison of Enalapril and Placebo • Primary Endpoint is 6-Month Mortality • Assumed Rates: 12.0% vs. 9.6%

23. CONSENSUS II Interim Monitoring • Key Design Features • Frequent Interim Analyses • Terminate If Interim Results Clearly Indicate Lack of Benefit • Monitoring Plan Based on Conditional Probability • Future Rates Assumed Between Current Rates and Originally-Assumed Rates • Alpha Reclaimed

24. CONSENSUS II Interim Results

26. CONSENSUS II Lessons Learned • Stopping for futility is a difficult problem • Without Clear Trend Toward Efficacy or Harm There’s No Ethical Imperative • Without Hope for Benefit Patients Should Not Be Subjected to Risks • Prior Agreement Required • Within DMC • Between DMC and Trial Leadership

27. CONSENSUS II Lessons Learned (continued) • Stopping Boundary • Flexibility Is an Advantage • Reclaiming Alpha May Not Be Appropriate • Basing Conditional Probabilities Only on Patients With Complete Follow-Up Was a Disadvantage