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 DMCs 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
• Sponsors Risk
• Quality Assurance
• Data Leaks
• What Constitutes Independence?

7
Scope of the DMCs 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
• Sponsors 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 HeparinTirofiban
• 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
Time Point Heparin (N351) Tirofiban (N345) Combination (N336)
2 Days 24 (6.8) 26 (7.5) 19 (5.6)
7 Days 59 (16.8) 59 (17.1) 39 (11.6)
30 Days 78 (22.2) 81 (23.5) 63 (18.8)
16
Interim Results of PRISM-PLUSDeath
Time Point Heparin (N351) Tirofiban (N345) Combination (N336)
2 Days 1 (0.3) 2 (0.6) 0 (0.0)
7 Days 4 (1.1) 16 (4.6) 5 (1.5)
30 Days 14 (4.0) 21 (6.1) 7 (2.1)
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 Sponsors 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
Time Point Heparin (N1616) Tirofiban (N1616)
2 Days 4 (0.2) 6 (0.4)
7 Days 25 (1.6) 16 (1.0)
30 Days 59 (3.6) 37 (2.3)
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
All Rand. Pts Pts w/6 Mo. FU Cond. Prob
Analysis Enal PBO Enal PBO Rej. Acc.
1st 40/6725.9 31/6334.9 None None
6th 178/20798.6 159/20827.6 38/35610.7 34/3519.7 1.1 16.5
7th 242/26909.0 215/26938.0 89/74412.0 74/72410.2 0.1 58.4
Final 312/304410.2 286/30469.4 164/147511.1 146/14779.9 0.01 94.8
25
(No Transcript)
26
CONSENSUS II Lessons Learned

• Stopping for futility is a difficult problem
• Without Clear Trend Toward Efficacy or Harm
  Theres 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