DMC Issues from a Pharmaceutical Industry Perspective

Steven Snapinn

Amgen

FDA-Industry Workshop

September 15, 2005

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

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

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

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

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”?

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

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?

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

Other Issues

• Partial vs. Full Unblinding

• Information Sharing Across DMCs

• Monitoring Noninferiority Trials

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

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

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

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

Interim Results of PRISM-PLUSComposite Endpoint

Time Point Heparin (N=351)

Tirofiban (N=345)

Combination (N=336)

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%)

Interim Results of PRISM-PLUSDeath

Time Point Heparin (N=351)

Tirofiban (N=345)

Combination (N=336)

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%)

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?

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?

Final Results of PRISMDeath

Time Point Heparin (N=1616)

Tirofiban (N=1616)

2 Days 4 (0.2%) 6 (0.4%)

7 Days 25 (1.6%) 16 (1.0%)

30 Days 59 (3.6%) 37 (2.3%)

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

Stopping for Futility (continued)

• One-Sided vs. Two-Sided Boundaries

• Can Alpha Be “Reclaimed”?

• Cost in Power and Secondary Objectives

• Need for Prior Agreement

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%

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

CONSENSUS II Interim Results

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%

All Rand. Pts Pts w/6 Mo. FU Cond. Prob

CONSENSUS II Final Results

0

0.02

0.04

0.06

0.08

0.1

0.12

1 31 61 91 121 151

Study Day

Pro

po

rtio

n D

ea

d.

Placebo

Enalapril

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

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