1. Data Monitoring committees and adaptive decision-making
Steven snapinn
global biostatistical science, Amgen

2. outline Overview of Data Monitoring Committees
Some Current Issues With DMCs From a Pharmaceutical Industry Perspective
Adaptive Clinical Trials
DMC Issues Specific to Adaptive Clinical Trials

3. Overview of data monitoring committees
History
Need for a DMC
Composition
Scope of Responsibilities
Independence of the DMC
Setting Statistical Boundaries

4. Some current issues with Dmcs from a pharmaceutical industry perspective
Program-Wide DMCs
Key advantage
Broad overview of safety and efficacy
Disadvantages
Potential to stop for efficacy based on a “meta-analysis”
Combined set of minutes
Stopping for Futility
Can save resources and lead to early stopping for unexpected harm with respect to efficacy variable
Remains controversial
Adaptive Clinical Trials

5. Adaptive trials and the need for data monitoring
Many Different Types of Adaptations
Blinded vs Unblinded
Some Unblinded Adaptations Fall Outside the Typical DMC’s Responsibilities
Examples
Adaptive Dose-Finding
Seamless Phase 2/3 Designs
Adaptive Sample Size Reestimation
Focus on Efficacy, Not Safety
The DMC Is a Natural Group to Take This Responsibility

6. Dmc issues specific to adaptive clinical trials
Composition of the Committee
Need for Sponsor involvement
Potential for Adpative Decisions to Unblind
Other Issues

7. Composition of the committee
Skills Required for Adaptive Decision-Making May Differ From Skills Required for Normal DMC Activities
May Be Necessary to Add or Change Members
Statistician Needs to Educate the Committee on Possible Adaptations
Potentially Long Commitment for Seamless Phase 2/3 Designs
May Consider Having a Separate Committee for Adaptive Decisions
Unclear Who Should Perform the Interim Analysis

8. Need for sponsor involvement
Some Adaptive Decisions May Be Too Important or Complex for the Sponsor to Allow It to Be Made By an External Committee
Allowing the Sponsor to Be Unblinded Can Increase Risk to Trial Integrity
Potentially Unquantifiable Operational Bias
Gallo (2006) Recommendations
Minimal Sponsor Representation
Not Otherwise Involved in the Trial
Access to Results Only at Time of Adaptation
Appropriate Firewalls to Ensure Limited Access to Results

9. Potential for adaptive decisions to unblind
All Interim Decision-Making Processes Have Potential to Convey Information About Interim Results to Blinded Individuals
Concern That Adpative Rules Are Particularly Sensitive to This Problem
Most Problematic Case Is Sample-Size Re-Estimation With 1:1 Correspondence Between Magnitude of Observed Treatment Effect And Revised Sample Size
Gallo (2006) Argues That Same Standard Should Apply to Traditional And Adaptive Rules

10. Other issues Potential for Conflict Between Adaptive Rule And Safety
Example: Three-Arm Trial (2 Doses and Control) With Adaptive Rule for Dropping Ineffective Arm, and Effective Arm Appears Less Safe
Example: Adaptive Rule to Alter Allocation Ratio Will Result in More Subjects Allocated to More Toxic Treatment
Logistical Issue: Rapid Data Collection
If Results Are Informative Enough to Make Adaptive Decision, Is Equipoise Lost?
Computation Complexity and Lack of Standard Software