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

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

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

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

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

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

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

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

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

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