Data Monitoring Committees: Current Issues and Challenges Some Discussion Points Jim Neaton University of Minnesota

A. Nunn – BIG BROTHER or friend in need Role of the DMC: Protect patient safety and safeguard interests of participants Ensure validity and credibility of trial How much expert independent advice? Examples of responding to external evidence/change in guidelines (without strong evidence) Timing and importance of initial DMC review of protocol. Educational and supportive role (a critical friend)

Questions Raised by Presentation: How do you see your role as a DMC member? Is it the same for all DMCs you sit on? Are expectations different for publically funded and industry funded studies? Whose responsibility is it to react to external information? Blinded investigators/sponsor/funder? Unblinded DMC?

J. Wittes – DMC’s Role in Monitoring Futility General review of futility and types trials where it should be considered. Two examples: Interim assessment of futility in the absence of guidelines (importance of considering safety – risk:benefit). DMC flexibility in using futility guidelines. Consideration of other factors, e.g., secondary outcomes, subgroups. Address futility up front with DMC and show how it plays out in practice.

Questions Raised by Presentation: How should risk:benefit be considered in futility guidelines? Appropriate timing of assessments? Is a null result important? How much flexibility should DMCs be permitted in assessing futility in the presence (or absence) of guidelines?

S. Snapinn – Adaptive Decision Making Following brief overview of DMCs and some issues relevant to pharma, focuses on DMC issues specific to adaptive trials. Unblinded vs blinded; for unblinded adaptations such as dose-finding, seamless phase 2/3 and sample size re-estimations, DMC is natural group, but… Composition of committee (perhaps add members or another committee) Sponsor involvement Potential unblinding Consideration of safety, logistics, loss of equipoise, and computational complexity.

Questions Raised by Presentation: Under what circumstances can unblinded adaption based on efficacy be safely performed? For seamless phase 2/3? For sample size increase? For dropping an arm? Who should carry out the adaptive decision making? DMC? Sponsor? Separate committee? Where is adaptive decision making described and how should patients be informed? Protocol? Informed Consent? Statistical Analysis Plan?

S. Ellenberg – Straying from Planned Monitoring Approach Guidelines, not rules. Balancing implication of trial results for current and future patients. Case example of HIV treatment trial in children in South Africa: Monitoring guidelines for efficacy; no specific guideline for safety. Changing standard of care/guidelines in developed countries. Economic implications. Treatment guidelines based on observational data. “Proof beyond reasonable doubt” and 3 SD monitoring plan. DMC uncomfortable with 3 SD plan. Request for unplanned analysis. Composite outcome of clinical endpoints and laboratory measures; difference in all-cause mortality.

Questions Raised by Presentation: How much flexibility should DMCs be permitted in assessing early efficacy? Proof beyond reasonable doubt? Can unblinded statisticians carry out unplanned analyses without knowledge of investigators/sponsor? Is the DMC experienced in subject matter?

General Themes Role and expertise of DMC Early review, particularly if you are planning to be a critical friend. Broad or narrowly defined independent oversight Adaptation Responding to new data/changing guidelines DMC flexibility Assessing futility without pre-specified guidelines and/or not following guidelines. Changing efficacy guidelines Requesting additional data without knowledge of investigator/sponsor