11 Add a DMC What if it acts inconsistently with guidelines? Something really unexpected happens? DMC initiates change Steering Committee initiates change
12 Reasons for unanticipated changes Unexpected high-risk group Changed standard of care Statistical method defective Too few endpoints Assumptions of trial incorrect Other
13 Examples 1.Too much censoring; DMC extends trial 2.Boundary not crossed but DMC stops 3.Unexpected adverse event 4.Statistical method defective 5.Event rate too low; DMC changes design
14 #1 Endpoint-driven trial Trial designed to stop after 200 deaths Observations different from expected Recruitment Mortality rate At 200 deaths, fu of many people<2 mo DMC: change fu to minimum 6 mo P-value: 0.20 planned; at end
15 #2. Boundary not crossed Endpoint Primary: 7 day MI Secondary: one-year mortality Very stringent boundary
16 What DMC sees Very strong result at 7 days No problem at 1 year Clear excess of serious adverse events
17 Haybittle-Peto bound (10%)
18 Haybittle-Peto bound (30%)
19 Haybittle-Peto bound (50%)
20 Haybittle-Peto bound (70%)
21 Haybittle-Peto bound (70%)
22 #3. Unexpected adverse event: PERT study of the WHI Prespecified boundaries for BenefitHarm Heart attackStroke FracturePE Colon cancerBreast cancer
24 Actions Informed the women about increased risk of stroke, heart attack, and PE Informed them again Stopped the study
25 #4. Statistical method defective Neurological disease 20 question instrument Anticipated about 20% would not come Planned multiple imputation- results: Scale: 0 to 80 Value for ID 001: ? ? MI values: -22, 176
26 #5. Too few endpoints Example: approved drug Off-label use associated with AE Literature: SOC event rate: 20 percent Non-inferiority design - = 5 Sample size: 800/group
27 Observation 400 people randomized 0 events What does the DMC do?
28 Choices Continue to recruit 1600 Stop and declare no excess Choose some sample size Tell the Steering Committee to choose a sample size What if n=1? 2? 5? 10?
29 Conclusions Ensure that DMC understands role Separate decision-making role of DMC and Steering Committee Distinguish between reasonable changes on the fly and cheating Expect fuzzy borders
30 Technical Changing plans can increase Type I error rate We need to adjust for multiple looks How do we adjust for changes?
31 Operational Unblind assessments Subtle change in procedures In clinical trials, the FDA and SEC