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Mass BioTech Council DMC Presentation Statistical Considerations Philip Lavin, Ph.D. October 30, 2007
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© 2007 Averion International Corp., All Rights Reserved. Agenda Phase III Adjuvant Cancer Study Endpoints FDA Recommendations and Requirements DMC Empowerment Interim Analysis Timing and Specifics Independent Review Committee Role Other Efficacy and Safety Endpoints Time Saving Decisions
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© 2007 Averion International Corp., All Rights Reserved. Pivotal Advanced Cancer Study Endpoints Primary: Disease-Free Survival (DFS) – Randomization Recurrence Secondary: Overall Survival (OS) – Randomization Death Safety: – SAEs, unexpected AEs, labs – Lack of efficacy is a safety issue
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© 2007 Averion International Corp., All Rights Reserved. FDA Recommendations We’ll accept DFS! Do not assess superiority while accruing OK to test futility at any time Perform sensitivity analysis –Censor patients at last complete visit if multiple missed follow-up visits
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© 2007 Averion International Corp., All Rights Reserved. Data Handling Rules for Missed Follow-up Visits DFS DFS missing RD ------------|---------|----------x--------|--------- DFS missing RD ------------|---------x---------x--------x--------|----- censored DFS missing RD ------------|---------x---------x--------x--------|----- Sensitivity analysis DFS: Disease-Free Survival RD: Recurrence or Death
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© 2007 Averion International Corp., All Rights Reserved. FDA Requirements The DMC should meet at least twice per year Please specify the interim stopping rules –End of accrual, after 200 events, at 2 years Please specify the alpha spending rules –O’Brien-Fleming, Pocock, Fisher, Schoenfeld Please specify if testing for superiority –Futility carries NO alpha penalty –Superiority spends some alpha…placing a bet
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© 2007 Averion International Corp., All Rights Reserved. DMC Empowerment Recommend OR decide? –DMC can have a NIH academic mentality –FDA likes DMC but it is for issue location –DMC can make devastating decisions: Circe DMC can recommend: –Suspension for unanticipated safety findings –Assumption testing to recompute sample size –Additional sensitivity analyses if results borderline BUT Sponsor needs the final decision authority
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© 2007 Averion International Corp., All Rights Reserved. Interim Analysis Timing: Example Formal safety review –Twice per year 1st interim analysis as accrual nears goal –100 events 2nd interim analysis for efficacy –200 events O’Brien-Fleming spending function
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© 2007 Averion International Corp., All Rights Reserved. Interim Analysis: Primary Endpoint Specifics Primary endpoint: DFS –Log rank test (emphasizes late failures) –Event-driven Recurrences, Deaths –Spend alpha = 0.0001 for each interim Allows for unlikely early “home run” win Secondary analysis –Proportional hazard model with strata
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© 2007 Averion International Corp., All Rights Reserved. Projecting Events: Roadmap To Expectation DFS Median: 24 vs. 30 Months 500 patients 1 st Interim 18 months 100 events 600 patients 2 nd Interim 24 months 200 events 700 patients Final analysis 30 months 300 events
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© 2007 Averion International Corp., All Rights Reserved. Interim Analysis Stopping Boundaries Z-Scale and Hazard Ratio Scale Planned Interim Analyses for DFS with early stopping rules based on statistical boundaries using the Z-scale and the Hazard Ratio scale Interim Analysis # Information Fraction Total Events (PFS) Total Alpha Spent Total Beta Spent Boundaries Z-Scale Boundaries Hazard Ratio Scale H0H0 H1H1 H0H0 H1H1 10.33100<0.00010.001-3.71.250.41.25 20.67 200 0.0060.01-2.5-0.300.61.1 Final1.0 300 0.0250.1-20.-2.00.67
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© 2007 Averion International Corp., All Rights Reserved. Interim Analysis DFS Stopping Boundaries p≥0.9 p≥0.4 p=0.0001p≤0.006 p≤0.024
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© 2007 Averion International Corp., All Rights Reserved. Independent Review Committee (IRC) Recognize bias potential –“Bad news first” bias potential –Deaths are real, progressions need confirmation Need to adjudicate before a final decision can be made –Investigators vs. IRC discordance –Keep up with adjudications Monitor discordance rates: 5%, 10%, 20%?
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© 2007 Averion International Corp., All Rights Reserved. Interim Analysis: Secondary Endpoint Secondary endpoint: Overall Survival –Same analyses approach as DFS –Longer follow-up required Issues: –Patients go on to other therapies –Death from other causes –Follow-up attrition –Other publications impact
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© 2007 Averion International Corp., All Rights Reserved. Interim Analysis: Safety Evaluation Lack of efficacy is a safety issue => Look at OS Semi-annual DMC reviews typical –Usually unblinded –Event adjudication can be an issue –Often hard to blind adverse events
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© 2007 Averion International Corp., All Rights Reserved. Time Saving Moves Use DMC for all drug development studies Use same tables and listings as in SAP –Get SAP and programming specs in place early –Avoids “painful” retrospective changes Use same core SAS/Stat production team: –Know the data, able to validate TLFs –Promotes efficient follow-up –Have separate unblinded team run unblinded TLFs Saves $ and time
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© 2007 Averion International Corp., All Rights Reserved. Questions
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For more information, contact: Philip Lavin, Ph.D. 508-597-6216 Or visit our website: www.averionintl.com
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