1. Mass BioTech Council DMC Presentation Statistical Considerations Philip Lavin, Ph.D. October 30, 2007

2. © 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

3. © 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

4. © 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

5. © 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

6. © 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

7. © 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

8. © 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

9. © 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

10. © 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

11. © 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

12. © 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     

13. © 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%?

14. © 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

15. © 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

16. © 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

17. © 2007 Averion International Corp., All Rights Reserved. Questions

18. For more information, contact: Philip Lavin, Ph.D. 508-597-6216 Or visit our website: www.averionintl.com