1. The Role of the Data Monitoring Committee Society for Clinical Research Associates Philadelphia, PA April 23, 2010

2. Role of Data Monitoring Committees (DMCs) Why use a DMC? Why use a DMC? Roles, Objectives and Setup for DMCs Roles, Objectives and Setup for DMCs Operational considerations Operational considerations (Brief) Statistical considerations: p-value adjustments (Brief) Statistical considerations: p-value adjustments Where do companies get it wrong: Where do companies get it wrong: Administrative analyses: look without adjustment Administrative analyses: look without adjustment Use DMCs for safety only Use DMCs for safety only Blinding the DMC Blinding the DMC

3. Reading List Guidance for Clinical Trial Sponsors http://www.fda.gov/cber/guidelines.htm Fundamentals of Clinical Trials Friedman, Furberg, DeMets Polio: An American Story David Oshinsky

4. Reasons for DMCs Ethics Ethics Insurance Insurance

5. Reasons for DMCs: Ethics Reasons for DMCs: Ethics Oversight function to insure patient safety Oversight function to insure patient safety Monitor and be able to quickly react to any untoward safety events Monitor and be able to quickly react to any untoward safety events

6. Reasons for DMC: Insurance Operational Issue Operational Issue Provide oversight function of study progress Provide oversight function of study progress Insure study will have reasonable likelihood of achieving basic objectives. Insure study will have reasonable likelihood of achieving basic objectives. Early warning system for operational issues Early warning system for operational issues Critical design parameters Critical design parameters Expected treatment difference, control response rate, variance of primary endpointExpected treatment difference, control response rate, variance of primary endpoint Stop early Stop early No efficacy or unacceptable safetyNo efficacy or unacceptable safety Early, compelling, untoward, unexpected efficacyEarly, compelling, untoward, unexpected efficacy

7. Committees Data Monitoring Committee Data Monitoring Committee Executive Committee Executive Committee Others Others Data Analysis Center Data Analysis Center Adjudication Committee Adjudication Committee Central Labs Central Labs

8. DMC Review data tabulations from ongoing clinical trial Review data tabulations from ongoing clinical trial Deliberations are confidential Deliberations are confidential Make recommendations to Exec. Committee Make recommendations to Exec. Committee

9. DMC Membership Independent clinical members Independent clinical members Therapeutic area experts Therapeutic area experts No vested interest in company or outcome of trial No vested interest in company or outcome of trial Independent statistician Independent statistician Ethicist (optional) Ethicist (optional)

10. No Involvement in DMCs Company/Sponsor/Client Company/Sponsor/Client Investigators participating in the study Investigators participating in the study The investigators contact at company The investigators contact at company Any individual who can change or influence the recruitment of patients Any individual who can change or influence the recruitment of patients Individuals with data classification responsibilities Individuals with data classification responsibilities Individuals who could control or change study design, objectives or planned analyses Individuals who could control or change study design, objectives or planned analyses

11. Executive Committee/Steering Committee Responsible for study oversight and conduct Responsible for study oversight and conduct Membership: company, investigators Membership: company, investigators Decision makers Decision makers

12. Key Point DMC DMC Independent Independent Access to data Access to data No decisions, recommendations to Exec Comm. No decisions, recommendations to Exec Comm. Exec Committee/Steering Committee Exec Committee/Steering Committee Company representation Company representation Investigator representation (optional) Investigator representation (optional) NO access to data NO access to data Decision makers, based on recommendations from DMC Decision makers, based on recommendations from DMC

13. DMC Charter Define roles and responsibilities of DMC members Define roles and responsibilities of DMC members Communication with Executive Committee Communication with Executive Committee Structure and timing of meeting Structure and timing of meeting Scope of data reviews Scope of data reviews

14. DMC Meetings Open sessions Open sessions Executive Committee Executive Committee DMC DMC No unblinded data No unblinded data Closed sessions Closed sessions Unblinded data review Unblinded data review DMC Only DMC Only Minutes Minutes Document deliberations Document deliberations Confidentiality is key Confidentiality is key

15. Example: Centocor Centoxin: potential blockbuster with estimated $1B/year market potential Centoxin: potential blockbuster with estimated $1B/year market potential NYT: 12 Feb 1993 NYT: 12 Feb 1993 Centoxin Centoxin Efficacy endpoint in pivotal study changed based on knowledge of interim results Efficacy endpoint in pivotal study changed based on knowledge of interim results NDA terminated NDA terminated

16. Operational Considerations Keep review scope focused (interim analysis is not final analysis) Keep review scope focused (interim analysis is not final analysis) Emphasize simple tables and graphics, not listings Emphasize simple tables and graphics, not listings Information needs to be Information needs to be Current Current Current is more important than clean Current is more important than clean

17. Plan for Rapid Retrieval of Outcomes Important to minimize time lag between CRF at site vs inhouse Important to minimize time lag between CRF at site vs inhouse Paper Paper Short forms, worksheets Short forms, worksheets Phone calls Phone calls Working/temporary databases Working/temporary databases Help Desk support Help Desk support EDC very helpful alternative to paper EDC very helpful alternative to paper

18. Statistical Issue When DMC looks at interim data, p-value adjustments are necessary When DMC looks at interim data, p-value adjustments are necessary Avoid over reaction to early trends Avoid over reaction to early trends Maintain nominal alpha level of 0.05 for the final analysis Maintain nominal alpha level of 0.05 for the final analysis

19. Goal: Control type I error and maintain nominal 0.05 alpha for final analysis Need to set a high statistical bar for Interim Looks Need to set a high statistical bar for Interim Looks Interim analyses utilize p-values at levels of approx. 0.0001 at each look vs 0.05 at each look Interim analyses utilize p-values at levels of approx. 0.0001 at each look vs 0.05 at each look E.g., 6 interim analyses (6 looks): E.g., 6 interim analyses (6 looks): final alpha = 0.05 – 6*0.0001 = 0.0494

20. Key Point There are sound reasons to have a DMC monitor ongoing data There are sound reasons to have a DMC monitor ongoing data P-value adjustments need to be made P-value adjustments need to be made Estimates of efficacy and safety effects are based on small sample sizes Estimates of efficacy and safety effects are based on small sample sizes Possibility exists to overreact to early trends Possibility exists to overreact to early trends P-value adjustments for interim looks can be very small and final alpha can be maintained very near 0.05 P-value adjustments for interim looks can be very small and final alpha can be maintained very near 0.05

21. Interim survival analyses comparing mortality in clofibrate and placebo- treated participants in the Coronary Drug Project. A positive Z value favors placebo.

22. Where Companies Get it Wrong Administrative analyses Administrative analyses DMC for safety only DMC for safety only Blinding the DMC Blinding the DMC

23. Administrative Analyses Look at data with no intent to modify study Look at data with no intent to modify study Look at data for operational (insurance) issues Look at data for operational (insurance) issues Since no intent to change, no adjustment of p-values should be necessary Since no intent to change, no adjustment of p-values should be necessary If efficacy data are involved, adjustment is needed If efficacy data are involved, adjustment is needed Always a potential to overreact to early trends Always a potential to overreact to early trends Major red flag Major red flag

24. DMC for Safety Only? DMC needs access to both efficacy and safety to assess risk and benefit DMC needs access to both efficacy and safety to assess risk and benefit

25. Blinding DMC Members? Not an FDA or ICH Requirement Not an FDA or ICH Requirement Imposed by Sponsors to Imposed by Sponsors to Prevent bias Prevent bias Avoid over reaction to early trends Avoid over reaction to early trends

26. ICH E9 4.1: Interim analysis requires unblinded access to treatment group assignments 4.1: Interim analysis requires unblinded access to treatment group assignments 4.5: Interim analysis …involves access to … unblinded data and results. 4.5: Interim analysis …involves access to … unblinded data and results.

27. Controlling Bias…Overreaction The DMC does not make decisions The DMC does not make decisions DMC has no vested interest (unlike company) DMC has no vested interest (unlike company) Monitoring boundaries are in place Monitoring boundaries are in place Degree of empowerment of DMC comes from Executive Committee and is described in the Charter Degree of empowerment of DMC comes from Executive Committee and is described in the Charter

28. DMCs in pre-NDA Setting Studies in pre-NDA setting seldom stop early for efficacy Need for adequate safety data (ISS requirements) will often override any early efficacy trends Need for adequate safety data (ISS requirements) will often override any early efficacy trends Monitoring boundaries make it unlikely that effect is significant enough to stop for efficacy Monitoring boundaries make it unlikely that effect is significant enough to stop for efficacy

29. EXAMPLE AMD Limited phase II dosing information Limited phase II dosing information First major entry into patients was two large Phase III studies. First major entry into patients was two large Phase III studies. Limited safety data Limited safety data Efficacy endpoint: mean difference of > 2 lines between treatment and placebo after two years of therapy. Efficacy endpoint: mean difference of > 2 lines between treatment and placebo after two years of therapy.

30. AMD Example Two large multicenter Phase III studies to show efficacy and establish safety in patients with wet AMD Two large multicenter Phase III studies to show efficacy and establish safety in patients with wet AMD Primary endpoint: slow vision loss relative to placebo using standard eye charts Primary endpoint: slow vision loss relative to placebo using standard eye charts Treatment duration: two years Treatment duration: two years Company: Miravant Company: Miravant

31. AMD Example Monitor for Safety Only Monitor for Safety Only AEs, labs, other safety information AEs, labs, other safety information Interest in acute, untoward decreases in vision Interest in acute, untoward decreases in vision ExamineExamine Decreases of 3-6 lines Decreases of 3-6 lines Within initial 3 months Within initial 3 months On individual patient basis On individual patient basis DMC was blinded DMC was blinded

32. AMD Example FDA mandated post hoc adjustment of p- values since DMC viewed data related to efficacy FDA mandated post hoc adjustment of p- values since DMC viewed data related to efficacy

33. AMD Results from 2 Year Follow-Up Proportion of Patients Losing <2 Lines of Vision ___________________________________________________________________ Overall test of no treatment p-value vs. no treatment p-value vs. Study Treatment N n (%) effect placebo_ 98EA001 Placebo 64 27 (42.2) 0.0045 SN050 107 62 (57.9) 0.0456 SN050 107 62 (57.9) 0.0456 SN075 108 39 (36.1) 0.4293 SN075 108 39 (36.1) 0.4293 98EA004 Placebo 55 23 (41.8) 0.1200 SN050 124 72 (58.1) 0.0444 SN050 124 72 (58.1) 0.0444 SN075 117 59 (50.4) 0.2908 SN075 117 59 (50.4) 0.2908

34. Summary Patient safety is key Patient safety is key DMC is an independent group DMC is an independent group Charter describes roles and responsibilities Charter describes roles and responsibilities Monitoring Boundaries are needed Monitoring Boundaries are needed DMC needs to be unblinded and needs to assess both benefit and risk DMC needs to be unblinded and needs to assess both benefit and risk