1. Community Clinical Oncology Program (CCOP) Updated: July 2006 Role of Data Safety Monitoring Board (DSMB) Mira Shah, CIM, CCRP March 2011

2. Disclaimer The views expressed in this presentation are the views of the speaker and do not necessarily reflect the views or policies of The U.T. M. D. Anderson Cancer Center (UTMDACC). The views expressed in this presentation are the views of the speaker and do not necessarily reflect the views or policies of The U.T. M. D. Anderson Cancer Center (UTMDACC).

3. Presentation Outline   Introduction of DSMB   Necessity of DSMB   Conduct of meetings   Processes involved with DSMB   Conclusions

4. Acronyms CCOPCommunity Clinical Oncology Program CNPEClosed to New Patient Entry DSMB Data Safety Monitoring Board DMCData Monitoring Committee IRBInstitutional Review Board NCINational Cancer Institute PIPrincipal Investigator

5. What is a DSMB?   DSMB is a formally appointed independent group of individuals with scientific expertise and lay representation that reviews accumulated research data from an ongoing clinical trial.

6. Need for DSMB All clinical trials require safety monitoring but not all trials require monitoring by a DSMB. All clinical trials require safety monitoring but not all trials require monitoring by a DSMB. All Phase III randomized comparative trials. All Phase III randomized comparative trials. Other higher risk trials. Other higher risk trials. Large multiple site trials. Large multiple site trials.

7. Options for Data Monitoring   Federal regulations require that IRB determine requirement for DSMB.   PI or project manager may monitor Phase I and II trials.   A group of Sponsor’s representatives may monitor trials.   Monitoring should commensurate with risks. 1998 NIH policy statement

8. Points to consider Some government agencies have required DSMB monitoring for selected trials. Some government agencies have required DSMB monitoring for selected trials. If the trial is accruing very quickly, would a DSMB be practical? If the trial is accruing very quickly, would a DSMB be practical? Current FDA regulations impose no requirements for the use of a DSMB except under 21 CFR 50.24* Current FDA regulations impose no requirements for the use of a DSMB except under 21 CFR 50.24* (*exception from IC requirements for emergency research where human subjects may be in a life-threatening situation)

9. Trials monitored by DSMB at MDACC   Randomized and/or blinded   Non-randomized but referred by IRB   High risk trials   Community Clinical Oncology Program (CCOP) trials

10. Issues to be Addressed at DSMB meeting  Should the study be stopped?  Inadequate accrual  Increased safety concerns  Have they met the stopping rule  Apparent outcome differences  Futility  Is there a need to change the study design?  Is additional data needed for adequate review to be completed?  Timing of the next review of the study.

11. UTMDACC DSMB Policy Per UTMDACC policy, a DSMB will monitor: Per UTMDACC policy, a DSMB will monitor: (1) all randomized studies that originate at MDACC or that are coordinated or analyzed by the MDACC and are not being monitored by another Data Safety Monitoring Board, unless exempted by the MDACC IRBs; and (1) all randomized studies that originate at MDACC or that are coordinated or analyzed by the MDACC and are not being monitored by another Data Safety Monitoring Board, unless exempted by the MDACC IRBs; and (2) any other non-randomized studies referred by the MDACC IRBs to the DSMB. (2) any other non-randomized studies referred by the MDACC IRBs to the DSMB. (HSRM 17.070 DSMB By-Laws) (HSRM 17.070 DSMB By-Laws)

12. Protocol Selection for MDACC DSMB DSMB oversight may be requested by:  PI -Single UTMDACC study - UTMDACC PI of consortium study  IRB  CCOP DSMB oversight waived if:  PI sends waiver request to IRB and may be approved if determined to be low risk.

13. Committee Membership of MDACC DSMB   No more than 15 members   Includes physicians to interpret toxicity and outcome differences   Statisticians to evaluate methodology and interpret probability statements (p-values)   Lay members as participant advocates   50% of members from outside UTMDACC to prevent bias

14. Review Frequency at MDACC  Annual review is required  Review frequency may increase based on:  Accrual  Reporting requirements in the trial  Level of risk to the subject/s

15. How the DSMB review process works at MDACC

16.   Eight weeks prior to meeting the PI and biostatistician are notified of trial presentation   PI provides data to Biostatistician   Biostatistician analyzes data and completes the report   One week before the meeting, the biostatistician provides the report to DSMB only Pre Meeting

17. Biostatistical Report  Accrual rates  Patient Characteristics  Eligibility and Evaluability  Efficacy  Toxicities Report prepared by biostatistician and presented to DSMB for review include  Adverse Events  Treatment Related Deaths  Maximum Toxicity  Special Toxicity Monitoring  Secondary Malignancies

18. Biostatistical Report

21. Confidential Confidential Not available to the PI or other investigators Not available to the PI or other investigators PI is made privy to trial results and analyses only after the DSMB officially releases those results to the PI PI is made privy to trial results and analyses only after the DSMB officially releases those results to the PI

22. DSMB Meeting (DSMB Meets Every Other Month) PI & biostatistician present study & answer committee questions Biostatistician discusses data and outcomes by treatment arm Biostatistician discusses data and outcomes by treatment arm After Discussion, After Discussion, Motion made & voted on by members PI asked to leave the room Biostatistician asked to leave the room

23.   Appropriate to continue study.   Additional information from PI or biostatistician is requested.   DSMB recommends revisions/ amendments.   CNPE for safety/efficacy concerns.   Closure due to futility. Common Outcomes

24.   DSMB provides memo to PI and biostatistician regarding protocol outcome   DSMB provides memo to IRB listing outcome for each protocol presented Post Meeting

25. All Revisions/Amendments of DSMB Designated Protocols PI revises protocol DSMB Designee/Scientific Editor reviews revision(s) Moves to IRB review APRPOVED REJECTED Revision not appropriate per DSMB Designee/Editor and is returned. PI notified of changes required.

26. PI requests to the DSMB Close trial to new patient entry Close trial to new patient entry Request to stop the trial Request to stop the trial Cease monitoring the trial and release trial results Cease monitoring the trial and release trial results Release interim results to the PI or department chair for planning of future trial Release interim results to the PI or department chair for planning of future trial Release interim results for publication Release interim results for publication These requests can be addressed anytime and are not restricted to scheduled meeting times.

27. PI responsibilities PI needs to request permission from the DSMB to publish Interim results for a trial PI needs to request permission from the DSMB to publish Interim results for a trial Copies of manuscripts or abstracts that are to be published must be submitted to DSMB Copies of manuscripts or abstracts that are to be published must be submitted to DSMB The DSMB plays no role in developing publications but may make recommendations

28. DSMB Conclusions Protects patient’s interests and scientific integrity of trial/s. Protects patient’s interests and scientific integrity of trial/s. Uses statistical analyses to provide expert guidance. Uses statistical analyses to provide expert guidance. May serve as scientific reviewer for trial/s. May serve as scientific reviewer for trial/s.

29. DSMB Resources FDA Guidance for Clinical Trial Sponsors – Establishment and operation of Clinical Trial Data Monitoring Committees (March 2006 – June 30, 2012): FDA Guidance for Clinical Trial Sponsors – Establishment and operation of Clinical Trial Data Monitoring Committees (March 2006 – June 30, 2012): http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf NIH Policy for Data and Safety Monitoring (June 10, 1998): NIH Policy for Data and Safety Monitoring (June 10, 1998): http://grants.nih.gov/grants/guide/notice-files/not98-084.html NIH Further Guidance on a Data Safety Monitoring for Phase I and Phase II Trials (June 5, 2000): NIH Further Guidance on a Data Safety Monitoring for Phase I and Phase II Trials (June 5, 2000): http://grants.nih.gov/grants/guide/notice-files/not-od-00-038.html OHSR Information Sheet: Guidelines for NIH Intramural Investigators and Institutional Review Boards on Data and Safety Monitoring (December 2006): OHSR Information Sheet: Guidelines for NIH Intramural Investigators and Institutional Review Boards on Data and Safety Monitoring (December 2006): http://ohsr.od.nih.gov/info/sheet18.html MDACC Human Subject Research Manual MDACC Human Subject Research Manual (17.070 Appendix E DMC By-laws) (17.070 Appendix E DMC By-laws)

30. Contact Information Mira D. Shah, CIM, CCRP The University of Texas M.D. Anderson Cancer Center 713-563-5437 mshah@mdanderson.org