Community Clinical Oncology Program

(CCOP)

Updated: July 2006

Role of

Data SafetyMonitoring Board (DSMB)

Mira Shah, CIM, CCRP

March 2011

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).

Presentation Outline

Introduction of DSMB Necessity of DSMB Conduct of meetings Processes involved with DSMB Conclusions

Acronyms

CCOP Community Clinical Oncology Program

CNPE Closed to New Patient EntryDSMB Data Safety Monitoring Board DMC Data Monitoring CommitteeIRB Institutional Review BoardNCI National Cancer InstitutePI Principal Investigator

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.

Need for DSMB All clinical trials require safety

monitoring but not all trials require monitoring by a DSMB.

All Phase III randomized comparative trials.

Other higher risk trials. Large multiple site trials.

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

Points to consider Some government agencies have

required DSMB monitoring for selected trials.

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* (*exception from IC requirements for emergency research where

human subjects may be in a life-threatening situation)

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

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.

UTMDACC DSMB Policy

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

(2) any other non-randomized studies referred by the MDACC IRBs to the DSMB. (HSRM 17.070 DSMB By-Laws)

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.

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

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

How the DSMB review process works at MDACC

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

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

Biostatistical Report

Biostatistical Report

Biostatistical Report

Biostatistical Report Confidential 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

DSMB Meeting(DSMB Meets Every Other

Month)PI & biostatistician present study

& answer committee questions

Biostatistician discusses data and outcomes by treatment arm

After Discussion, Motion made & voted on by members

PI asked to leave the room

Biostatistician asked to leave the room

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

DSMB provides memo to PI and biostatistician regarding protocol outcome

DSMB provides memo to IRB listing outcome for each protocol presented

Post Meeting

All Revisions/Amendments of DSMB Designated

ProtocolsPI revises protocol

DSMB Designee/Scientific Editorreviews revision(s)

Moves to IRB review

APRPOVED REJECTED

Revision not appropriate per DSMB Designee/Editor and is returned.

PI notified of changes required.

PI requests to the DSMB Close trial to new patient entry Request to stop the trial 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 for publicationThese requests can be addressed anytime and are not restricted to scheduled meeting times.

PI responsibilities 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

The DSMB plays no role in developing publications but may make recommendations

DSMB Conclusions

Protects patient’s interests and scientific integrity of trial/s.

Uses statistical analyses to provide expert guidance.

May serve as scientific reviewer for trial/s.

DSMB Resources 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): 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):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):http://ohsr.od.nih.gov/info/sheet18.html

MDACC Human Subject Research Manual (17.070 Appendix E DMC By-laws)

Contact Information

Mira D. Shah, CIM, CCRP

The University of Texas M.D. Anderson Cancer Center

713-563-5437mshah@mdanderson.org