THE ROLE OF DSMB’s in THE ROLE OF DSMB’s in CLINICAL RESEARCHCLINICAL RESEARCH

Data and SafetyData and Safety

Monitoring Monitoring

Data and Safety Monitoring Data and Safety Monitoring

Every clinical trial should have Every clinical trial should have provision for data and safety provision for data and safety monitoringmonitoring

The size of the monitoring committee The size of the monitoring committee depends upon the nature, size, and depends upon the nature, size, and complexity of the clinical trial complexity of the clinical trial

The Principal Investigator was The Principal Investigator was expected to perform the monitoring expected to perform the monitoring function but may have had others to function but may have had others to help help

Data and Safety MonitoringData and Safety Monitoring

19941994

It was recommended that every It was recommended that every clinical trial, even those that pose clinical trial, even those that pose little likelihood of harm have an little likelihood of harm have an external monitoring bodyexternal monitoring body

Data Safety Monitoring Boards Data Safety Monitoring Boards

19981998 Establishment of Data Safety Monitoring Establishment of Data Safety Monitoring

Board (DSMB) is required for multi-site Board (DSMB) is required for multi-site clinical trials involving interventions that clinical trials involving interventions that entail potential risk to the participantsentail potential risk to the participants

The functions and oversight of such The functions and oversight of such activities are distinct from the activities are distinct from the requirement for study review and requirement for study review and approval by an IRB approval by an IRB

A DSMB is your FriendA DSMB is your Friend

Not your EnemyNot your Enemy

DefinitionsDefinitions

Data Safety Monitoring Data Safety Monitoring Plan (DSMP)Plan (DSMP) describes how the study describes how the study

investigators plan to investigators plan to oversee research subject oversee research subject safety and how adverse safety and how adverse events will be events will be characterized and characterized and reportedreported

The intensity and The intensity and frequency of monitoring frequency of monitoring should be tailored to fit should be tailored to fit the expected risk level, the expected risk level, complexity, and size of complexity, and size of the particular studythe particular study

Data and Safety Data and Safety Monitoring Board Monitoring Board (DSMB/DMC)(DSMB/DMC) A group of individuals A group of individuals

with pertinent expertise with pertinent expertise that review on a regular that review on a regular basis accumulating data basis accumulating data from ongoing an clinical from ongoing an clinical trialtrial

Advises sponsor Advises sponsor regarding safety of regarding safety of current and future current and future participants and validity participants and validity and scientific merit of the and scientific merit of the trialtrial

DSMBs perform 3 fundamental functions

Review accumulating clinical data relating to the efficacy and safety of the investigational product (drug, biologic and/or device).

Conduct interim analysis of the clinical data to determine whether the study needs to be terminated for safety reasons.

Ensure the continued scientific validity and merit of the study

Roles of a Data Safety Roles of a Data Safety CommitteeCommittee

Monitor adverse eventsMonitor adverse events Is Risk:Benefit is not alteredIs Risk:Benefit is not altered Does Informed Consent need to be changedDoes Informed Consent need to be changed

Monitor enrollmentMonitor enrollment Is study meeting target? Can it be Is study meeting target? Can it be

Completed?Completed? Potentially monitor subject outcomesPotentially monitor subject outcomes Monitor new information relative to the Monitor new information relative to the

studystudy

To be effectiveTo be effective

1.1. Monitoring must be performed on a Monitoring must be performed on a regular basisregular basis

2.2. Conclusions should be discussed with PI Conclusions should be discussed with PI if he/she not part of the committeeif he/she not part of the committee

3.3. Conclusions of the monitoring must be Conclusions of the monitoring must be reported to the IRB reported to the IRB

Specifics of the plan will depend Specifics of the plan will depend upon the nature, size, complexity upon the nature, size, complexity

and risk of the clinical trialand risk of the clinical trial Observation Study, no interventionObservation Study, no intervention Observation study, non-randomized Observation study, non-randomized

interventionintervention Randomized Controlled Trial using Randomized Controlled Trial using

approved drugs/devicesapproved drugs/devices IND/IDE StudiesIND/IDE Studies Multi-center RCTsMulti-center RCTs

Observation Study, no Observation Study, no interventionintervention

PI and 1-2 othersPI and 1-2 others Meet annuallyMeet annually Report to IRB – enrollment status, Report to IRB – enrollment status,

recommendation to continuerecommendation to continue

Observation study, non-Observation study, non-randomized interventionrandomized intervention

2-4 Members, PI not Chair, at least 1 2-4 Members, PI not Chair, at least 1 member not involved with the studymember not involved with the study

If low Risk, meet annuallyIf low Risk, meet annually Report enrollment, Adverse Events.Report enrollment, Adverse Events. Review SSS and ICS for needed Review SSS and ICS for needed

changeschanges

Randomized Controlled Trial Randomized Controlled Trial using approved drugs/devicesusing approved drugs/devices

2-4 members, PI should not be a member but may 2-4 members, PI should not be a member but may attend meetings at discretion of chairattend meetings at discretion of chair Consider a biostatistician as memberConsider a biostatistician as member

No member should be involved (Co-I) on studyNo member should be involved (Co-I) on study Meet semiannually depending on enrollement pace Meet semiannually depending on enrollement pace Report enrollment, Adverse Events.Report enrollment, Adverse Events. Review SSS and ICS for needed changesReview SSS and ICS for needed changes Review group outcome differences, if large may need Review group outcome differences, if large may need

to break blind in executive sessionto break blind in executive session May need to recommend discontinuation if:May need to recommend discontinuation if:

One group has significantly better outcomesOne group has significantly better outcomes Adverse events serious and mostly in one interventionAdverse events serious and mostly in one intervention

IND/IDE Studies and/or IND/IDE Studies and/or Multi-center RCTsMulti-center RCTs

Require a formally constituted Data Require a formally constituted Data Safety Monitoring Board (DSMB)Safety Monitoring Board (DSMB) No conflicts of interestNo conflicts of interest Formal Stopping rulesFormal Stopping rules Regular scheduled meetingsRegular scheduled meetings Reports to IRB and FDAReports to IRB and FDA Generally set up by the study sponsorGenerally set up by the study sponsor

Data and Safety Monitoring Plan Data and Safety Monitoring Plan and Boardand Board

A description of the plan and the A description of the plan and the composition of the monitoring board composition of the monitoring board are required at the time of the IRB are required at the time of the IRB submission.submission.

SECTION IX: DATA SAFETY MONITORING PLAN

For all research that is greater than minimal risk, a Data Safety Monitoring Plan (DMSP) must be developed. This is a plan to assure the research includes a system for appropriate oversight and monitoring of the conduct of the study to ensure the safety of subjects and the validity and integrity of the data.

Monitoring Plan ChecklistMonitoring Plan Checklist □ N/A. The research is minimal risk. □ The DSMP is contained in the protocol. State where in the

protocol the description is located:       NOTE: Ensure that all points outlined below are addressed

in the description in the protocol. If any points are not addressed, within the protocol, they should be addressed below.

□ The DSMP is NOT contained in the protocol; however, this is a repository/database protocol and the primary risk is that of loss of confidentiality; thus, I do not need to complete this section.

□ The DSMP is NOT contained in the protocol. Complete the questions below.

 

Section IX – A

Who will be responsible for the data and safety monitoring? Examples include: a DSMC or DSMB,

medical monitor, investigator, independent physician)

Clarify if this individual or committee is independent from the sponsor and/or investigator.

Section IX –BWhat will be monitored

Examples include: data quality, subject recruitment, accrual, and retention, outcome and adverse event data, assessment of scientific reports or therapeutic development, results of related studies that impact subject safety, procedures designed to protect the privacy of subjects

Section IX-C What are the procedures for

analysis and interpretation of data, the actions to be taken upon specific events or endpoints, the procedures for communication from the data monitor to the IRB and site, and other reporting mechanisms

Section IX – D

What is the frequency of monitoring? The appropriate frequency of data and

safety monitoring will be dependent on the nature and progress of the research; however, monitoring must be performed on a regular basis (e.g, at least annually).

Section IX – E What information will be reported to the

IRB? IRB requires the following information at the time of

continuing review: 1) frequency and date(s) of monitoring; 2) summary of cumulative adverse events; 3) assessment of external factors (i.e. scientific

reports, therapeutic developments, results of related studies) that impacted the safety of subjects;

4) summary of subject privacy and research data confidentiality outcomes; and

5) any changes to the risk-benefit ratio.

Data and Safety Monitoring Plan Data and Safety Monitoring Plan and Boardand Board

Description should include:Description should include:

1.1. DSMB chair and membersDSMB chair and members

2.2. How frequently the study will be How frequently the study will be evaluatedevaluated

3.3. The method of detecting adverse The method of detecting adverse eventsevents

4.4. How events will be scoredHow events will be scored

Translational Research Ethics Translational Research Ethics ConsultationConsultation

Service (TREX)Service (TREX) Available to researchers to help clarify and Available to researchers to help clarify and

address ethical issues that arise in planning, address ethical issues that arise in planning, carrying out, and analyzing human subjects carrying out, and analyzing human subjects research. research.

Areas for possible consults include but are not Areas for possible consults include but are not limited to:limited to:o Recruitment and informed consent issuesRecruitment and informed consent issueso Vulnerable, pediatric, or impaired research Vulnerable, pediatric, or impaired research

subjectssubjectso Data sharing with research subjects or a Data sharing with research subjects or a

broader communitybroader communityo Biobank construction and governanceBiobank construction and governanceo Data Safety Monitoring Plans or BoardsData Safety Monitoring Plans or Boards

TREXTREX

Free of charge, offered by the IU Center the Free of charge, offered by the IU Center the Bioethics (IUCB) as a service of the Bioethics and Bioethics (IUCB) as a service of the Bioethics and Subject Advocacy Program (BSAP), a part of the Subject Advocacy Program (BSAP), a part of the Indiana Clinical and Translational Sciences Indiana Clinical and Translational Sciences Institute (CTSI).Institute (CTSI).

Confidential and anonymous when appropriate. Confidential and anonymous when appropriate. Conclusion of the consult is a memo issued as Conclusion of the consult is a memo issued as

advice to the requestor.advice to the requestor. Researchers can request a consult by emailing Dr. Researchers can request a consult by emailing Dr.

Peter Schwartz (Peter Schwartz (phschwar@iupui.edu), Director of ), Director of TREX, or Dr. Eric Meslin (TREX, or Dr. Eric Meslin (emeslin@iupui.edu), ), Director of IUCB. Director of IUCB.

To learn more about the IUCB and BSAP go to To learn more about the IUCB and BSAP go to www.bioethics.iu.edu/bsap