THE ROLE OF DSMB’s in CLINICAL RESEARCH

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 MonitoringData and Safety Monitoring NIH PolicyNIH Policy Each Institute/Center should have a Each Institute/Center should have a

system for the appropriate oversight and system for the appropriate oversight and monitoring of the conduct of clinical trials monitoring of the conduct of clinical trials

Must ensure the safety of participants Must ensure the safety of participants andand

Should protect the validity and integrity Should protect the validity and integrity of the data for all of the data for all NIH-supported/conducted trialsNIH-supported/conducted trials

DATA and SAFETY MONITORINGDATA and SAFETY MONITORING

Clinical Trials have a relationship Clinical Trials have a relationship between participants and between participants and investigatorsinvestigators

Both must fulfill certain obligations Both must fulfill certain obligations

Data and Safety MonitoringData and Safety Monitoring

Participants:Participants:

Must be fully informed of the study Must be fully informed of the study requirements throughout the studyrequirements throughout the study

Should comply with the rigors of the Should comply with the rigors of the research protocol or be allowed to research protocol or be allowed to withdraw from participationwithdraw from participation

Data and Safety MonitoringData and Safety Monitoring Investigators:Investigators:

Must protect the health and safety of Must protect the health and safety of participantsparticipants

Inform participants of information Inform participants of information relevant to their continued participationrelevant to their continued participation

Pursue the research objectives with Pursue the research objectives with scientific diligencescientific diligence

Data and Safety Monitoring Data and Safety Monitoring 19791979 Every clinical trial should have provision Every clinical trial should have provision

for data and safety monitoringfor data and safety monitoring 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 expected The Principal Investigator was expected to perform the monitoring function but to perform the monitoring function but may have had others to help may have had others to 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

Data and Safety Monitoring Data and Safety Monitoring Principles of monitoring data and Principles of monitoring data and

safety in studies include:safety in studies include: Physiologic, toxicity, and dose-finding Physiologic, toxicity, and dose-finding

studies—Phase Istudies—Phase I Efficacy studies—Phase IIEfficacy studies—Phase II Efficacy, effectiveness and Efficacy, effectiveness and

comparative trials—Phase IIIcomparative trials—Phase III

Data and Safety MonitoringData and Safety Monitoring Monitoring should be commensurate with Monitoring should be commensurate with

the degree of risk involvedthe degree of risk involved A data and safety monitoring committee A data and safety monitoring committee

should determine safe and effective should determine safe and effective conduct and conduct and

Recommend conclusion of the trial when Recommend conclusion of the trial when significant benefits or risks have developed significant benefits or risks have developed or or

The trial is unlikely to be concluded The trial is unlikely to be concluded successfully successfully

Data and Safety MonitoringData and Safety Monitoring Risk associated with participation in Risk associated with participation in

research must be minimized to the research must be minimized to the extent practicalextent practical

Size and complexity will determine if Size and complexity will determine if a single person or a committee is a single person or a committee is needed to oversee the studyneeded to oversee the study

Data and Safety MonitoringData and Safety Monitoring Performance of Data and Safety MonitoringPerformance of Data and Safety Monitoring1.1. Is to protect the integrity of the system for Is to protect the integrity of the system for

monitoring trial data and participant safetymonitoring trial data and participant safety2.2. Monitoring must be performed on a regular Monitoring must be performed on a regular

basisbasis3.3. Conclusions of the monitoring must be Conclusions of the monitoring must be

reported to the IRB and the Research reported to the IRB and the Research Subject Advocate Committee (RSA) on the Subject Advocate Committee (RSA) on the GCRCGCRC

Data and Safety MonitoringData and Safety Monitoring IRB/RSA responsibilitiesIRB/RSA responsibilities May direct who shall perform the May direct who shall perform the

monitoring activitiesmonitoring activities May direct the composition of the May direct the composition of the

monitoring group including that:monitoring group including that: the PI is not to chair the Data and the PI is not to chair the Data and

Safety Monitoring Board nor be the Safety Monitoring Board nor be the single person doing the monitoringsingle person doing the monitoring

Data and Safety Monitoring PlanData and Safety Monitoring Plan

All protocols receiving GCRC support All protocols receiving GCRC support are required to have a Data and are required to have a Data and Safety Monitoring Plan whichSafety Monitoring Plan which

1.1. Monitors the progress of the research Monitors the progress of the research study and the safety of participantsstudy and the safety of participants

2.2. Plans for assuring compliance with Plans for assuring compliance with requirements for reporting adverse requirements for reporting adverse eventsevents


3.3. Plans for assuring that any action Plans for assuring that any action resulting in a temporary or resulting in a temporary or permanent suspension of the permanent suspension of the clinical trial is reported to all clinical trial is reported to all responsible partiesresponsible parties

4.4. Plans for assuring protocol Plans for assuring protocol compliance and data accuracy compliance and data accuracy


The plan should include the The plan should include the following:following:

1.1. Committee chair and membersCommittee chair and members2.2. Frequency of evaluationFrequency of evaluation3.3. Method of detecting adverse eventsMethod of detecting adverse events4.4. How adverse events will be scoredHow adverse events will be scored


Adverse event reporting requirementsAdverse event reporting requirements

A description of interim efficacy A description of interim efficacy analysis if appropriateanalysis if appropriate

Distribution of Data and Safety Distribution of Data and Safety

Monitoring Board (DSMB) reports—Monitoring Board (DSMB) reports—must go to GCRC RSA for review must go to GCRC RSA for review


Specifics of the plan will depend upon Specifics of the plan will depend upon the nature, size, complexity and risk the nature, size, complexity and risk of the clinical trialof the clinical trial

A monitoring committee is required to A monitoring committee is required to determine safe and effective conduct determine safe and effective conduct

Or to recommend conclusion of the Or to recommend conclusion of the trial when significant benefits or risks trial when significant benefits or risks have developedhave developed

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

Single individual—if trial is small with Single individual—if trial is small with little risklittle risk

IU GCRC has decided that the IU GCRC has decided that the Principal Investigator cannot be the Principal Investigator cannot be the chair of the DSMB and cannot be the chair of the DSMB and cannot be the only monitor of a research study in only monitor of a research study in order to eliminate any potential order to eliminate any potential conflict conflict


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 GCRC are required at the time of the GCRC submission.submission.

This description should be included in This description should be included in Section G of the GCRC applicationSection G of the GCRC application


Description should include:Description should include:1.1. DSMB chair and membersDSMB chair and members2.2. How frequently the study will be How frequently the study will be

evaluatedevaluated3.3. The method of detecting adverse The method of detecting adverse

eventsevents4.4. How events will be scoredHow events will be scored


5.5. Adverse event reporting Adverse event reporting requirementsrequirements

6.6. A description of interim efficacy A description of interim efficacy analysis if appropriate analysis if appropriate

7.7. The distribution of DSMB reports The distribution of DSMB reports

Significant Risk ProtocolsSignificant Risk Protocols

Definition of Risk is a complex sum of Definition of Risk is a complex sum of individual contributors to the overall individual contributors to the overall risk of participation in the studyrisk of participation in the study

Significant Risk ProtocolsSignificant Risk Protocols Risk to study subjects may be thought of Risk to study subjects may be thought of

as encompassing aspects of:as encompassing aspects of:

1.1. Study designStudy design

2.2. Potential for loss of confidentialityPotential for loss of confidentiality

3.3. And the nature of the study population And the nature of the study population involved involved

Significant Risk ProtocolsSignificant Risk Protocols The risk of the intervention is a The risk of the intervention is a

function of the potential for adverse function of the potential for adverse events (AE) and the severity of adverse events (AE) and the severity of adverse eventsevents

1.1. The potential for adverse events includes the The potential for adverse events includes the expected frequency of adverse eventsexpected frequency of adverse events

2.2. When the frequency of AEs is unknown or identifying When the frequency of AEs is unknown or identifying the frequency of AEs is one of the endpoints of the the frequency of AEs is one of the endpoints of the trial such as Phase I trials, the risk is highertrial such as Phase I trials, the risk is higher

Significant Risk ProtocolsSignificant Risk Protocols The severity of adverse events The severity of adverse events

should also be considered should also be considered independent of the frequency of independent of the frequency of AEsAEs

1.1. Study procedures which are not expected to Study procedures which are not expected to lead to frequent AEs, but include the possibility lead to frequent AEs, but include the possibility of severe AEs, confer higher riskof severe AEs, confer higher risk


The amount of experience with the The amount of experience with the study intervention also affects the study intervention also affects the risk, since the risk of AEs may not be risk, since the risk of AEs may not be fully defined.fully defined.

Significant Risk ProtocolsSignificant Risk Protocols Study Population Study Population Participation of vulnerable subjects Participation of vulnerable subjects

confers greater risk than non confers greater risk than non vulnerable populationsvulnerable populations

1.1. Examples include children under 18, prisoners, Examples include children under 18, prisoners, and employees of the workplace and employees of the workplace


Normal volunteer populations require Normal volunteer populations require special consideration since any special consideration since any intervention confers greater risk than intervention confers greater risk than would be experienced by subjects would be experienced by subjects not participating in a study not participating in a study

Significant Risk ProtocolsSignificant Risk Protocols The gravity of loss of confidentialityThe gravity of loss of confidentiality

Loss of confidentiality for study participants in Loss of confidentiality for study participants in genetic studies, studies of stigmatized conditions, genetic studies, studies of stigmatized conditions, or studies where loss of confidentiality could lead or studies where loss of confidentiality could lead to social harms may be considered high riskto social harms may be considered high risk

Significant Risk ProtocolsSignificant Risk Protocols Physical, emotional and psychosocial Physical, emotional and psychosocial

harmsharms Example: a genetic study which might lead to a Example: a genetic study which might lead to a

diagnosis of or identify a predisposition for a diagnosis of or identify a predisposition for a serious disease in study participants would be serious disease in study participants would be considered high risk such as Huntington’s diseaseconsidered high risk such as Huntington’s disease

A study including known illegal drug users could A study including known illegal drug users could be considered high risk since loss of be considered high risk since loss of confidentiality of study participants could lead to confidentiality of study participants could lead to great social harmgreat social harm

Significant Risk ProtocolsSignificant Risk Protocols Significant Risk may be conferred by the Significant Risk may be conferred by the

degree of severity of a single degree of severity of a single consideration or the combined weight of consideration or the combined weight of several considerationsseveral considerations

By mandate, all studies using GCRC By mandate, all studies using GCRC facilities or resources which are facilities or resources which are considered to be of significant risk will be considered to be of significant risk will be required to establish an independent data required to establish an independent data safety monitoring board safety monitoring board

Significant Risk ProtocolsSignificant Risk Protocols Independent Data and Safety Independent Data and Safety

Monitoring BoardMonitoring Board Is made up of at least one member who is not Is made up of at least one member who is not

directly involved with the studydirectly involved with the study

Should not be a member of the PIs or co-PIs division Should not be a member of the PIs or co-PIs division within a given departmentwithin a given department

If the PI is a division director, then the DSMB cannot If the PI is a division director, then the DSMB cannot be made up of more junior members of his or her be made up of more junior members of his or her divisiondivision

Significant Risk ProtocolsSignificant Risk Protocols Studies requiring an Independent Studies requiring an Independent

DSMBDSMB Early clinical trialsEarly clinical trials All Phase I studiesAll Phase I studies Phase II studies unless they involve low risk Phase II studies unless they involve low risk

interventionsinterventions Studies of devices or invasive techniques with Studies of devices or invasive techniques with

which the PI or the community has little which the PI or the community has little experienceexperience

Gene Therapy trials Gene Therapy trials

Significant Risk ProtocolsSignificant Risk Protocols Genetic StudiesGenetic Studies Studies that examine more than 20 genetic lociStudies that examine more than 20 genetic loci Studies which seek to examine stigmatized Studies which seek to examine stigmatized

conditionsconditions Lethal or disabling diseases for which no Lethal or disabling diseases for which no

treatment is availabletreatment is available Or conditions where loss of confidentiality within Or conditions where loss of confidentiality within

the study could lead to serious emotional, the study could lead to serious emotional, psychological, or social consequences.psychological, or social consequences.

Significant Risk ProtocolsSignificant Risk Protocols Studies in vulnerable populationsStudies in vulnerable populations Children under 18Children under 18 PrisonersPrisoners Decisional-impaired subjects involving more than Decisional-impaired subjects involving more than

minimal risk minimal risk

Studies that involve administering Studies that involve administering agents manufactured on campus agents manufactured on campus

The Role of DSMB’s in Clinical The Role of DSMB’s in Clinical Research Research

Produced and Presented by Produced and Presented by Carole Weir, RN, MSNCarole Weir, RN, MSN

[email protected]@iupui.edu DirectorsDirectors

Edward Liechty, MDEdward Liechty, [email protected]@iupui.edu

Peter Schwartz, MDPeter Schwartz, [email protected]@iupui.edu

The Research Subject Advocate The Research Subject Advocate CommitteeCommittee

mailto:[email protected]



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THE ROLE OF DSMB’s in CLINICAL RESEARCH