MADHURI.M. M’PHARMMADHURI.M. M’PHARM

Data and Safety Data and Safety Monitoring Monitoring Boards Boards (DSMB)(DSMB)

What is a D(ata)S(afety)M(onitoring)B(oard)?What is a D(ata)S(afety)M(onitoring)B(oard)?

A committee charged with monitoringA committee charged with monitoring safetysafety efficacyefficacy progress of a clinical trialprogress of a clinical trial

Aka Aka DMC, DSMC, IDMC, …DMC, DSMC, IDMC, …

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

19941994 It was recommended that every clinical It was recommended that every clinical

trial, even those that pose little likelihood trial, even those that pose little likelihood of harm have an external monitoring bodyof harm have an external monitoring body

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

2006 2006

FDA guidance :FDA guidance :Establishment and Operation Establishment and Operation of Clinical Trial Data Monitoring of Clinical Trial Data Monitoring CommitteesCommittees

CompositionComposition

Voting Voting •Physician(s) in specialty area (disease, Physician(s) in specialty area (disease, side effects)side effects)•Epidemiologist/trial methodologistEpidemiologist/trial methodologist•StatisticianStatistician•Clinical pharmacologist/safety specialist? Clinical pharmacologist/safety specialist? •Ethicist, patient representative, lawyer?Ethicist, patient representative, lawyer?•Need effective chairmanNeed effective chairman

Non-VotingNon-Voting

•Study or steering committee chairStudy or steering committee chair

•Sponsor representativesSponsor representatives

•Reporting statisticianReporting statistician

Voting membersVoting members

3-10 experts in disease, study drug, clinical 3-10 experts in disease, study drug, clinical trialstrialsMultidisciplinary, independentMultidisciplinary, independentDisinterested – no conflict of interestDisinterested – no conflict of interestExperience on other DSMBsExperience on other DSMBs

Chair & statisticianChair & statistician Some inexperienced to train themSome inexperienced to train them

Must take responsibilities seMust take responsibilities seriouslyriously

QualificationsQualifications1.1. Expertise in the fieldExpertise in the field

2.2. Experience in conduct of CT & statistical Experience in conduct of CT & statistical knowledgeknowledge

3.3. Independence from direct management Independence from direct management of CTof CT

4.4. No conflict of interestNo conflict of interest

Rationale for using DSMBs in Rationale for using DSMBs in researchresearch

Ethical compact protecting trial Ethical compact protecting trial participantsparticipants

Sponsor: Sponsor: regulatory responsibilitiesregulatory responsibilities

May also advise about changes in protocol, May also advise about changes in protocol, proceduresprocedures

NIH often uses DSMB in an advisory NIH often uses DSMB in an advisory capacity – different from industry-sponsored capacity – different from industry-sponsored trialstrials

Trials that need a DSMBTrials that need a DSMB

Double-blindDouble-blind

Large (hundreds, thousands of subjects)Large (hundreds, thousands of subjects)

Multi-center/multi-nationalMulti-center/multi-national

Long durationLong duration

Endpoint: death or stroke or …Endpoint: death or stroke or …

Participants have high intrinsic mortality Participants have high intrinsic mortality riskrisk

HIV infection, cancerHIV infection, cancer Sepsis, pulmonary disease, cardiac Sepsis, pulmonary disease, cardiac

failurefailure

Trial studying a new chemical entityTrial studying a new chemical entity

Recommended (strongly) by regulatory Recommended (strongly) by regulatory agency agency

Trials that DON’T need a DSMBTrials that DON’T need a DSMB

Phase I studies, pilot studies (some)Phase I studies, pilot studies (some) Studies of symptom reliefStudies of symptom relief Studies with other very close safety Studies with other very close safety

monitoringmonitoring

Timeline so short the DSMB can’t Timeline so short the DSMB can’t operateoperate

Requirements for DSMB’sRequirements for DSMB’s NIHNIH

Typically require DSMBTypically require DSMB• Protocols that generate Protocols that generate

blinded/randomized blinded/randomized datadata

• Multicenter protocols; Multicenter protocols;

> minimal risk> minimal risk• Gene transfer protocolsGene transfer protocols

May require DSMBMay require DSMB• Protocols requiring Protocols requiring

special scrutinyspecial scrutiny High public interestHigh public interest Vulnerable Vulnerable

populationspopulations

FDAFDA Risk to trial participantsRisk to trial participants

• Study endpointStudy endpoint

• Large trials of long-Large trials of long-durationduration

PracticalityPracticality

• Short trialsShort trials Assurance of scientific validityAssurance of scientific validity

• Inclusion of new scientific Inclusion of new scientific knowledge without adding knowledge without adding biasbias

Purpose of DSMBPurpose of DSMB

• Identify high rates of ineligibility determined after Identify high rates of ineligibility determined after randomizationrandomization

• Identify protocol violations that suggest Identify protocol violations that suggest clarification of changes to protocol are neededclarification of changes to protocol are needed

• Identify unexpectedly high drop out rates that Identify unexpectedly high drop out rates that threaten the trial’s ability to produce credible threaten the trial’s ability to produce credible resultsresults

• Ensure validity of study resultsEnsure validity of study results

Duties of DSMBDuties of DSMB

RReview the research protocol and plans for eview the research protocol and plans for data and safety monitoringdata and safety monitoring

Evaluate the progress of the trial with Evaluate the progress of the trial with periodic assessments of data quality periodic assessments of data quality and timeliness, participant recruitment, and timeliness, participant recruitment, participant risks and benefits; participant risks and benefits; Reports from related studiesReports from related studies

Make recommendations to the IRB Make recommendations to the IRB and investigators concerning and investigators concerning continuation or conclusion of the continuation or conclusion of the trialtrial

Review the adverse event reports.Review the adverse event reports.

Timing of meetingsTiming of meetings

Meets annuallyMeets annually

Periodically whenPeriodically when Risk to subjects is highRisk to subjects is high Vulnerable subjectsVulnerable subjects Large volume of data to reviewLarge volume of data to review

MeetingsMeetings

(Brief executive session)(Brief executive session)Open sessionOpen sessionClosed sessionClosed sessionExecutive sessionExecutive sessionDisseminate recommendationsDisseminate recommendations

Open sessionOpen sessionDirectly to sponsor representativeDirectly to sponsor representative

Initially an open session is Initially an open session is conducted conducted

• members of the clinical trial may be members of the clinical trial may be presentpresent

• may focus on accrual, protocol may focus on accrual, protocol compliance, and general toxicity compliance, and general toxicity issuesissues

• no outcome results discussed during no outcome results discussed during this sessionthis session

Followed by a closed sessionFollowed by a closed session• DSMB members onlyDSMB members only• outcome results discussedoutcome results discussed• statistical reports (if necessary)statistical reports (if necessary)

Finally an executive sessionFinally an executive session• DSMB members onlyDSMB members only• discuss the general conduct of the trialdiscuss the general conduct of the trial• all outcomes (including toxicities and all outcomes (including toxicities and

AE)AE)• develop recommendations and vote if develop recommendations and vote if

necessarynecessary

Contents and intent of Contents and intent of reportreport

Purpose –allow DSMB to make informed decisionsPurpose –allow DSMB to make informed decisions

1.1. Summary of protocol and outstanding issuesSummary of protocol and outstanding issues2.2. Recruitment and follow-upRecruitment and follow-up3.3. Baseline dataBaseline data4.4. Check of randomizationCheck of randomization5.5. Timeliness of data & adjudication of endpointsTimeliness of data & adjudication of endpoints6.6. Adverse events with study-specific codingAdverse events with study-specific coding7.7. Dosage of study medicationDosage of study medication8.8. Vital signs and laboratory parametersVital signs and laboratory parameters9.9. Outcome dataOutcome data

Recommendations from the DSMBRecommendations from the DSMB

Shared with Sponsor, Steering Committee, Shared with Sponsor, Steering Committee, IRBsIRBsMust prevent unblinding of study teamMust prevent unblinding of study teamBe careful with communications! Be careful with communications! During the trial, everyone reads tea leavesDuring the trial, everyone reads tea leavesDSMB must keep impeccable recordsDSMB must keep impeccable records

What did they know and when did they What did they know and when did they know it?know it?

Did they change their behavior and Did they change their behavior and rules in response to data?rules in response to data?

Are There Disadvantages to Are There Disadvantages to Having a DSMB?Having a DSMB?

* YES!* YES! Increases complexity of trial Increases complexity of trial

managementmanagement Increases costsIncreases costs If the ethical imperatives discussed If the ethical imperatives discussed

earlier are not applicable, other earlier are not applicable, other (simpler) monitoring approaches are (simpler) monitoring approaches are usually acceptableusually acceptable

Dechallange & RechallangeDechallange & Rechallange Dechallenge Dechallenge -The clinical decision to withdraw drug treatment -The clinical decision to withdraw drug treatment

after a possible ADR occurred after a possible ADR occurred

Considered to be - Considered to be - +ve : if the reaction occurs at each dose & abates completely or +ve : if the reaction occurs at each dose & abates completely or partially after withdrawal of drug partially after withdrawal of drug -ve :  if the reaction does not abate  after withdrawal of drug -ve :  if the reaction does not abate  after withdrawal of drug

Not applicable where : Not applicable where :

* Drug is one dose treatment (vaccine ) * Drug is one dose treatment (vaccine ) * Reactions occurred after the drug was discontinued * Reactions occurred after the drug was discontinued * congenital anomaly (irreversible ) * congenital anomaly (irreversible )

Rechallenge- Rechallenge- Reintroduction of the same drug which had been Reintroduction of the same drug which had been withdrawn due to  ADR following +ve   dechallenge withdrawn due to  ADR following +ve   dechallenge

Considered to be Considered to be +ve : reoccurrance of similar signs & symptoms as that of +ve : reoccurrance of similar signs & symptoms as that of previous previous -ve : failure of appearance of similar signs & symptoms as that of -ve : failure of appearance of similar signs & symptoms as that of previous one previous one

Not applicable where Not applicable where * same as that of rechallenge* same as that of rechallenge

for ethical reasons rechallenge is rarely performed but it may eb for ethical reasons rechallenge is rarely performed but it may eb carried out when the results are in the interest of patient carried out when the results are in the interest of patient  suffering the reaction, particularly when there are no suitable  suffering the reaction, particularly when there are no suitable alternative drugsalternative drugs

Thank you!Thank you!

Merci!Merci!