Data & safety monitoring boards
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Transcript of Data & safety monitoring boards
MADHURI.MMADHURI.M
ICRIICRI
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!