DSMB Experiences Mary A. Foulkes, Ph.D. Office of Biostatistics and Epidemiology Center for...
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DSMB ExperiencesDSMB Experiences
Mary A. Foulkes, Ph.D.
Office of Biostatistics and Epidemiology
Center for Biologics Evaluation and Research
Association of GCRC Statisticians
Toronto
August 8, 2004
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DSMB Stat ExperienceDSMB Stat Experience
• OPTIMA• ERSET• ATN• ICTDR• ACES• Hermansky-Pudlak• VA Coop Studies
2002 – Present
2002 - Present
2002 – 2004
2000 – 2002
1998 – 2004
1998 – 2001
1984 - 1995
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Other ExperienceOther Experience
• CHS (OSMB)-NHLBI• SOCA – NEI/NIAID• Therapeutic Trials • Prevention Trials• LRC CPPT
1998 – Present
NIAID Pgm Rep
NIAID Pgm Rep
NIAID Pgm Rep
1975 – 1980
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OPTIMAOPTIMA
NO ARDFP + Standard ART
HIV+ patients for whom HAART has failed
ARDFP + Standard ART
ARDFP + Mega ART NO ARDFP + Mega ART
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ERSETERSET
Patients with Mesial Temporal Lobe Epilepsy (MTLE), whose seizures have failed to respond to 2 medications, and who have not had disabling seizures for more than 2 years
Early surgical intervention
Continued optimal pharmacotherapy
Primary Outcome: Freedom from disabling seizures
Secondary: Freq & severity, QoL, psych & social func
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ATNATN
• NICHD Adolescent Medicine Trials Network• HIV+ adolescents• Short-cycle therapy• Structured treatment interruption• Hep-B vaccine trials• QoL, Compliance, VL monitoring
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ATN WorkloadATN Workload
• Two trials -- ~ 4 days/year– Face-to-face – 2 days– Review quarterly reports – ½ day– Conf calls – 1 day
• More trials -- ~ 6-7 days/year– Face-to-face – 3 days– Review quarterly reports – 1day– Conf calls – 2 day
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ICTDRICTDR
• Multiple trials in TB, malaria, diarrhea, hantavirus, dengue, malnourishment
• Often unblinded, vs stand of care• Multinational enrollment, developing
countries• NIAID Div Microbiology & ID network
est. 1991
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ACESACES
Pts w hx of MI or revascularization or > 50% stenosis
Azithromycin 600 mg/wk
Placebo 1 tablet/wk
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Hermansky-Pudlak TrialHermansky-Pudlak Trial
Puerto Rican HPS patients w HPS mutations admitted to NIH Clinical Center w FVC 40-75% of predicted
Anti-fibrotic (pirfenidone)
Placebo
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Data Monitoring CommitteeData Monitoring Committee
• Need an Independent DSMB
–Mortality or irreversible
morbidity outcome–Pivotal Phase III trials
• Need independence of stat func
www.fda.gov/cber/gdlns/clindatmon.htm
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DMC ReviewsDMC Reviews
Recruitment
Baseline Variables
- Eligibility & Comparability
Outcome Measures
- Primary & Secondary
Toxicity/Adverse Effects
Compliance
Specified Subgroups
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DMC RelationshipsDMC Relationships& Responsibilities& Responsibilities
• Patients• Study Investigators• Sponsor• Local IRBs• Regulatory Agencies
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Early AnalysisEarly AnalysisDMC and Executive CommitteeDMC and Executive Committee
Recruitment/Entry Criteria
Baseline Comparisons
Design Assumptions• Control only• Combined groups
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Design ModificationsDesign Modifications(For Example)(For Example)
• Entry Criteria
• Treatment Dose
• Sample Size Adjustment
• Frequency of Measurements
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DMC RecommendationsDMC Recommendations
• Continue Protocol Unmodified
• Modify Protocol
• Terminate Trial
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Reasons for Early TerminationReasons for Early Termination
• Serious toxicity
• Established benefit
• Futility or no trend of interest
• Design, logistical issues too
serious to fix
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Decision PhilosophyDecision Philosophy
Decide Ahead of Time
• Positive Beneficial Trend– How convincing?
• Negative Harmful Trend
– Symmetric or Asymmetric?
• No Trend
– Futility?
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Complex Decision-making ProcessComplex Decision-making Process
• Recruitment Goals
• Baseline risk and comparability
• Compliance
• Primary & secondary outcomes
• Safety
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Complex Decision-making ProcessComplex Decision-making Process
• Internal consistency
• External consistency
• Benefit/Risk
• Current vs. future patients
• Clinical/Public impact
• Statistical issues
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DMC MembershipDMC Membership
Needed expertise– Clinical– Basic science– Clinical trial methodology– Biostatistics– Epidemiology– Medical ethics
• Helpful expertise– Regulatory
• Some experience essential
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DMC MembershipDMC Membership
• One can represent multiple areas of expertise
• Recommend minimum size of 3
• Max depends on complexity
• Recommend size >5 for multicenter trials or multiple trials
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DMC MembershipDMC Membership
• Jointly agreeable to both sponsor and investigators (e.g. Exec Comm)
• Formal appointment often made by sponsor or delegated to Exec Comm
• An honor but not honorary – must assume serious responsibility
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DMC MembershipDMC Membership
• Groups with conflicts of interest– Sponsor
• Industry• Government• Disease Societies
– Trial investigators– Regulatory agencies– Individuals with financial incentives
or intellectual investment
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DMC ChairDMC Chair
• A critical appointment
• Needs clinical trial experience
• Ideally, DMC experience
• Consensus building talent
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DMC Decision Making RoleDMC Decision Making Role
• DMC makes recommendations, not final decisions
• Independent review provides basis for recommendations
• DMC makes recommendations to Exec Comm, or to sponsor directly
• DMC may, if requested, debrief Exec Comm and/or sponsor
• DMC recommendations are rarely rejected
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DMC Meeting StructureDMC Meeting Structure
E xe cu tive S ess ion
D e b rie fin g S e ss ion
C lo sed S ess ion
O p e n S ess ion
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DMC Meeting FormatDMC Meeting Format
• Open Session – Progress, blinded data
– Sponsor, Exec Comm, DMC, SAC
• Closed Session– Unblinded data
– DMC, SAC
– Sponsor rep? (usually not)
• Executive Session – DMC only
• Debriefing Session– DMC Chair, Sponsor rep, Exec Comm rep
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DMC Needs “On-Line”DMC Needs “On-Line”Data Mgmt & AnalysisData Mgmt & Analysis
• DMC reluctant to make decisions on “old data”
• Be prepared from start (e.g., ACTG 076)
• Focus on key variables, not complete case reports (delays can be problematic)
• Minimize data delay and event verification (e.g., ACTG 019)
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ACTG #019
1.00
0.95
0.90
0.85
0.700 4 8 12 16 20 24
Time to HIV Progression (months)
Pro
babi
lity
HIV Progression (8/2/89)
ZDV 500 mgPlacebo
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ACTG #019
1.00
0.95
0.90
0.85
0.700 4 8 12 16 20 24
Time to HIV Progression (months)
Pro
babi
lity
HIV Progression (8/16/89)
ZDV 500 mgPlacebo
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DMC ReportDMC Report
• Screening & recruitment
• Baseline variables /Risk factors
• Compliance
• Primary & secondary outcomes
• DMC Report Example:
• Adverse Events
• Laboratory outcomes
• Concomitant therapy
• Subgroups
• Interim analysis assessment
http://www.medsch.wisc.edu/biostat/clintrials/sdac/sdacpdf.html
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Masking/Blinding DMC ReportMasking/Blinding DMC Report
• A vs. B, C vs. D, ….. X vs. YNOT RECOMMENDED!
• A vs. B for all tables and require masked decisionsNOT RECOMMENDED!
• A vs. B for all tables– unblind on a “need-to-know” basis or– identify labels at meeting
RECOMMENDED!
• Named treatment vs. control tablesNOT RECOMMENDED!
• DMC masking not an FDA requirement
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DMC ConfidentialityDMC Confidentiality• In general, interim data must remain
confidential– DMC may rarely release specific/
limited interim data (e.g. safety issue)• Members must not share interim data
with anyone outside DMC• Leaks can affect
– Patient Recruitment– Protocol Compliance– Outcome Assessment– Trial Support
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ConclusionsConclusions
• Learn from history (e.g., NHLBI)• Develop DMC experience• Evolving process• “Eye on the prize” – Patient
safety and protection