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
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
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
OPTIMAOPTIMA
NO ARDFP + Standard ART
HIV+ patients for whom HAART has failed
ARDFP + Standard ART
ARDFP + Mega ART NO ARDFP + Mega ART
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
ATNATN
• NICHD Adolescent Medicine Trials Network• HIV+ adolescents• Short-cycle therapy• Structured treatment interruption• Hep-B vaccine trials• QoL, Compliance, VL monitoring
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
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
ACESACES
Pts w hx of MI or revascularization or > 50% stenosis
Azithromycin 600 mg/wk
Placebo 1 tablet/wk
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
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
DMC ReviewsDMC Reviews
Recruitment
Baseline Variables
- Eligibility & Comparability
Outcome Measures
- Primary & Secondary
Toxicity/Adverse Effects
Compliance
Specified Subgroups
DMC RelationshipsDMC Relationships& Responsibilities& Responsibilities
• Patients• Study Investigators• Sponsor• Local IRBs• Regulatory Agencies
Early AnalysisEarly AnalysisDMC and Executive CommitteeDMC and Executive Committee
Recruitment/Entry Criteria
Baseline Comparisons
Design Assumptions• Control only• Combined groups
Design ModificationsDesign Modifications(For Example)(For Example)
• Entry Criteria
• Treatment Dose
• Sample Size Adjustment
• Frequency of Measurements
DMC RecommendationsDMC Recommendations
• Continue Protocol Unmodified
• Modify Protocol
• Terminate Trial
Reasons for Early TerminationReasons for Early Termination
• Serious toxicity
• Established benefit
• Futility or no trend of interest
• Design, logistical issues too
serious to fix
Decision PhilosophyDecision Philosophy
Decide Ahead of Time
• Positive Beneficial Trend– How convincing?
• Negative Harmful Trend
– Symmetric or Asymmetric?
• No Trend
– Futility?
Complex Decision-making ProcessComplex Decision-making Process
• Recruitment Goals
• Baseline risk and comparability
• Compliance
• Primary & secondary outcomes
• Safety
Complex Decision-making ProcessComplex Decision-making Process
• Internal consistency
• External consistency
• Benefit/Risk
• Current vs. future patients
• Clinical/Public impact
• Statistical issues
DMC MembershipDMC Membership
Needed expertise– Clinical– Basic science– Clinical trial methodology– Biostatistics– Epidemiology– Medical ethics
• Helpful expertise– Regulatory
• Some experience essential
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
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
DMC MembershipDMC Membership
• Groups with conflicts of interest– Sponsor
• Industry• Government• Disease Societies
– Trial investigators– Regulatory agencies– Individuals with financial incentives
or intellectual investment
DMC ChairDMC Chair
• A critical appointment
• Needs clinical trial experience
• Ideally, DMC experience
• Consensus building talent
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
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
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
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)
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
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
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
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
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
ConclusionsConclusions
• Learn from history (e.g., NHLBI)• Develop DMC experience• Evolving process• “Eye on the prize” – Patient
safety and protection