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DSMB Experiences

DSMB 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. OPTIMA ERSET ATN ICTDR ACES Hermansky-Pudlak VA Coop Studies. 2002 – Present 2002 - Present

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DSMB Experiences

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  1. DSMB 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

  2. OPTIMA ERSET ATN ICTDR ACES Hermansky-Pudlak VA Coop Studies 2002 – Present 2002 - Present 2002 – 2004 2000 – 2002 1998 – 2004 1998 – 2001 1984 - 1995 DSMB Stat Experience

  3. 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 Other Experience

  4. OPTIMA HIV+ patients for whom HAART has failed ARDFP + Standard ART NO ARDFP + Standard ART ARDFP + Mega ART NO ARDFP + Mega ART

  5. ERSET 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

  6. ATN • NICHD Adolescent Medicine Trials Network • HIV+ adolescents • Short-cycle therapy • Structured treatment interruption • Hep-B vaccine trials • QoL, Compliance, VL monitoring

  7. ATN 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

  8. ICTDR • 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

  9. ACES Pts w hx of MI or revascularization or > 50%stenosis Azithromycin 600 mg/wk Placebo 1 tablet/wk

  10. Hermansky-Pudlak Trial Puerto Rican HPS patients w HPS mutations admitted to NIH Clinical Center w FVC 40-75% of predicted Anti-fibrotic (pirfenidone) Placebo

  11. Data 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

  12. DMC Reviews Recruitment Baseline Variables - Eligibility & Comparability Outcome Measures - Primary & Secondary Toxicity/Adverse Effects Compliance Specified Subgroups

  13. DMC Relationships& Responsibilities • Patients • Study Investigators • Sponsor • Local IRBs • Regulatory Agencies

  14. Early AnalysisDMC and Executive Committee Recruitment/Entry Criteria Baseline Comparisons Design Assumptions • Control only • Combined groups

  15. Design Modifications(For Example) • Entry Criteria • Treatment Dose • Sample Size Adjustment • Frequency of Measurements

  16. DMC Recommendations • Continue Protocol Unmodified • Modify Protocol • Terminate Trial

  17. Reasons for Early Termination • Serious toxicity • Established benefit • Futility or no trend of interest • Design, logistical issues too serious to fix

  18. Decision Philosophy Decide Ahead of Time • Positive Beneficial Trend • How convincing? • Negative Harmful Trend • Symmetric or Asymmetric? • No Trend • Futility?

  19. Complex Decision-making Process • Recruitment Goals • Baseline risk and comparability • Compliance • Primary & secondary outcomes • Safety

  20. Complex Decision-making Process • Internal consistency • External consistency • Benefit/Risk • Current vs. future patients • Clinical/Public impact • Statistical issues

  21. DMC Membership Needed expertise • Clinical • Basic science • Clinical trial methodology • Biostatistics • Epidemiology • Medical ethics • Helpful expertise • Regulatory • Some experience essential

  22. DMC 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

  23. DMC 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

  24. DMC Membership • Groups with conflicts of interest • Sponsor • Industry • Government • Disease Societies • Trial investigators • Regulatory agencies • Individuals with financial incentives or intellectual investment

  25. DMC Chair • A critical appointment • Needs clinical trial experience • Ideally, DMC experience • Consensus building talent

  26. DMC 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

  27. DMC Meeting Structure

  28. DMC 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

  29. DMC Needs “On-Line”Data 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)

  30. ACTG #019 HIV Progression (8/2/89) 1.00 0.95 0.90 0.85 0.70 Probability ZDV 500 mg Placebo 0 4 8 12 16 20 24 Time to HIV Progression (months)

  31. ACTG #019 HIV Progression (8/16/89) 1.00 0.95 0.90 0.85 0.70 Probability ZDV 500 mg Placebo 0 4 8 12 16 20 24 Time to HIV Progression (months)

  32. Screening & recruitment Baseline variables /Risk factors Compliance Primary & secondary outcomes DMC Report Example: Adverse Events Laboratory outcomes Concomitant therapy Subgroups Interim analysis assessment DMC Report http://www.medsch.wisc.edu/biostat/clintrials/sdac/sdacpdf.html

  33. Masking/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 meetingRECOMMENDED! • Named treatment vs. control tables NOT RECOMMENDED! • DMC masking not an FDA requirement

  34. DMC 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

  35. Conclusions • Learn from history (e.g., NHLBI) • Develop DMC experience • Evolving process • “Eye on the prize” – Patient safety and protection

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