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