Transcript Presentation

Setting up a Data Safety Monitoring Board
ASENT Meeting
March 6, 2008
Jennifer Schumi, PhD
Statistics Collaborative, Inc.
[email protected]
1
Five steps to setting up a DSMB
1.
2.
3.
4.
5.
Decide why you need one
Choose the Board and its chairman
Choose the reporting statistician
Define how the Board operates
Write its charter
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What is a D(ata)S(afety)M(onitoring)B(oard)?
•A committee charged with monitoring
• safety
• efficacy
• progress of a clinical trial
•Aka
DMC, IDMC, …
3
Rationale for using DSMBs in research
•Ethical compact protecting trial participants
•Sponsor:
regulatory responsibilities for reporting
financial incentive to end trial early
•May also advise about changes in protocol, procedures
•NIH often uses DSMB in an advisory capacity –
different from industry-sponsored trials
1. Define why you need an external DSMB
•Scope of advice and decisions
 Broad: Safety and efficacy and data quality
 More limited: safety only
•Who makes final decisions for each area
5
Standards for clinical trials
•
NIH Clinical Trial Committee Guide, 1979
“every clinical trial should have provision for data and
safety monitoring… should be commensurate with risks”
•
During the 1980’s
Many models developed; vary across U.S. & Europe
•
1994 NIH Committee on Clinical Trial
Monitoring:
“all trials, even those that pose little likelihood of harm,
should consider an external monitoring body.”
6
Standards for clinical trials, continued
•
2006 FDA guidance document:
Establishment and Operation
of Clinical Trial Data Monitoring Committees
“Full employment act” for statisticians
Describes in detail…
need for independence of DMC
possible models for reporting statistician
role of study team, interaction with sponsor
7
Trials that need a DSMB
•Double-blind
•Large (hundreds, thousands of subjects)
•Multi-center/multi-national
•Long duration
•Endpoint: death or stroke or …
8
Trials that need a DSMB, cont’d
•Participants have high intrinsic mortality risk
 HIV infection, cancer
 Sepsis, pulmonary disease, cardiac failure
•Trial studying a new chemical entity
•Recommended (strongly) by regulatory agency
9
Trials that DON’T need a DSMB
 Phase I studies, pilot studies (some)
 Studies of symptom relief
 Studies with other very close safety monitoring
 Timeline so short the DSMB can’t operate
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NIH-type trial
The Public
Sponsor
(Not blind)
DSMB
(Not blind)
Exec Comm
Steering Committee
Coordinating center
(Not blind)
Labs
Clinics
Participants
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Industry trial
The FDA
Coordinating center (CRO)
Sponsor
Shareholders
Exec Comm
DSMB
(not blind)
Steering Committee
DSMB Statistician
(not blind)
Labs
Clinics
Participants
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Monitoring safety data
•Serious adverse events (in cancer, Grades 3 and 4)
•Adverse events (severity, related to drug)
•Laboratory data
liver function tests, hematology,
changes over time
•Disease/treatment specific scales
•Discontinuation rates
13
Who watches safety? And how?
•Investigators – individual patients
•Pharmacovigilance – SAEs, case by case, across study
•IRBs – SAEs at individual study sites
•Study team (sponsor) –
SAEs, other data, individual cases
pooled across all treatment groups
•DSMB –
SAEs, other data, aggregated by treatment group
14
Problems with knowing
unblinded interim results
•New science, finances may cause want to change:
 primary endpoint
 entry criteria, evaluable population
 concomitant medications
 size of the trial
•Not appropriate if proposer of change knows
interim results
Roles of DSMB – safety and efficacy
•Establish statistical boundaries for efficacy and
futility
•Statistical issues for efficacy settled
•Statistical issues for futility in flux
but reasonably settled
•Type I error not the most important thing to protect
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Roles of DSMB-expanded
•Safety
•Efficacy
•Study and scientific integrity
•Review protocol, CRFs
•Review procedures that would affect data quality
•Review quality & integrity of study data
•Monitor accrual & drop out, compliance
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2. Members and chairman
•Voting
•Physician(s) in specialty area (disease, side effects)
•Epidemiologist/trial methodologist
•Statistician
•Clinical pharmacologist/safety specialist?
•Ethicist, patient representative, lawyer?
•Need effective chairman
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2. Members and chairman
•Non-Voting
•Study or steering committee chair
•Sponsor representatives
•Reporting statistician
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Voting members
•3-10 experts in disease, study drug, clinical trials
•Multidisciplinary, independent
•Disinterested – no conflict of interest
•Experience on other DSMBs
 Chair & statistician
 Some inexperienced to train them
•Must take responsibilities seriously
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3. Choose the reporter
•NIH – someone from the coordinating center
•Industry –
 In-house statistician
 Contract research organization
 Independent statistical group
 Statistician on the DSMB
•Independence  ignorance
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4. Define the operations
•Data
 “Cleanliness is next to godliness”
Not for DSMB!!!
 Timeliness more important than cleanliness
 Report must aim for clarity and focus
•Structure of meetings
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Meetings
•(Brief executive session)
•Open session
•Closed session
•Executive session
•Disseminate recommendations
Open session
Directly to sponsor representative
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Purpose of open session
•Update on progress of the trial
 Report from the sponsor, Steering Committee
 Relevant information from related trials
•Open and honest discussions
•Sponsor, investigators, and DSMB can share
concerns
Participants in closed session
•The DSMB only?
+ the statistician(s) preparing the report?
+ the Chair of the Steering Committee?
+ the sponsor?
•Executive session – DSMB only
Contents and intent of report
Purpose –allow DSMB to make informed decisions
1.
2.
3.
4.
5.
6.
7.
8.
9.
Summary of protocol and outstanding issues
Recruitment and follow-up
Baseline data
Check of randomization
Timeliness of data & adjudication of endpoints
Adverse events with study-specific coding
Dosage of study medication
Vital signs and laboratory parameters
Outcome data
26
Reports to the DSMB: comments
•Should not just be a subset of final tables
•Purpose of interim monitoring  purpose of final
analysis
•Changing the study during the trial  what does the
study show
•Don’t be locked into rigid rules!
•Data should NOT be blind (not everyone agrees)
27
Recommendations from the DSMB
•Shared with Sponsor, Steering Committee, IRBs
•Must prevent unblinding of study team
•Be careful with communications!
•During the trial, everyone reads tea leaves
•DSMB must keep impeccable records
 What did they know and when did they know it?
 Did they change their behavior and rules in
response to data?
28
Monitoring for safety
•Searching for the unknown
•Rare and often unexpected events
•Extreme problem of multiplicity
“I make no mockery of honest ad hockery”-
I. J. Good
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What type of safety bounds?
•None – just rely on the judgment of the DSMB
•Futility bounds for efficacy
Symmetric –
as hard to call unsafe as to call efficacy
Asymmetric –
less stringent than for efficacy
we do not want to prove harm
•Careful balance of risks and benefits
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Taxonomy of adverse events
•Expected events – balance risk to benefits
•Unexpected, but not serious
•Unexpected, serious
•Unexpected, very serious
•Not credible, but scary if true
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Enhancing safety data
•
•
Spontaneous reports notoriously ambiguous
Formal data collection
 Diaries
 Endpoint committees
 Ongoing reporting of prognostic factors
 Special data collection forms
32
Reporting safety data
•Don’t rely on coding systems
•Classify and reclassify
•Look at relevant lab data
 Means (remember the CLT!)
 High percentiles (but not min and max)
 Outliers for very rare events
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5. Write the Charter
 Mission and goals
 Responsibilities (confidentiality, lack of conflict)
 Communications by DSMB
 Governance: chair, minutes, quorum, tie votes
 Frequency of meetings
 Requirement for decision rules, statistical guidelines
 Obtaining data for review
34
Issues to hammer out
•Blind, unblind, or partially blind
•Sharing data with other DSMBs
•Participating on related committees
35
Stopping a trial
•Early stopping is a major decision
 Can hurt patients/product if stopping delayed
 Can doom product if stopping premature
•DSMB must aim for defensible decisions
•Once recommended – very hard to change
After the door is open
•Full and honest disclosure of what happened
Recommendations to sponsor
•Sponsor and DSMB must trust each other
•Must choose DSMB on basis of expertise
 Membership is not a “reward” for good
recruitment in other trials
 Structure of the meeting should not impede the
ability of the DSMB to do its work
 Always have face-to-face meetings when the
DSMB is thinking about stopping
Recommendations to investigators
•Need careful safety monitoring plan
•Investigators in a multi-center trial should
look at the monitoring plan
39
Suggestions from other DSMBs
•Should be multidisciplinary
•Should be committed to the trial
•Meet in person when possible
•Reporting group must understand trial and data
•DSMB must have the right
 to ask for additional presentations without telling sponsor
 to hold executive sessions
 to request/recommend additional expertise
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Questions?
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Informed consent
•Agreement describing risks and benefits
•People don’t enter trials to prove
intervention is harmful
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