Transcript Slide 1

The Role of the Data Monitoring
Committee
Society for Clinical Research Associates
Philadelphia, PA
April 23, 2010
Role of Data Monitoring
Committees (DMCs)
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Why use a DMC?
Roles, Objectives and Setup for DMCs
Operational considerations
(Brief) Statistical considerations: p-value
adjustments
Where do companies get it wrong:
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Administrative analyses: look without adjustment
Use DMCs for safety only
Blinding the DMC
Reading List
Guidance for Clinical Trial Sponsors
http://www.fda.gov/cber/guidelines.htm
Fundamentals of Clinical Trials
Friedman, Furberg, DeMets
Polio: An American Story
David Oshinsky
Reasons for DMCs
 Ethics
 Insurance
Reasons for DMCs: Ethics
 Oversight
function to insure patient safety
 Monitor and be able to quickly react to any
untoward safety events
Reasons for DMC: Insurance
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Operational Issue
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Provide oversight function of study progress
Insure study will have reasonable likelihood of
achieving basic objectives.
Early warning system for operational issues
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Critical design parameters
• Expected treatment difference, control response rate,
variance of primary endpoint
Stop early
• No efficacy or unacceptable safety
• Early, compelling, untoward, unexpected efficacy
Committees
 Data
Monitoring Committee
 Executive Committee
 Others
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Data Analysis Center
Adjudication Committee
Central Labs
DMC
 Review
data tabulations from ongoing
clinical trial
 Deliberations are confidential
 Make recommendations to Exec.
Committee
DMC Membership
 Independent
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clinical members
Therapeutic area experts
No vested interest in company or outcome of
trial
 Independent
statistician
 Ethicist (optional)
No Involvement in DMCs
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Company/Sponsor/Client
Investigators participating in the study
The investigator’s contact at company
Any individual who can change or influence the
recruitment of patients
Individuals with data classification
responsibilities
Individuals who could control or change study
design, objectives or planned analyses
Executive Committee/Steering
Committee
 Responsible
for study oversight and
conduct
 Membership: company, investigators
 Decision makers
Key Point
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DMC
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Independent
Access to data
No decisions, recommendations to Exec Comm.
Exec Committee/Steering Committee
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Company representation
Investigator representation (optional)
NO access to data
Decision makers, based on recommendations from
DMC
DMC Charter
 Define
roles and responsibilities of DMC
members
 Communication with Executive Committee
 Structure and timing of meeting
 Scope of data reviews
DMC Meetings
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Open sessions
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Closed sessions
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Executive Committee
DMC
No unblinded data
Unblinded data review
DMC Only
Minutes
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Document deliberations
Confidentiality is key
Example: Centocor
 Centoxin:
potential blockbuster with
estimated $1B/year market potential
 NYT: 12 Feb 1993
 Centoxin
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Efficacy endpoint in pivotal study changed
based on knowledge of interim results
NDA terminated
Operational Considerations
 Keep
review scope focused (“interim
analysis” is not final analysis)
 Emphasize simple tables and graphics,
not listings
 Information needs to be
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Current
Current is more important than clean
Plan for Rapid Retrieval of
Outcomes
 Important
to minimize time lag between
CRF at site vs inhouse
 Paper
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Short forms, worksheets
Phone calls
Working/temporary databases
Help Desk support
 EDC
very helpful alternative to paper
Statistical Issue
 When
DMC looks at interim data, p-value
adjustments are necessary
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Avoid over reaction to early trends
Maintain nominal alpha level of 0.05 for the
final analysis
Goal: Control type I error and
maintain nominal 0.05 alpha for
final analysis
 Need
to set a high statistical bar for
Interim Looks
 Interim analyses utilize p-values at levels
of approx. 0.0001 at each look vs 0.05 at
each look
 E.g., 6 interim analyses (6 looks):
final alpha = 0.05 – 6*0.0001 = 0.0494
Key Point
 There
are sound reasons to have a DMC
monitor ongoing data
 P-value adjustments need to be made
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Estimates of efficacy and safety effects are
based on small sample sizes
Possibility exists to overreact to early trends
 P-value
adjustments for interim looks can
be very small and final alpha can be
maintained very near 0.05
Interim survival analyses comparing mortality in clofibrate and placebotreated participants in the Coronary Drug Project. A positive Z value
favors placebo.
Where Companies Get it Wrong
 Administrative
analyses
 DMC for safety only
 Blinding the DMC
“Administrative Analyses”
 Look
at data with no intent to modify study
 Look at data for operational (“insurance”)
issues
 Since no intent to change, no adjustment
of p-values should be necessary
 If efficacy data are involved, adjustment is
needed
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Always a potential to overreact to early trends
Major red flag
DMC for Safety Only?
 DMC
needs access to both efficacy and
safety to assess risk and benefit
Blinding DMC Members?
 Not
an FDA or ICH Requirement
 Imposed by Sponsors to
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“Prevent bias”
“Avoid over reaction to early trends”
ICH E9
“Interim analysis requires unblinded
access to treatment group assignments”
 4.1:
“Interim analysis “…involves access
to … “unblinded data and results.”
 4.5:
Controlling Bias…Overreaction
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DMC does not make decisions
 DMC has no vested interest (unlike
company)
 Monitoring boundaries are in place
 Degree of empowerment of DMC comes
from Executive Committee and is
described in the Charter
DMCs in pre-NDA Setting
Studies in pre-NDA setting seldom stop
early for efficacy
 Need for adequate safety data (ISS
requirements) will often override any early
efficacy trends
 Monitoring boundaries make it unlikely that
effect is significant enough to stop for
efficacy
EXAMPLE AMD
 Limited
phase II dosing information
 First major entry into patients was two
large Phase III studies.
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Limited safety data
 Efficacy
endpoint: mean difference of > 2
lines between treatment and placebo after
two years of therapy.
AMD Example
 Two
large multicenter Phase III studies to
show efficacy and establish safety in
patients with wet AMD
 Primary endpoint: slow vision loss relative
to placebo using standard eye charts
 Treatment duration: two years
 Company: Miravant
AMD Example
 Monitor
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for Safety Only
AEs, labs, other safety information
Interest in acute, untoward decreases in
vision
• Examine
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Decreases of 3-6 lines
Within initial 3 months
On individual patient basis
DMC was blinded
AMD Example
 FDA
mandated post hoc adjustment of pvalues since DMC viewed data related to
efficacy
AMD Results from 2 Year Follow-Up
Proportion of Patients Losing <2 Lines of Vision
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Overall test of
no treatment
p-value vs.
Study
Treatment
N
n (%)
effect
placebo_
98EA001
98EA004
Placebo
SN050
SN075
64
107
108
27 (42.2)
62 (57.9)
39 (36.1)
0.0045
Placebo
SN050
SN075
55
124
117
23 (41.8)
72 (58.1)
59 (50.4)
0.1200
0.0456
0.4293
0.0444
0.2908
Summary
 Patient
safety is key
 DMC is an independent group
 Charter describes roles and
responsibilities
 Monitoring Boundaries are needed
 DMC needs to be unblinded and needs to
assess both benefit and risk