Use of Data Monitoring Committees
(DMC) in Device Trials: An FDA
Division of Cardiovascular Devices
(DCD) Perspective
Bram Zuckerman MD, FACC
Bram.zuckerman@fda.hhs.gov
Director, Division of Cardiovascular Devices
Center for Devices and Radiological Health
1
1
Introduction
• Most literature on Data Monitoring Committees
(DMC) deals with drug trial applications
• DMCs have been employed at FDA Device
Center (CDRH) over the last decade
Today's goals:
• Talk about use of DMCs at CDRH
• Comment on FDA DMC Guidance Document
2
2
CDRH and Data Monitoring
Committees (DMCs)
• HHS Office of Inspector General recommended
in 1998 that FDA clarify appropriate role and
procedure for DMCs
• In 2006 FDA issued the DMC Guidance
www.fda.gov/cber/gdlns/clintrialdmc.htm
• The Guidance is applicable to CBER, CDER,
and CDRH trials
3
3
What is a Clinical Trial Data
Monitoring Committee?
• A Clinical Trial Data Monitoring Committee
(DMC) is a group of individuals with pertinent
expertise that reviews on a regular basis
accumulating data from an ongoing clinical
trial
• The DMC advises the sponsor regarding the
continuing safety of current participants and
those yet to be recruited, as well as the
continuing validity and scientific merit of the
trial
4
4
Other Oversight Groups
Interact with DMCs
• Clinical Endpoints Committee (CEC) –
independently reviews important endpoints
reported by trial investigators to determine
whether they meet protocol-specified criteria
• Institutional Review Board (IRB) – responsible
for evaluating a trial to determine whether
“risks to subjects are minimized” and “risks to
subjects are reasonable in relation to
anticipated benefits” (21 CFR 56.111(a)(1) and
(3))
5
5
Which Device Trials need
DMCs?
• All clinical trials require safety monitoring (21
CFR312.32 (c)) but this does mean that every
trial needs a formal committee external to the
trial organizers and investigators
• A DMC is required by FDA in the case of
waived informed consent (21 CFR 50.24) (e.g.,
emergency research for CPR devices)
• A DMC is not needed or advised for every
clinical trial, although it may prove valuable
and Least Burdensome
6
6
Which Device Trials Need
DMCs?
• Consider relevant ethical and scientific reasons (i.e., high
risk to trial participants, long-term trial) for institution of a
Data Monitoring Committee in large multisite studies
• For cardiovascular disease trials the primary (or
secondary) endpoint is often mortality or major morbidity
for pivotal trials of arrhythmia, heart failure, myocardial
infarction, and anti-restenosis therapies
• Would a favorable or unfavorable result ethically and\or
scientifically require early termination?
7
7
Which Device Trials Need
DMCs?
Will institution of a DMC allow for the use of optimal
statistical and clinical trial methodologies?
A) If differences in major response variables are
unimpressive at an interim analysis is it justifiable
in terms of time, money, and effort to continue?
B) Alternatively, if the difference in the primary
endpoint is less than expected a DMC might be
useful for legitimately helping to modify
inclusion\exclusion criteria or sample size
8
8
Which Device Trials Need
DMCs?
Special concerns about risks to trial participants:
A) Is the treatment to be tested novel, so that there
is little prior information on clinical safety, or is
there prior information that raises concerns about
the potential for serious problems? (e.g., DMCs
are useful in feasibility device trials as well as
pivotal trials)
B) Safety concerns are usually heightened in
studies performed in potentially fragile
populations (e.g., children or the elderly)
9
9
Which Cardiovascular
Device Trials Need DMCs?
• Last decade has seen increasing importance of
device therapy for treatment of cardiovascular
disease
• Most of the prior bullet points apply to the
cardiovascular device trials arena
• DCD use of DMCs has been extensive
• DCD recommends use of DMCs for feasibility and
pivotal trials when dealing with complex product
development
10
10
General Operational Issues
• DMCs should have well-defined standard
operating procedures
• The DMC and Sponsor should be able to
operate per the planned operational timeline
• Members should be carefully selected
(experienced biostatistician, independent and
objective expert clinicians, DMC Chair should
have experience in clinical trials as well as the
disease of interest)
11
11
General Operational Issues
• The plan for interim looks at data and the alpha
spending function need to be prospectively defined
in the IDE protocol
• Any plan for possible increase of sample size needs
to be prospectively stated in the IDE protocol
• It is not uncommon in the “closed” section of a DMC
meeting that the DMC may need to see unblinded
trial results in order to effectively determine the
risk/benefit profile at an interim analysis
12
12
Operational Problems
Encountered by DCD
• In many cases DMCs have not been able to
operate per the planned operational timeline
• As a result DCD often only gives “conditional
approval” for IDE studies
• Full IDE approval is dependent on the
Sponsor and DMC demonstrating that they
can operate effectively
• DCD may not agree with evaluation strategy
and conclusions reached by DMC and
exercise its authority accordingly [21CFR
13 812.150(b)10]
13
Major Reasons for Early Termination
of a Trial
• The trial may show serious adverse effects in the
entire intervention group or in a dominating
subgroup
• There may be greater than expected beneficial
effects
• It may become clear that a statistically significant
difference by the end of the trial is improbable
• Logistical or data-quality problems may be so
severe that correction is not feasible
14
14
The Early Termination of a Clinical
Trial Can be Difficult
• Issues involved may be complex because study
results are often mixed
–Statistical stopping “rules” are useful guides in
this process but should not be viewed as an
absolute
–Examine differences in prognostic factors,
possible role of bias due to non-blinding, impact
of missing data, side effects and outcomes of
secondary response variables, internal
consistency across subgroups and between
centers, outcomes of similar trials, and impact of
early termination on general acceptance of
results in clinical practice
15
15
DCD Experience with Early Trial
Termination
• Sponsor Consultation with FDA on
implications of early stopping may be helpful
• FDA will rarely, if ever, tell a sponsor which
decision to make but only provide scientific
and regulatory guidance on the possible
implications of early termination
• Percusurge Panel Transcript (2/05/01) on FDA
website provides one detailed DCD device
example
16
16
Conclusions
• Use of DMC is recommended for many device
trials
• General DMC principals apply to device and
drug trials even though devices are not drugs
• Real time DMC implementation has been a
challenge for many DCD trials
• A “conditional IDE approval” mechanism has
been helpful for practically improving DMC
performance
17
17