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The Adjudicators: Role and
Responsibilities of the CEC
Roxana Mehran, MD
Professor of Medicine (Cardiology) and Health Evidence Policy
Director of Interventional Cardiovascular Research and Clinical Trials
The Icahn School of Medicine at Mount Sinai, New York, NY
Chief Scientific Officer
Cardiovascular Research Foundation, New York, NY
Cardiovascular Research Technology - CRT
February 23-26, 2013
Washington, DC
Roxana Mehran, MD
Consulting: AstraZeneca, Johnson and Johnson,
Merck and Company, Inc., and Abbott Laboratories
Grant Support: Bristol-Myers Squibb, Sanofi, The
Medicines Company, Lilly and Daiichi Sankyo
Honoraria: Regado Bio-Sciences
Roxana Mehran, MD
Institutional Grant/Research Support :
 Bristol-Myers Squibb/ Sanofi
Lilly/ Daichii Sankyo
The Medicines Company
Consulting Fees/Honoraria
Abbott Vascular
Astra Zeneca
Merck
Regado Biosciences
Janssen (J+J)
Clinical Events Committee:
Why Do we need it?
• Clinical trials are the cornerstone to
approval of Drugs/devices
• The quality and independence of the
conduct of the clinical trials is central to
evaluate the results of any study
• CEC provides blinded, unbiased,
independent assessment of critical
endpoints using source documents and
expert evaluation
CEC Responsibilities
• The CEC is an organization formed to review specific
information obtained from research subjects who are
participating in a clinical trial.
• The committee is empowered to make judgments
regarding this information and to draw conclusions
about pre-specified events that may or may not have
happened during the course of a clinical trial.
• The committee may or may not agree with
conclusions drawn by the investigator from a
specific site; in this case the committee’s conclusion
will serve as the final decision for submission to
regulatory authorities and/or for the purposes of
reporting and publication.
Responsibilities
• To review specific information available for
research subjects participating in the trial and
experiencing pre-specified events (endpoints)
• To use the most up-dated scientific, technical and
clinical information in order to reach their
conclusions
• To draw the conclusions independently from those
of treating physician, PI or sponsor (if different from
those of the site investigator, the CEC’s conclusion
will be considered final)
Adverse Event Reporting
• Adverse event: Any untoward or
unfavorable medical occurrence in a
human subject, including any abnormal
sign (for example, abnormal physical
exam or laboratory finding), symptom, or
disease
(Definition from1996 International Conference on Harmonization E-6
Guidelines for Good Clinical Practice)
Serious Adverse Event
• Any event temporally associated with the
subject’s participation in research that
meets any of the following criteria:

results in death

is life threatening (places the subject at
immediate risk of death from the event as it
occurred)

requires inpatient hospitalization or
prolongation of existing hospitalization
(Definition from1996 International Conference on Harmonization E-6
Guidelines for Good Clinical Practice)
Serious Adverse Event -2
• Results in a persistent or significant
disability/incapacity
• Results in a congenital anomaly/birth
defect
• Any other adverse event that, based upon
appropriate medical judgment, may
jeopardize the subject’s health and may
require medical or surgical intervention to
prevent one of the outcomes listed above
(Definition from1996 International Conference on Harmonization E-6
Guidelines for Good Clinical Practice)
Composition of the CEC
• Typically the committee is composed of odd
number of members with at least three members
present during each meeting (Quorum).
• The members should include those with
expertise in the field as it relates to the trial:
Cardiologists, Interventional Cardiologist,
Cardiothoracic surgeon, Neurologist (especially
if Stroke is a primary endpoint event)
• The committee is supported by team to facilitate
a timely review of cases identified as having
potential endpoints, as well supervising the flow
of work and adherence to the CEC Charter
Important Tips:
• Develop standardized CEC processes

Meeting schedule and required attendees

Signature form for each meeting

Adjudication process

Meeting minutes

Tracking process for event adjudication status
• Develop a reconciliation process

For events discovered by the CEC during adjudication
that meet study endpoints but were not coded or
reported as such by site staff

Reconciliation of the clinical database site reported
events against CEC adjudicated events and all database
entries (multiple Core Lab database entries- QCA, IVUS,
ECG, etc.) and CEC adjudicated outcomes
Clinical Event Committees: Tips
• Include CEC members who are



Independent from the study
Knowledgeable in the therapeutic area
being studied
Experienced in the conduct of clinical
research
• Train CEC members to

Study protocol, study definitions, CEC
procedures, case report forms,
adjudication forms
Prior to the Start of the Adjudication Process
• Train CEC members to

Study protocol- a full understanding of
the protocol is essential prior to start of
any adjudication

Study definitions-All members should
be familiar and agree on their
interpretation of the study definitions

CEC procedures, case report forms,
adjudication forms
Goals
• Unbiased, independent assessment of
events
• Identification of events through review
of reported events
• Fair and non-judgmental adjudication
of endpoints---Blinding required
• Quality control and consistent
adjudication
Conclusions
• CEC process

must be consistently rigorous to maximize the
clinical and research value of the clinical data
obtained

continually evaluated throughout the trial
• CEC harmonization is paramount to assure
confidence in the quality and interpretation of
large sets of clinical data
• However, we must remain cautious not to take
away the true independence of CEC!
Randomized Trials vs
Observational Studies:
Advantages and Disadvantages
Roxana Mehran, MD
Professor of Medicine (Cardiology) and Health Evidence Policy
Director of Interventional Cardiovascular Research and Clinical Trials
The Icahn School of Medicine at Mount Sinai, New York, NY
Chief Scientific Officer
Cardiovascular Research Foundation, New York, NY
Cardiovascular Research Technology - CRT
February 23-26, 2013
Washington, DC
Clinical-Decision Making
Medicine is the ART of “Balance”
Randomized
Controlled
Trials
Observational
Registries
Evidence-based Medicine
Study Design
Treatment Assigned by
Investigator?
No
Yes
Observational: Nature takes its
course, ‘natural experiments’
Cohort: subjects defined by
presence/absence of exposure
Retrospective: Events have
occurred at study onset
Experimental Studies (Trials):
Randomized or non-randomized
Case-Control: subjects defined by
presence/absence of disease
Prospective: Events have not
occurred at study onset
Adapted from Aschengrau et al., Essentials of Epidemiology, 2nd ed. 2008
Study Types: Randomized
• Defined as:
–
“Comparative studies with an intervention and
control group; assignment of the participants
to a group is determined by randomization.
Randomization, in the simplest case, is a
process by which all participants are equally
likely to be assigned to the intervention or
control group.”
Friedman et al. Fundamentals of Clinical Trials, p. 43.
Randomized Trials: Advantages
• Removal of bias in allocating participants
to one group vs. another (Selection bias)
• Randomization produces groups that are
similar in both known and unknown
confounders (Baseline characteristics
table)
• Validity of statistical tests is guaranteed
• A RCT is the equivalent of controlled
‘experiment’ in clinical research
Randomized Trials: Disadvantages
• Certain hypotheses
cannot be randomized
–
Impact of bleeding on
outcomes
• Strict inclusion/exclusion
criteria often preclude
generalizability
(COURAGE: 35K screened
 2.8K randomized
Randomized Trials: Disadvantages
• Poor design

Choice of controls

Poor Assumptions- Underpowered

Inappropriate delta for non-inferiority trials

Poor Definitions- not standardized
• Poor execution

Protocol deviations

Crossovers/Withdrawals

Absence of blinding

Bias in endpoint assessment or adjudication
Randomized Trial Interpretation
• Intention to Treat (ITT) vs Per Protocol analysis
–
To maintain the benefits of randomization (i.e.
balance in risk factors between comparative groups),
analysis must be performed by ITT
–
Any other analysis (subgroups, per protocol etc.) is
a non-randomized comparison and therefore subject
to the identical limitations of observational designs
Types of Randomized Trials
• Superiority
–
Superiority aims to show that one therapy is definitively
different (“better”) than another
• Null hypothesis states that event rate with treatment A is equal to
event rate with treatment B
–
Basic superiority question: What is the probability that this
difference could have occurred by random chance?
• If the probability is less than 5% (arbitrary), then one concludes
that treatment A is ‘different’ (i.e. better) to treatment B
Types of Randomized Trials
• Non-inferiority
–
Non-Inferiority aims to show that one therapy is no
worse than another
–
Worse is defined by pre-specified Δ that is arbitrarily
assigned.
–
Null Hypothesis: Event rate (Tx) – Event rate (Control)
≥Δ
–
Alternative Hypothesis: Event rate (Tx) – Event rate
(Control) < Δ
Summary: Randomization
• Each patient has equal chance of getting a
new or standard treatment
• It cannot be predicted in advance
• Treatment groups should have similar
baselines
• Helps keep ancillary care and patient
evaluation handling identical
• Avoids bias
28
Observational Studies: Retrospective
• Defined as:
–
All events have happened already, and patients’
information is collected from the past (through
chart review, phone calls, etc)
• Pros
–
Inexpensive
–
Fast to execute
–
Rarely any ethical/regulatory hurdles
• Cons
–
Subject to bias
–
unable to address causality
–
very low level of evidence
Observational Studies: Case Control
• Defined as:
–
Patients with events of interest (cases) are identified
and then compared to patients without events
(controls)
• Pros
–
Useful to study rare diseases/outcomes,
–
Fast to execute
–
Inexpensive
• Cons
–
Difficult in choosing ideal control group, bias
Observational Studies: Cohort
• Defined as:
–
A group of patients followed until they have events (very
common – Framingham, Dallas Heart, etc.)
• Pros
–
Best design for studying cause of a condition, course of
disease, or risk factors
–
Correct time sequence to provide strong evidence
• Cons
–
expensive
–
Time consuming
–
unable to prove causality
– (ASSOCIATION ≠ CAUSALITY!)
Observational Studies:
Prospective Single Arm
• Defined as:
–
Following patients undergoing therapy for evaluation of
outcome of interest
• Pros
–
Able to detect low frequency safety events
–
A good post-market tool
–
Real world
–
Track Practice Trends
• Cons
–
Selection Bias
–
Un-measured Confounders can skew the data
–
unable to prove causality
What are Unmeasured Confounders?
Obvious prognostic factors that aren’t collected
- E.g. LVEF, renal function, concomitant medications
Less obvious factors that aren’t collected
- E.g. socioeconomic status, education, compliance,
frequency of physician visit
Physician’s own practice bias
Variables difficult or impossible to measure
- E.g. genotype, endothelial function, extent of
atherosclerosis
- Other factors which have not yet been implicated
in disease pathophysiology (but will in the future!)
Which Registry is Right?
SCAAR Registry
March 8th, 2007
3 year mortality
increased 18%
with DES
Ontario Registry
October 4th, 2007
3 year mortality
decreased 29%
with DES
Randomized Controlled Trials vs.
Observational Registry Studies
The Essential Elements:
1. Unmeasured confounders are inherent in all registries;
their impact cannot be overcome by even the most
sophisticated statistical analyses, leading to frequently
incorrect results and bias in interpretation based on preconceived beliefs
2. By eliminating the effect of unmeasured confounders,
prospective RCTs represent the highest level of
scientific achievement, and when appropriately
performed must be the predominant driver of clinical
(and policy) decision-making
Observational Registries
1) Adavanteges of registries include their real-world nature with few
exclusion criteria, large size, and low cost
2) Invaluable to identify low frequency safety events, and practice
patterns
3) However, registries are limited by variable quality of data collection,
minimal/absent monitoring, and lack of independent event
adjudication and core labs
4) However, unmeasured confounders are inherent in all registries;
which can lead to incorrect results and bias in interpretation based
on pre-conceived beliefs
5) As a result, registries should not be used for comparative
effectiveness analysis, other than to generate hypotheses to be
tested in appropriately powered randomized trials
Randomized Controlled Trials
1) Prospective RCTs represent the highest level of scientific
achievement, and when appropriately performed should be the
predominant driver of clinical (and policy) decision-making
2) However, randomized trials may also be of variable quality, and if
under-powered may generate false negative and positive findings
3) Secondary endpoints and subgroup analyses from RCTs should be
considered hypothesis-generating only, unless pre-specified and
appropriately powered
4) Randomized trials and registry studies are complementary! To fully
characterize the safety and efficacy of therpies (drugs or devices),
high quality, well powered RCTs enrolling “real world” patients must
be performed, followed by high quality post-market approval
registry surveillance studies
What really matter?
Quality
QUALITY
QUALITY