CALL TO ORDER
Panel Chair Michael Wilson, MD, called the meeting to
order at 9:47 AM. The Panel
Executive Secretary Freddie Poole read the conflict of interest statement and
noted that wavers had been granted to Drs. Ng and Nachamkin,
which allowed their full participation in todayís meeting.
Further, matters of past interest had been
considered for Drs. Baron, Carroll,
Nolte, Reller and Sanders and their full participation was allowed. Dr. Wilson then asked the panel members and consultants to
PRESENTATION OF THE PREMARKET APPROVAL APPLICATION
Sepsis Inc, Endotoxin Activity Assay (EAA) P 0100226.
An in vitro diagnostic device for
the determination of endotoxin activity in human blood samples, to rule out Gram
Paul Walker, MD, Ph.D., President & CEO, Sepsis Inc., introduced the
Endotoxin Activity Assay (EAA) and described the interactive review process and
presented the intended use, to rule out the presence of gram negative organisms
Ė a shift in diagnostic paradigm strategies.
R. Phillip Dellinger, MD, a Site Investigator, Director, Critical Care
Medicine, Rush Presbyterian St. Lukeís Medical Center, explained the proposed
use of EAA in the decision making process for infections in the intensive care
unit. In their pivotal study, the
MEDIC Trial, 18% of the patients had confirmed infection and 8% had gram
negative infection. He concluded
that the because there is now general consensus that endotoxemia occurs in
absence of gram negative infection these findings can be used with negative
blood cultures to tailor patientsí treatment.
Alex Romaschin, Ph.D., Scientific Director, Sepsis Inc., and Associate
Professor of Laboratory Medicine and Surgery, University of Toronto, described
the technology of the chemo-luminescent assay.
The antibody used in this assay has high specificity and sensitivity to
the Lipid A molecule found in endotoxins. Gram
positive bacteria, pathogenic fungi and their cell walls or disruptive membrane
products do not react in this assay. Lipopolysaccharide
binding proteins, which are problematic in the LAL assays, did not confound this
reaction. He concluded that the
unit dosage format of the assay, and the reproducibility with which it could be
performed, and that the assay is completed in one hour, makes this assay a good
indicator for the absence of gram negative infection.
Debra Foster. BSc. Clinical Project Manager, Sepsis Inc., presented the clinical
investigative plan for the Multi-center Endotoxin Detection in Critical Illness
(MEDIC) Trial. Ten centers in four
different countries (US, Canada, Belgium and UK) participated in the study.
The inclusion criteria were all ICU patients suspected of having an
infection. These patients had at least one set of blood cultures and were
followed for seven days. The CDC
criteria were initially used to interpret gram negative infection.
A clinical evaluation committee (CEC) was later employed to adjudicate
the interpretation of the data.
John Marshall, MD, Principal Investigator, Research Director Medical-Surgical ICU,
Toronto General Hospital, discussed the pivotal trial in which 408 evaluable
patients were enrolled from intensive care units and tertiary care facilities.
He further explained the necessity of the CEC and the shortcomings of
using only CDC interpretive criteria. Eighteen per cent of the evaluable
patients showed gram-negative growth in their blood specimens.
Thirteen percent met the CEC criteria and 8% met the CDC criteria for
infection. The specificity and sensitivity of these tests were similar between
the two criteria, roughly 33% and 80% respectively. If the blood culture and the assay were drawn on the same day
and were negative, there was a 94% negative predictive value (NPV) (likelihood
that the patient did not have a gram negative infection) with the CEC criteria
and 91% NPV with the CDC criteria..
Dr Paul Walker summarized the presentation by noting Sepsis Inc. has proposed EAA as
an adjunct test with blood culture in ruling out gram negative infection in
patients admitted to the ICU, at risk of or suspected of having an infection.
Dr. Wilson invited
the panel members to question the sponsor.
The panel wanted to know the effect of polymorphonuclear leukocytes,
albumin, antibiotics, and corticosteroids and immunosuppression response on the
assay. The firm responded that
there were no effects. Other
questions asked were: Did fungal infection and gram positive infection lead to
false positives? What would a
clinician do differently with a positive or negative assay?
The sponsor responded that they were not making claims for a positive EAA
however a negative test would infer that the patient did not have a gram
negative infection. How much weight
did this test have on its own merit? The
firm responded that it was an added piece if information. The negative
predictive value was based on an erroneous assumption that a negative culture
meant that the patient did not have infection.
Another panel member commented that the pretest probability was 83-87, or
maybe 92, but with the EAA the probability is 91 percent.
Marian Heyliger, MS, Senior Scientific Reviewer, Bacteriology Devices Branch, presented an
overview of the spectrum of sepsis and laboratory diagnosis.
She pointed out the differences in the false negative rates using CDC and
CEC criteria. The EAA sensitivity
of 80%, was based on gram negative infection, however, there was no evaluation
of false positive rates due to a lack of specificity of endotoxin production.
It is well documented that endotoxins arise from other sources than gram
negative infection. She stated that
FDA would like to know if the false-positive results should be included in the
evaluation of the assay. She
described the organisms isolated and the various sites of infection in the false
negative population. She noted EAA
is limited by non-hematogenous and remote sites of infection, and false positive
bacterial cultures due to colonization. In
closing, she raised two questions: 1) could infection outcomes be better
measured beyond Day 1 and 2) does the negative predictive value (NPV) of 91% and
94%, as found in this study, indicate a role for this assay in clinical
John Dawson, MS, JD, Mathematical Statistician, Division of Bio-statistics, Office of
Surveillance and Biometrics, presented the FDAís statistical perspective on
the application. He explained that
negative predictive value (NPV) requires a gold standard for unbiased
evaluations. When there is no gold
standard, NPV stands on its own
Since the NPV takes prevalence into account, it is more accurate to interpret
negative predictive value as a probability, that is, probability a patient would
have a negative test, if he had been in the study.
Dr. Wilson then invited the panel to ask
questions of the FDA. The panel had
questions concerning the validity of the confidence level in such a small study,
the meaning of a negative culture, the threshold level between positive and
negative cases, the composition of ICU patients that is, proportion of medical
and surgical patients and species bias, (did EAA miss Serratia, Pseudomonas and
E. coli?) Other concerns expressed were the EAA 0.4 cutoff vs. 0.3; and criteria
used by the CEC.
Wilson opened the meeting for comments from the public.
There were no comments from the public.
The Open Public Hearing session was then closed.
Question #1: The performance parameters used to describe this assay
included sensitivity, specificity, positive predictive value (PPV) and negative
predictive value (NPV). Are the
diagnostic endpoints used in these calculations (CDC criteria and Clinical
Evaluation Criteria) appropriate to support these terms or should alternative
descriptive terms (% agreement, etc) be used?
Dr. Nachamkin felt that there was no compelling evidence presented with this limited
data for the ability of the test to rule out infection.
A report of endotoxin present, is not
a safe method of reporting an assay. He
believes that the sponsor might not have taken the clinician decision making
into account. Dr.
Charache thought that the values are expressed as predictive values and are
stated as predictive of infection, when in fact there is no documentation that
it is. If you look at percent agreement then you have to add all your false
positives and false negatives. If
the goal of the test is to get a no answer then you should look only at the
negative tests. Dr. Nolte wondered how
the difference in CDC and CEC data influenced the clinical outcome.
He didnít think there is any choice but not to use conventional
parameters of sensitivity and specificity.
Dr. Durak suggested that FDA
consider using a quasi-gold standard.
Dr. Reller stated that the test did
not give sufficient confidence to dictate appropriate clinical action.
Dr. Solomkin advised the
sponsor to look at each gram
Question #2: The sponsor
stated that the NPV is the key parameter in the EAA assay. Is the NPV of 91% (84
to 96% Cl) adequate and acceptable for this assay?
Is the PPV of 15% (11 to 20% Cl) adequate and acceptable for this assay?
Consider: 1) the use of the device and how it affects patient management
and treatment decisions, and 2) the varying prevalence of gram negative
infection in different ICU populations.
Dr. Baron thought the sponsor should re-look at the threshold of positivity and
apply the larger pool of results to the ROC, which might improve the NPV.
Dr. Nachamkin was not
comfortable with the wide confidence interval for the negative predictive value,
and thinks the negative predictive value is an unacceptable test for predicting
Charache worried about a test that missed 25% of the true culture positive
Question #3: The primary outcome of the MEDIC
Study was the documentation of gram negative infection.
The difficulty of determining gram negative infection was shown by the
implementation of a Clinical Evaluation Committee (CEC) to provide a second
evaluation of a patientís infection status.
Should device performance be evaluated using the CDC criteria, the CEC
criteria or both? Is use of
clinical and laboratory information from Day 1 of the study an appropriate
endpoint to characterize performance?
Dr. Wilson asked the panel to focus on the second part of the question since the
first part had already been discussed. Dr.
Durak commented that it was important to distinguish clinical value
and performance, since they may not be the same. Dr. Baron wanted
to know what happened to the endotoxin levels on Day 2 and Day 3, so that the
clinician could make an informed decision.
Dr. Nolte asked about the
interval for using the test. Would the test be used on admission and then daily?
Dr. Danner wanted to know about repeat testing
how many tests have to be done before one positive test results,
for endotoxemia may be intermittent.
There may not be any performance criteria that could describe this in the
Dr. Baron reiterated that the study had ten false negative patients, and only 33
that were excluded. This did not
appear to meet the primary objective..
Question #5: What recommendations and
suggestions should be provided to improve the labeling of this assay?
Dr. Nachamkin stated that the package insert should include the fact that only one
company supplied all the tubes for this test, therefore any other tube should be
evaluated before use. Dr.
Durak thought antibiotics and other drugs such as aspirin and cardio-active
drugs, which could possible be interfering substances, should be added to the
list in the labeling. Dr.
Baron stated that since EAA works better with sepsis than pneumonia, the
labeling could list which types of infectious diseases EAA rules out.
Dr. Nachimkin disagreed, and
stated that because the numbers are so small, no generalizations can be made
about the type of infection. Dr.
Reller suggested that we defer this question until one had a product to
Dr. Wilson opened the Open Public Hearing session. No one came forward to speak. He therefore closed the session.
Dr. Dellinger noted that using a panel of experts to decide if a patient was infected
provided the best possible predictability. Dr. Romaschin
stated that the overall precision found in the trial study was 11% for all
centers weighted by the number of patients. Dr.
Romaschin added that fluctuations in endotoxin were not observed over time
with extensive repeat tests. Dr.
Walker stated that Sepsis Inc. has not found a drug that interferes with this
FDA had no further comments.
Executive Secretary Freddie Poole
read the names of the voting and temporary voting members.
She then explained the voting options for premarket approval that the
panel could recommend. A motion was
made and seconded, and the Panel voted that the PMA was not approvable.
The panel voted unanimously for not approval of the PMA.
The panel provided the reasons for their vote.
Comments related to numbers being too small in the study, no clinical
role for the test, and possible use in the research setting.
panel then provided suggestions as to how the sponsor could make the device
approvable. They recommended that
the sponsor should consider increasing the sample size, which should increase
the confidence in the negative results. The
test as it was had no clinical role in clinical management. The study design should be revised to obtain meaningful
outcomes irrespective of differences between patients, sites and personal
characteristics. Endotoxemia does
not equate with infection. The
false positives may provide further information on what the test is detecting.
The gold standard issue and the negative predictive value must be
thanked the panel members for their participation and the sponsor for its
Dr. Wilson adjourned the meeting at 3:37 PM.