SUMMARY MINUTES OF THE

CLINICAL CHEMISTRY AND

> CLINICAL TOXICOLOGY DEVICES PANEL MEETING
>
> OPEN SESSION
>
> March 24, 2000
>
> 9200 Corporate Blvd.
>
> Room 20 B
>
> Rockville, Maryland
>
> Clinical Chemistry and Clinical Toxicology Devices Panel Meeting
>
> March 24, 2000
>
> PANEL
>
> [Acting Chairperson]{.underline}
>
> Martin H. Kroll, M.D.
>
> [Voting Members]{.underline}
>
> Barbara R. Manno, Ph.D.
>
> Nader Rifai, Ph.D.
>
> Arlan L. Rosenbloom, M.D.
>
> [Temporary Voting Members]{.underline}
>
> Jeffrey A. Brinker, M.D.
>
> Stephen Clement, M.D.
>
> Philip C. Comp, M.D., Ph.D.
>
> James Everett, M.D., Ph.D.
>
> Cassandra E. Henderson, M.D.
>
> Milton Packer, M.D.
>
> [Consumer Representative]{.underline}
>
> Stanley M. Reynolds
>
> [Industry Representative]{.underline}
>
> Erika B. Ammirati, R.A.C.
>
> FDA PARTICIPANTS
>
> Veronica Calvin, M.A.
>
> Panel Executive Secretary
>
> Jean M. Cooper, M.S., D.V.M.
>
> Branch Chief
>
> Clinical Chemistry and Clinical Toxicology Branch
>
> Steven I. Gutman, M.D., M.B.A.
>
> Director
>
> Division of Clinical Laboratory Devices
>
> Ruth Chesler, B.S., M.T.
>
> Scientific Reviewer
>
> Clinical Chemistry and Clinical Toxicology Branch
>
> Marina Kondratovich, Ph.D.
>
> Mathematical Statistician
>
> Division of Biostatistics

SPONSOR PRESENTERS FOR BIOSITE DIAGNOSTICS

John F. Bruni, Ph.D.

Director, Clinical and Regulatory Affairs

Alan Maisel, M.D.

Professor of Medicine, UCSD

Robert H. Christenson, Ph.D.

University of Maryland

Kenneth F. Buechler, Ph.D.

Biosite Diagnostics

Gunars E. Valkirs, Ph.D.

Biosite Diagnostics

Jeffrey A. Dahlen, Ph.D.

Biosite Diagnostics

Brian Chambers

Biosite Diagnostics

OPEN SESSION---MARCH 24, 2000

Acting Panel Chairperson Dr. Martin Kroll began the Open Session at 9:32
a.m. Panel Executive Secretary Veronica Calvin introduced the topic of
discussion, a premarket approval application (PMA) for a peptide test
indicated as an aid in diagnosis of congestive heart failure. She
briefly summarized the results of the December 6 and 7, 1999 panel
meeting, at which the panel unanimously voted to recommend as approvable
with conditions a PMA for the GlucoWatch Biographer from Cygnus, Inc.,
and provided advice and recommendations on over-the-counter vaginal pH
devices.

Ms. Calvin introduced Acting Panel Chair Dr. Kroll, substitute Consumer
Representative Stanley Reynolds and Industry Representative Erika
Ammirati, and noted other panel representatives on loan from the
Hematology and Pathology Devices Panel, the Circulatory Devices Panel,
and the Cardiovascular and Renal Drugs Advisory Committee. She asked the
rest of the panel to introduce themselves. Ms. Calvin read the conflict
of interest statement and noted there were no conflicts to report. Ms.
Calvin also read the appointment to temporary voting status for Drs.
Brinker, Clement, Comp, Everett, Henderson, and Packer.

PRESENTATION

Philip J. Phillips, Deputy Director for Science and Regulatory Policy,
FDA, discussed the "least burdensome" provisions of the FDA
Modernization Act (FDAMA) of 1997. He cited the references in the Act
and examined them in detail, clarifying that FDAMA did not change the
standard for clearance and approval of PMAs or 510ks (demonstration of
safety and effectiveness or substantial equivalence). Mr. Phillips
described the FDA efforts to implement FDAMA through a series of
meetings, publications, and the Least Burdensome Industry Task Force.
These efforts have produced an interim FDA definition of least
burdensome as the successful means of addressing a premarket issue that
involves the smallest investment possible of time, effort, and money.
Mr. Phillips addressed whether FDAMA required a change in FDA culture,
stressing that there are multiple approaches to satisfying regulatory
requirements, that collaboration and compromise are important, and that
the spirit of the law should be understood and followed. He stressed
there is not a conflict between least burdensome requirements and
scientific integrity because good science includes cost effectiveness
and all scientific endeavors are affected by availability of resources.
Mr. Phillips listed a number of mechanisms to lessen the regulatory
burden, such as making sure all regulatory decisions relate to relevant
statutory criteria, factoring in all available public information, and
using a variety of alternatives to randomized clinical trials. He
concluded that it is necessary to factor least burdensome concepts into
all premarket activities and to remain open-minded about methods of
implementation.

There was a question from the panel about the application of these
provisions to the realm of in vitro diagnostic testing.

OPEN PUBLIC HEARING\
There were no requests to address the panel.

SPONSOR PRESENTATION

Dr. John Bruni introduced the PMA for the B-Type or Brain or
Brain-derived Natriuretic Peptide (BNP) Test. In his overview, he
summarized the history of natriuretic peptides and the physiological and
pathophysiological studies that have been performed to establish the
significance of BNP in left ventricular dysfunction (LVD) and congestive
heart failure (CHF). Dr. Bruni discussed the potential clinical
applications of BNP in the diagnosis of heart failure, as a screening
test for LVD, and in ventricular remodeling following acute myocardial
infarction. He looked at statistics on heart disease and the progression
of cardiovascular disease before describing the device as a point of
care assay system with a portable instrument and disposable device. He
noted that it provides easier, faster monitoring than current lab-based
systems, and he outlined the steps involved.

Dr. Bruni discussed the use of the New York Heart Association (NYHA)
classification that can be combined with statistical analyses to show
that the concentrations of BNP increase with severity of disease. He
outlined potential intended uses as an aid in the diagnosis of
congestive heart failure, in the diagnosis and management of patients
with CHF, or as a point of care test for the diagnosis and management of
patients with CHF.

Dr. Bruni presented statistics on concentrations of BNP in hypertensive
versus normal men and women. He looked at sensitivity, specificity,
agreement, and positive and negative predictive values at various
cut-off levels for a range of ages.

Dr. Alan Maisel discussed BNP in the emergency department and assessment
of left ventricular dysfunction. He presented statistics on heart
failure and noted the need for but difficulty of correct diagnosis in
the emergency room, where dyspnea is unspecific in the elderly and obese
and echocardiography is limited and costly. Dr. Maisel described two
methods of assessing such patients. The first involved 250 patients
presenting to the emergency department with shortness of breath, for
whom data were recorded and assessment made while BNP values were
recorded. The second was a later, "gold standard" assessment by two
cardiologists with access to any later tests such as echocardiography
and other information. He presented a graph showing BNP levels of
patients diagnosed with CHF, baseline LVD, and without CHF and then
showed a univariate analysis of signs such as wheezing and murmurs and
of BNP levels in predicting heart problems. He showed ROC curves for BNP
and diagnosis and distribution of misdiagnosed cases using BNP at the
80pg/ml cut-off.

Dr. Maisel stated that while echocardiography is the cornerstone for
diagnosis of LVD, it is expensive, not always readily available, and
sometimes difficult to perform. He hypothesized that BNP levels might
serve as a screening blood test in patients referred for
echocardiography for evaluation of LV function. After looking at the
patient characteristics in this study, he analyzed mean BNP levels for
normal versus abnormal LV function and mean BNP levels for systolic
versus diastolic LV dysfunction.

BNP statistics in the echocardiography study included sensitivity,
specificity, positive predictive and negative predictive values, and
accuracy at various cut-off levels. He also looked at patient
demographics for normal versus abnormal LV function in the echo study
and the distribution of patient referral for echocardiography. Dr.
Maisel concluded by asking for guidance from the panel on the best
intended use for the device.

*Questions for Sponsor*

Questions from the panel concerned differences between male and female
response to the device, the area where the device fits into the clinical
evaluation of patients with congestive heart failure, and the selection
of patient and control groups. The panel also commented that the control
group was extremely small.

FDA PRESENTATION

Ruth Chesler, FDA reviewer, introduced the FDA review team and gave a
brief summary of the basic principles of device operation. She explained
that the Triage BNP test is a fluorescence immunoassay with a single-use
cartridge that uses whole blood or EDTA plasma. She noted that the
sponsor measured BNP levels in three different populations: normal
subjects, hypertensive subjects without congestive heart failure, and
congestive heart failure subjects. The studies were conducted at four
clinical sites, which she described. Patients were selected
sequentially, and patients in each of the New York Heart Association
classes were studied. She provided data on the patients studied, noting
that age was not provided on all patients, although literature notes
that BNP levels increase with age. Ms. Chesler explained how the
sponsors conducted precision studies and showed the precision results as
they are proposed for product labeling. Sponsors tested various
substances for possible interference, only two of which showed
interference levels of 10% or greater.

Dr. Marina Kondratovich, from the FDA Division of Biostatistics,
discussed the age-matched ROC analysis for healthy subjects versus all
CHF and healthy subjects versus patients with CHF from classes I and II,
as well as hypertensive versus all CHF and hypertensive versus CHF class
I and II. She noted that it is important that the diseased group and
non-diseased group are age-matched because BNP increases with age.
Without such age matching, sensitivity and specificity are overstated.
Dr. Kondratovich showed how the ROC age-matched analysis produced
different specificities and sensitivities at various cut-offs.
Age-matched ROC analysis separately for females showed that the test has
almost the same characteristics of performance, but because females have
a tendency to have bigger values of BNP, gender also contributes to
potential misclassification of CHF subjects. She stated that precision,
which is 12-16%, and drug interference can also contribute to potential
misclassification of CHF patients but do not affect significantly the
ability of the test to separate CHF patients from other categories.

Before concluding the FDA presentation, Ms. Chesler read the five
questions for panel discussion.

*Questions for FDA*

Panel questions to the FDA presenters focused on whether the small
number of observations could give statistical power, the effect of the
limited elderly population on ROC curves, whether the CVs were
reasonable, commercially available peptide tests, and use of the test
with African Americans subjects.

OPEN COMMITTEE DISCUSSION

One panelist noted concerns with the lack of data or information on
comparison to commercially available peptide tests, standardization,
frequency and type of calibration verification, stability of the
calibrators and controls, linearity of method, and interference with
renal failure patients. Another panelist's comments focused on the
imprecision, logistics of the clinical trial, need for evaluating
functional sensitivity, internal calibration, use with women, and
validation of the intended use setting. Another panelist raised concerns
involving the diabetes subpopulation, followed by one who listed five
questions to be answered. They included whether the assay reliably
measures the peptide, whether the level of peptide correlates to
pathophysiologic conditions, whether the peptide level is affected by
other metabolic processes or pharmacologic manipulations, what the
likelihood of misinformation is, and what else the sponsor can do to
improve the data set or to better direct device use. A question was
raised about whether the only effective population for the test was in
young males and if patients on estrogen supplements were included in the
normal population.

OPEN PUBLIC HEARING\
Gary Robinson of IGEN pointed out that the prevalence of congestive
heart failure was not presented in the material, which raised questions
for him about the predictive value of the test.

OPEN COMMITTEE DISCUSSION

*FDA Questions to the Panel*

Ms. Chesler then read the FDA questions to the panel for discussion.

In answering the first of the FDA questions for discussion, the majority
of the panel thought that the limitations of an age-matched analysis are
already clear in that the sensitivity and specificity in the real
intended population are not shown. As age of the patient increases, the
cutoff should also increase and a higher cut-off is appropriate, but
there are no data to provide the basis for decision.

The panel expressed a reservation that the second question assumed an
automatic approval of the device. Dr. Gutman acknowledged an assumption
from the review team that the device can meet the least burdensome
provisions for approval but stressed that the panel was free to give
scientific advice to the contrary. He also clarified that there were two
issues involved: performance in point of care versus controlled
laboratory settings and performance in pre-selected population bases.
The panel had a diversity of response, with some members thinking it
important to include in the labeling the fact that studies were done by
trained laboratory personnel and not in real-world use.

On possible ways to portray the data and calculate sensitivity and
specificity, the panel recommended including all the comparisons listed,
with a summary of the data so people can understand the potential
variable performance of the assay.

The panel thought evaluation of the cut-off using age-matched data and
ROC curves was not relevant to the disease-bearing population and stated
that more data that would allow analysis were needed before reaching a
conclusion on the cut-off.

The panel recommended that the BNP results stratified by NYHA
classification should remain in the labeling, but recommended adding
that there is still significant potential for error in the
stratification. One member noted it would be interesting to know if this
stratification applies to diabetics or if diabetes makes a difference in
the stratification.

FINAL RECOMMENDATIONS AND VOTE

Executive Secretary Veronica Calvin read the voting instructions and
options.

A motion was made and seconded to recommend the PMA as nonapprovable. In
discussion, the motion was opposed by those who saw value to the test
not to detect class 1 or 2 heart failure but as an aid in differential
diagnosis of heart failure symptoms and in follow-up of heart failure.
In addition, they felt the labeling could be cautiously worded. The
panel discussed whether approval pending collection of further data was
feasible, citing concerns about performance of the test in older men and
women with CHF. The motion to recommend the PMA as nonapprovable was
passed by a vote of six to three.

*Sponsor Comments*

Representatives for the sponsors commented that despite its
shortcomings, the product has clinical utility as an aid in the
diagnosis of CHF and thanked the panel for its review.

*Panel Comments*

Panel comments focused on technical aspects that had not been
substantiated and the need for sponsors to address deficiencies in the
data by getting more data on the normal, healthy elderly population and
on the elderly with other illnesses such as mild hypertension and renal
insufficiency as compared to major heart failure. It was suggested that
the sponsors look for a limited indication with more focused data and a
careful screening of the control group.

Dr. Kroll thanked the panel, sponsor, representatives, and the FDA
review team and adjourned the meeting at 4:00 p.m.

.

> I certify that I attended the meeting of the Clinical Chemistry and
> Clinical Toxicology Devices Panel on March 24, 2000, and that these
> minutes accurately reflect what transpired.
>
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Veronica Calvin
>
> Executive Secretary

I approve the minutes of this meeting as recorded in this summary.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Martin H. Kroll, M.D.

Acting Chairperson