**SUMMARY MINUTES**

**OF THE**

### MICROBIOLOGY DEVICES PANEL MEETING

### OPEN SESSION

**July 27-28, 2000**

**Gaithersburg Holiday Inn**

**Whetstone Room**

**Gaithersburg, MD**

**July 27, 2000**

# Microbiology Devices Panel

Michael L. Wilson, M.D., Panel Chair

Denver Health Medical Center

Margaret R. Hammerschlag, M.D.

State University of NY Health Science Center

Valerie L. Ng, Ph.D., M.D.

San Francisco General Hospital

Carmelita U. Tuazon, M.D.

George Washington University Hospital

Melvin P. Weinstein, M.D.

Robert Wood Johnson Medical School

# 

David T. Durack, M.D., Ph.D., Industry Representative

Becton Dickinson Microbiology Systems

# 

Stanley M. Reynolds, Consumer Representative

Pennsylvania Department of Health

**Microbiology Devices Panel Consultants**

Ellen Jo Baron, Ph.D.

Stanford Health Services

Douglas M. Hawkins, Ph.D.

University of Minnesota

Frederick S. Nolte, Ph.D.

Emory University School of Medicine

L. Barth Reller, M.D.

Duke University Medical Center

Margot A. Smith, M.D.

Washington Hospital Center

Steven C. Specter, Ph.D.

University of South Florida College of Medicine

John A. Stewart, M.D.

National Center for Infectious Diseases, CDC

**Panel Discussants**

Col. Erik A. Henchal, Ph.D.

U.S. Army Medical Research Institute of Infectious Diseases

Richard F. Meyer, Ph.D.

National Center for Infectious Diseases

# Guest Speaker

Joseph L. Curtis, Ph.D.

SVERDUP Technology, Quantico, VA

**FDA Personnel**

Freddie Poole

Panel Executive Secretary

Steven I. Gutman, M.D.

Director, Division of Clinical and Laboratory Devices (DCLD)

# OPEN SESSION---JULY 27, 2000

Panel Chair **Michael L. Wilson** called the meeting of the Microbiology
Devices Panel to order at 10:05 a.m. and asked the panel members to
introduce themselves. The Executive Secretary **Freddie Poole** read the
conflict of interest statement, noting that limited waivers had been
granted to all the panel members and consultants for today's issues
meeting. She also noted that the employers of **Col.** **Erik Henchal,
Ph.D.** and **Richard Meyer, Ph.D**., the panel discussants, have
interests in the topic to be discussed.

**Dr. Wilson** then stated that the panel's task was to discuss the
appropriate types of important, relevant, and reasonable data and
information required to assess safety and effectiveness of diagnostic
tests intended to identify the presence of biothreat agents, when used
on different specimen types, and under different conditions, for
evidence of exposure to biothreat agents.

**Opening Statement**

**Elizabeth D. Jacobson, Ph.D.,** Senior Advisor for Science in the
Office of the Commissioner, Food and Drug Administration, stressed that
the focus of the day's session was on science and on the types of
general scientific evidence needed for characterizing safety and
efficacy of assays used to identify organisms used in bioterrorist
attacks. These assays include diagnostic reagents and kits that could be
used in laboratories on different specimen types to provide evidence of
exposure to biological agents. She acknowledged the participation of
experts from the Centers for Disease Control (CDC) and the U.S.
military, thanking **Col. Erik Henchal, Ph.D.,** from the U.S. Army
Medical Research Institute of Infectious Diseases (USAMRIID) and
**Richard Meyer, Ph.D.** of the CDC, and guest speaker **Joseph L.
Curtis, Ph.D.** of the SVERDUP Technology, Inc. for their help. She
concluded by stressing the need for cooperation on this topic among the
military, the scientific community, the regulatory agencies, and law
enforcement groups.

# Overview of Issues

**Steven I. Gutman, M.D., M.B.A.,** Director of the Division of Clinical
Laboratory Devices emphasized that the objective of today's meeting was
to have a scientific review of the general types of evidence needed to
support premarket safety and effectiveness decisions for reagents and
test kits used to identify biothreat agents. Dr. Gutman said that the
focus of the day's session was on *in vitro* products used to test
cultures from human specimens, and emphasized the critical role of
laboratories in bioterrorism preparedness.

Dr. Gutman explained the various types of intended uses for these
assays, such as direct detection from human samples, detection in human
specimens prior to culture, identification of isolates recovered from
cultured specimens, and serologic identification of human host response
as an indication of infection or exposure. He also presented some
challenges in detecting these agents, the safety requirements involved
in handling biothreat agents, the limitations that exist with using
banked specimens, and the difficulties in culturing certain agents. Dr.
Gutman concluded by presenting three questions for panel consideration.

**Colonel Erik Henchal, Ph.D.** of USAMRIID provided information on the
Department of Defense (DOD) research program on medical diagnostics. He
presented an overview of the chemical/biological defense doctrine and
listed more than 50 possible infectious and biological diseases. Col.
Henchal provided information on an analysis of clinical specimens in
three different patient scenarios: early, acute, and late exposure, and
described the use of an integrated process for identification of agents
in clinical specimens.

Col. Henchal explained the laboratory response network for bioterrorism,
with different levels of capability for detection, which was developed
to fulfill a requirement for a comprehensive system for global response.
He described the 520^th^ Theater Army Medical Laboratory and its
responsibilities, particularly in regards to special pathogens sample
testing, and development of tools for rapid specimen preparation and
portable gene amplification detection. He stated that avoiding
technological surprise by broadening reagents to detect infection early
through use of biomarkers is critical. He suggested that evaluation
studies should include analytical specificity, sensitivity, detection
limits, precision, and reproducibility---all of which must be evaluated
for each specific agent. Evaluation trials have been conducted in the
lab, on animals, in the field, and in hospitals, using a standardized
nucleic acid panel. He concluded with a description of proposed model
systems for biothreat and infection which use a bacterial reference
collection and a specimen hierarchy.

**Richard Meyer, Ph.D.** of the Bioterrorism Rapid Response and Advanced
Technology Laboratory, NCID, CDC, described the joint CDC/DOE effort to
develop and validate tailored assays for the user community. The
objective of this effort, he stated, is to develop and provide assays to
public health organizations for detection and identification of possible
biothreat agents. The two main assay formats are molecular, which
identifies unique target specific sequence signatures, and antigen
detection, which identifies highly specific antibodies to each agent.
Dr. Meyer defined the terms used in assay development process, as well
as the steps in that process. Assay in-house evaluation is based on
specificity, sensitivity, and the clinical matrix used. Assay validation
is based on a multi-center, collaborative study, involving five to ten
public health labs, military labs, and other participants using a
specific preparation. Performance analysis, such as accuracy and
reproducibility, determines if assays are ready for dissemination
through the CDC National Public Health Network of tiered laboratories.

# OPEN PUBLIC HEARING

There were no requests to address the panel.

Guest speaker **Joseph Curtis, Ph.D. of** SVERDUP Technology, Inc.
presented the Advanced Concept Technology Demonstration involving a
Chem--Bio Individual Sampler that detects exposure of the individual war
fighter and measures sub-clinical exposure to chemical-biological
agents. The analyzer unit uses light to detect upconverting phosphor
reporter (UCR)-technology-labeled antibodies in a lateral flow
immunoassay. This system detects and measures individual exposure at
sub-clinical levels from environmental samples.

# OPEN COMMITTEE DISCUSSION

Dr. Wilson opened the Committee discussion by asking if there were any
other questions of the speakers or issues that could be addressed. There
being none, Dr. Wilson suggested that the panel address FDA's questions:

**Question \# 1:** What types of data and information would be
considered appropriate to evaluate safety and effectiveness when these
assays are used to: a) identify culture isolates from human specimens,
b) to detect the agents directly, and c) to determine exposure in
clinical labs or at point of care?

The panel recommended that sensitivity of the assays should be close to
100% when used for 'rule-out' type assays in level A laboratories in the
civilian sector because an effective response to unannounced events
would be dependent on accurate laboratory information. The panel also
acknowledged the importance of specificity for mass exposure and the
announced event.

**Question \# 2:** To determine or infer effectiveness for these
devices, can specimens from naturally or experimentally infected animals
be used when appropriate specimens from humans cannot be obtained?

The panel suggested that spiked samples were valuable for analytical
studies, but would have limited use for predicting performance with
clinical specimens. They suggested that while no animal model appears
appropriate as a surrogate for humans, animal models could be useful for
estimating exposure variables and providing a source of infected
specimens (vs. spiked specimens) to study matrix effects. They cautioned
that animal testing should not be expected to duplicate performance with
human specimens. They recommended that animal testing should be limited
to those types of studies that could get relevant performance
information, that preliminary animal testing be done with the lowest
level animal possible, and that specimens from infected animals could
also be used for comparing different tests.

**Question \# 3:** Are there issues not addressed in above questions,
that would impact on reliability of using these assays for evidence of
human exposure or infection?

The panel responded that specimen handling and storage conditions were
very critical to detection of agents. They recommended that specimen
handling and storage conditions should be evaluated. Studies to assess
specificity of the assay should include testing of a substantial number
of specimens from normal individuals and also a broad range of potential
conflicting agents. Validation is critical for each instrument and each
reagent. Additionally, the rationale for why testing was conducted on
certain agents should be provided.

The panel noted that there is such a wide array of biothreat agents and
samples that no one size test or specification fits all needs. Because
such tests are to be used infrequently, there should be studies done to
evaluate proficiency testing, stability data on controls, inter-user
variability, and shelf life limitation. Risks to users should be noted.
CLIA regulations and requirements on performance in the hands of
untrained users should be stressed.

**OPEN PUBLIC HEARING\
Jack Sewiki** of Geomet Technologies suggested that the FDA spur
development of commercial kits by providing specific guidance for
industry to follow. Mr. Sewiki also asked the panel and FDA to consider
how environmental testing could be validated to help First Responders,
many of whom are now purchasing unregulated kits. He suggested that the
FDA address regulation of such kits, which may or may not have been
validated using a standardized format. He noted that many government
agencies provide grants for preparedness, which are used to purchase
such devices, the end result of which is more widespread use of
unvalidated detectors.

# 

# Final Panel Recommendations

The panel recommended that the standards for tests used to identify
biothreat agents become progressively more challenging. The panel
suggested that appropriate cross-reactivity studies are important, and
interference and inter-observer variability should be determined
adequately. Both sensitivity and specificity are very important. It is
key to specify the rationale for use of spiked specimens, choice of
appropriate matrix, and method of specimen collection. Because animal
studies can be a problem with some isolates, animal studies should not
be a requirement for investigational studies. Commonly, while no animal
model appears appropriate as a surrogate for humans, animal studies can
provide some useful information on particular agents. It was recommended
that preliminary animal testing be done with the lowest level animal
possible.

**Dr. Gutman** thanked the panel and presenters and invited them to
submit any further comments. **Dr. Wilson** also thanked the panel
discussants, the guest speaker, and the panel members and consultants
for their participation, and then adjourned the session for the day at
3:30 p.m.

# July 28, 2000

# 

# Microbiology Devices Panel

Michael L. Wilson, M.D., Panel Chair

Denver Health Medical Center

Margaret R. Hammerschlag, M.D.

State University of NY Health Science Center

Carmelita U. Tuazon, M.D.

George Washington University Hospital

Melvin P. Weinstein, M.D.

Robert Wood Johnson Medical School

# 

David T. Durack, M.D., Ph.D., Industry Representative

Becton Dickinson Microbiology Systems

# 

Stanley M. Reynolds, Consumer Representative

Pennsylvania Department of Health

F. Blaine Hollinger, M.D., CBER BPAC

Baylor University, College of Medicine

Steven C. Specter, Ph.D., Temporary Voting Member

University of South Florida College of Medicine

**Microbiology Devices Panel Consultants**

Ellen Jo Baron, Ph.D.

Stanford Health Services

Margot A. Smith, M.D.

Washington Hospital Center

John A. Stewart, M.D.

National Center for Infectious Diseases, CDC

###### FDA Personnel

Freddie Poole

Panel Executive Secretary

Steven I. Gutman, M.D.

Director, Division of Clinical and Laboratory Devices (DCLD)

John R. Ticehurst, M.D.

Medical Officer, Microbiology Branch

# OPEN SESSION---JULY 28, 2000

Panel Chair **Michael Wilson, M.D.** called the meeting to order at 9:05
a.m. and asked the panel members and consultants to introduce
themselves. The Panel Executive Secretary **Freddie Poole** announced
that Dr. Wilson's appointment as Panel Chair was confirmed. She then
read the conflict of interest statement, noting that a limited waiver
had been granted allowing Dr. Baron to participate, but not vote, and
that matters concerning Drs. Hammerschlag and Hollinger had been
considered and their full participation was allowed.

# New Business:

**Jean Toth-Allen, Ph.D.,** from the Office of Compliance, Division of
Bioresearch Monitoring, presented information on IVD device development,
component, and feasibility testing on human tissue samples, and the
regulations concerning institutional review boards (IRBs). She stated
that an IRB must review all studies supporting submissions using human
subjects and /or specimens, and the review cannot be waived by anyone
other than the FDA. It may be exempted if the risk to subjects is
minimal.

For repository collections, research samples, and identification of
subjects, she explained that the FDA is adopting the same terminology as
the National Bioethics Advisory Commission (NBAC). The NBAC August 1999
Report on research involving human biological materials cited the
concern for the safety and welfare of study subjects. Informed consent
is now recommended for IRB-approved prospective studies and "repository"
sample collections, and documentation for banked samples because of
issues such as consent information and privacy laws and other legal
considerations. Dr. Toth-Allen noted that there were state and local
government differences on legal questions involving privacy and health
insurance. She concluded by providing web sites for IVD guidance on
clinical trials and information on human subject protection.

Panel members asked Dr. Toth-Allen about the effect of the IRB
requirement in "gutting" research efforts and about the need for
informed consent even for repository or banked sample specimens. She
replied that there are more legal issues involved in protection of
privacy and that this was an educational effort to raise panel awareness
of this issue. A question was raised on use of banked specimens, to
which Dr. Toth-Allen urged consultation with whichever division/branch
responsible for the device in question. In answer to a panel question on
whether she was suggesting general IRB consent for all microbiology
studies, she replied that this was the advice currently provided by
NBAC.

**Clara A. Sliva,** Acting CLIA Coordinator in the Division of Clinical
Laboratory Device**,** presented new information on the Clinical
Laboratory Improvement Amendments of 1988 (CLIA), and reported on CLIA
categorization at the FDA. She stated that since January 2000 the FDA
was responsible for the categorization of commercially marketed test
systems, and the CDC was responsible for the categorization of
laboratory procedures.

Ms. Sliva outlined the history of regulatory provisions for waiving CLIA
provisions. She noted that a CLIA waiver workshop was planned for August
14-15, 2000, for interested parties such as consumers, the medical
community, and industry, and that this workshop will revisit the
criteria for CLIA waivers. Ms. Sliva concluded that it is unclear
whether the waived test list will be expanded or limited in the future.

There being no further questions of the FDA presenters, Dr. Wilson
closed the Business section and began the Open Discussions of the PMA.

**PRESENTATION OF THE PREMARKET APPROVAL APPLICATIONS**

**Dr. Wilson** reminded the panel that their today was to consider two
premarket approval applications (PMAs) from Roche Molecular Systems
(RMS). The devices are nucleic acid amplification in vitro diagnostic
qualitative devices to detect hepatitis C virus (HCV) ribonucleic acid
(RNA). They are the AMPLICOR HCV test v. 2.0 and the semi-automated
version COBAS AMPLICOR HCV Test v. 2.0, neither of which is intended for
blood donor screening.

##### Sponsor Presentation

**Mr. David B. Thomas,** Vice President for Clinical and Regulatory
Affairs for RMS, presented a brief summary of the devices. He stated
that because 1) this product was the first to seek approval as a direct
test for HCV RNA; 2) of the limitations of the available quantification
methodologies to characterize HCV; and 3) there is no independent gold
standard for assessing clinical HCV infection, he would focus his
discussion on the specifics of the devices and the product labeling.

**Karen Gutekuunst,** Ph.D., Director of Product Development for RMS,
provided an overview of the nonclinical performance data**.** She
presented a description of the technology of the assays, a brief
background of HCV and the structure of the HCV virion RNA, and described
how the new assay differed from the Roche version 1.0 assay. She also
explained the kit format and test procedure. Dr. Gutekuunst provided an
overview of the nonclinical studies performed and explained how
preliminary cutoff determinations were conducted. She discussed the WHO
International Standard for HCV RNA assays 96/790, and the National
Institute of Biological Standards and Controls (NIBSC) working reagent.
She presented results of the anti-HCV seroconversion panels. Dr.
Gutekuunst stated that the specificity studies showed no
cross-reactivity to other microorganisms or viruses and no interference
by endogenous and exogenous substances and co-infections. She explained
the design of the reproducibility study and concluded by stating that
the assay performance on serum and plasma demonstrated comparable
detection of HCV in serum, ACD plasma, and EDTA plasma. Studies
conducted to evaluate genotype detection provided evidence of detection,
and produced comparable detection of known genotypes of HCV.

**Michael Fried, M.D.,** Consultant to RMS and Principal Investigator
for the Clinical trials, presented information on the use of PCR assays
for detection of HCV viremia. He summarized the principles of patient
evaluation, the risk factors for hepatitis C, and he compared the
available screening methods for HCV. Dr. Fried concluded that diagnosis
of chronic hepatitis C involves multiple modalities, including history,
exam, lab tests, and liver biopsy. Supplemental assays, such as RIBA,
are most useful in the low-risk patient population. HCV RNA testing is
required to determine the presence of active viremia and is the
second-line test of choice for patients with suspected chronic hepatitis
C infection. Genotypic differences are unlikely to affect diagnosis of
hepatitis C, given the high levels of HCV RNA in untreated patient
populations.

**Alison Murray, M.D.** Director of Clinical Affairs at RMS, discussed
the clinical performance of the devices. She stated the objectives of
the clinical study and described the four study sites. She described the
reference methods used to evaluate the performance of the two devices;
i.e., anti-HCV enzyme immune assay (EIA 3.0), anti-HCV recombinant
immune blot (RIBA 2.0), alanine transaminase, and liver biopsy histology
reports, if available. She described the patient groups evaluated and
the demography of those subjects. She stated that the analysis of the
performance of the devices, when compared to anti-HCV serology and to
ALT and liver histology, demonstrated that the assays performed
consistently across matrices, patient groups, and sites. The majority of
the assay results were supported by serologic testing. When serologic
testing was not available, the results were supported by the ALT level,
the histology data, the clinical history, and/or alternate PCR assays.
There was a very high percentage of agreement with serology, ALT levels,
and liver histology for those patients with histology data.

Dr. Murray concluded that these data support the clinical utility of the
devices for testing patients with liver disease and antibodies to HCV.
Both tests performed consistently and were specific and sensitive at the
50 IU/mL limit and demonstrated comparable detection of all genotypes
listed in the consensus classification of HCV. The assays produced
comparable detection of HCV in serum, ACD plasma, and EDTA plasma in
nonclinical and clinical studies. The Cobas Amplicor and the Amplicor
HCV results were supported by serologic data and clinical evidence of
infection.

**Dr. Wilson** then invited the panel to ask questions of the sponsor.

The Panel questioned the rationale for specimen selection for
sensitivity and cross-reactivity studies, the lack of Flaviviruses and
inhibitory samples in the selected specimens, interfering endogenous
samples, amplicon contamination in specificity studies, and
reproducibility study results.

# OPEN PUBLIC HEARING

There were no responses from the public to address the panel.

# FDA Presentation

**John R. Ticehurst, M.D.,** Medical Officer for the Microbiology
Branch, provided a brief background to HCV RNA assays and the challenges
involved in appropriately reviewing an HCV RNA assay. He discussed the
PMA claims for equivalent detection of HCV genotypes and stated that the
FDA would ask the panel to consider the appropriate threshold for
determining performance for detecting HCV genotypes, as well as
appropriate use of the WHO genotype 1 standard and its international
unit quantifier.

Dr. Ticehurst explained that the submission was granted expedited review
status because of the public health significance, and that it underwent
collaborative review among various FDA divisions and branches, as well
as between FDA and the manufacturer. Dr. Ticehurst then discussed the
relevance of genotypes and subtypes and presented FDA's analysis of the
RMS studies. He described the clinical studies for a diagnostic
indication and the lack of data that could demonstrate anti-HCV
seroconversion. He stated that no data was submitted for monitoring of
chronic infection. He discussed the Indications for Use and the warning
statements presented by the sponsor in the package inserts and closed by
presenting the FDA questions to the panel.

**Dr. Wilson** then invited the panel to ask questions of the sponsor or
the FDA. The questions were all directed to the sponsor concerning the
false positive results in the specificity study, the reactivity of a
patient with primary biliary cirrhosis, and HCV genotypes.

# 

# OPEN COMMITTEE DISCUSSION

**Dr. Wilson** invited the panel to begin the committee discussion by
first addressing the FDA's questions.

**Question \# 1:** Is the proposed indications for use appropriate? "The
Amplicor HCV test is indicated for patients who have liver disease and
antibodies to HCV that were detected by enzyme immunoassay and
immunoblot assay, and who are suspected to have active HCV infection.
Detection of HCV RNA is evidence of active HCV infection but does not
distinguish between acute and chronic infection."

The panel suggested revising the proposed indication for use to remove
the phrase "that were detected by enzyme immunoassay and by immunoblot
assay." The Warning statements should be revised as follows: Bullet #1
should read "Performance has not been demonstrated for diagnosis of
individuals who were not tested for antibodies to HCV." Bullet \# 2
should be revised to include that "Performance has not been demonstrated
for monitoring of progress of disease." Bullet \# 3 should be revised by
deleting the last clause of the statement to read "Although a wide range
of HCV genotypes can be detected, analytical sensitivity and other
performance characteristics have not been determined for all HCV
genotypes."

**Question \# 2**: Based on data submitted to support the proposed
indications for use, are the data from patients who were treated with
antiviral agents or who had received a liver transplant, appropriate for
evaluating the diagnostic indications for use? Were the data
appropriately analyzed? Are data sufficient for determining specificity
in appropriate populations? Should additional instructions be provided
for interpreting an 'HCV RNA not detected' result? Do the data support
the proposed indication?

The panel suggested that the data on the 31 patients treated with
antiviral agents or who had received a liver transplant could be
included in the package insert for information only and no claims should
be made for testing these type of patients. The panel had no comment on
whether clinical data were appropriately analyzed. The panel members
thought the data were not sufficient for determining specificity in
appropriate populations but provided useful information. As to whether
additional instructions should be provided to laboratories and primary
care clinicians for interpreting a result of "HCV RNA not detected," the
panel suggested use of an algorithm. A statement should be added about
not diluting the test specimen for further testing if results were
unclear; a new specimen should be used. The data on interference from
heparin were clear and should be included in information provided by
sponsors. Data on dialysis patients were limited.

**Question \# 3**: Based on data submitted for detecting HCV genotypes
and subtypes; and to verify performance to the WHO Standard for genotype
1 RNA, are the proposed warnings and limitations appropriate, and should
additional genotype studies or other approaches be done?

The panel suggested that if there were specific claims made for specific
genotype detection then the studies should confirm this. The panel did
not suggest any other confirmatory methods other than PCR.

**Question \# 4:** Concerning standard reference materials, how should
quantitative data such as limits of detection be expressed with
reference to the WHO Genotype 1 Standard?

The panel recommended that the device package inserts should state that
the limits of detection of the test could be described as genome
equivalents in terms of IU, which correlates to the WHO Genotype 1
standard. The panel commented that most HIV PCR assays and other HCV
assays saw differences between plasma and serum, but Amplicor exhibited
no differences. The sponsor noted that there were no reproducible
differences between various matrices probably because this was a
qualitative assay and they deliberately over-sampled in order to have
adequate sample.

There were additional discussions on the package insert, the position of
the controls in the run, a clear explanation of the manual separation
technique, and training and certification for the technologists. The
panel noted that the package insert should clearly state that if the
internal control is invalid, the entire run is invalidated.

# OPEN PUBLIC HEARING

There were no requests to address the panel.

# FDA Closing Comments

The FDA made no additional remarks.

# 

# Sponsor Closing Comments

The sponsor thanked the panel for their useful and interesting comments.

# 

# FINAL RECOMMENDATIONS AND VOTE

**Freddie Poole** read the voting options and instructions, and
identified the voting and temporary voting members.

The Panel voted separately on each PMA. It was moved and seconded that
the Amplicor HCV (version 2) NAT test PMA be approvable with conditions
as follows:

1)  A phrase should be deleted from the indication for use so that it
    reads as follows: "The AMPLICOR HCV Test is indicated for patients
    who have liver disease and antibodies to HCV and who are suspected
    to have active HCV infection. Detection of HCV RNA is evidence of
    active HCV infection but does not distinguish between acute and
    chronic states of infection." (This motion carried unanimously.)

2)  The third bulleted warning should be amended as follows: "A negative
    AMPLICOR HCV test result does not exclude active HCV infection.
    Although a wide range of HCV genotypes can be detected, analytical
    sensitivity and other performance characteristics have not been
    determined for all HCV genotypes." The panel recommended that a
    statement, to be worked out by the company and the FDA, be included
    that lists any genotype or subtype numbers. (This motion carried
    unanimously.)

3)  A warning should be added about the use of heparin interfering with
    the test. (This motion carried unanimously.)

4)  An HCV RNA test with an indeterminate result should not be diluted
    to retest the same assay specimen, but rather a new specimen should
    be collected. (This motion passed unanimously.)

5)  The second warning bullet should be revised to state: "Performance
    has not been demonstrated for monitoring of disease progression in
    HCV-infected patients or of response to treatment." (This motion
    passed unanimously.)

6)  Whenever quantitative data is noted in the package insert, it should
    be noted that the standard was based on the WHO 1 Standard IU/mL of
    the international standard for HCV genotype 1." (This motion passed
    unanimously.)

> (A motion to state that HCV RNA had not been detected in hemodialysis
> patients was withdrawn, as was a motion to add to the second bullet
> that further serologic testing may be indicated to elaborate the
> result of "HCV RNA not detected.")
>
> The Panel also recommended that the AMPLICOR placement of controls in
> the microwell plate be addressed in the labeling and that the sponsor
> submit reproducibility data to the FDA.
>
> The motion to recommend the PMA as approvable subject to the above
> conditions was unanimously passed. The panel members stated that they
> voted for Approvable with Conditions because they thought the device
> was a safe and effective test for measuring HCV RNA, but the
> application required some revisions to the labeling and the FDA's
> satisfactory analysis of the reproducibility data.
>
> The Panel agreed that the AMPLICOR COBAS HCV NAT Test was essentially
> the same as the AMPLICOR HCV test and that the same conditions apply.
> It was moved, seconded, and unanimously agreed to recommend the
> AMPLICOR COBAS as Approvable with conditions, the conditions being
> identical to those above.
>
> **Dr. Wilson** thanked the panel members and consultants, and the FDA
> for their participation. He commended the sponsor for a very well
> presented application. The meeting was adjourned at 4:00 p.m.

I certify that I attended

the Meeting of the Microbiology Devices Panel on July 27-28, 2000, and
that this summary accurately reflects what transpired.

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

Freddie Mae Moody Poole

Executive Secretary,

> Microbiology Devices Panel

I approve the minutes of this meeting

as recorded in this summary.

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

Michael L. Wilson, M.D.

Panel Chair

Summary minutes prepared by

Aileen M. Moodie

9821 Hollow Glen Pl.

Silver Spring, MD 20910

301-587-9722

Edited and Revised by

FM Poole 8/24-9/26/00

Reviewed: DRDubois 9/27/00

Final: FM Poole: 10/16/00

Review: Dr. Wilson 10/17/00