**SUMMARY MINUTES**

**OF THE**

**MICROBIOLOGY DEVICES**

**PANEL MEETING**

**OPEN SESSION**

**March 7, 2002**

**Gaithersburg Holiday Inn**

**Gaithersburg, MD**

**Attendees**

**Microbiology Devices Advisory Panel Meeting**

**March 7, 2002**

##### *Microbiology Devices Panel*

Michael L. Wilson, M.D., Chair

Denver Health Medical Center

Kathleen G. Beavis, M.D.

Cook County Hospital

Margo A. Smith, M.D.

Washington Hospital Center

Stanley M. Reynolds

Consumer Representative

Pennsylvania Department of Health

##### *Panel Consultants*

Irving Nachamkin, Dr. P.H.

Hospital of the University of Pennsylvania

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

San Francisco General Hospital

L. Barth Reller, M.D.

Duke University Medical Center

Lauri D. Thrupp, M.D.

University of California, Irvine

Carmelita U. Tuazon, M.D.

George Washington University Hospital

Ronald J. Zabransky, Ph.D.

##### *FDA Personnel*

Steven I. Gutman, M.D., M.B.A.

Director, Division of Clinical Laboratory Devices

Freddie Poole

Panel Executive Secretary

Roxanne Shively, MS

Sr. Review Scientist, Bacteriology Branch, Division of Clinical
Laboratory Devices

### OPEN SESSION 

### Panel Chair Michael L. Wilson, M.D., called the meeting of the Microbiology Devices Panel to order at 10:37 a.m. and asked the panel members to introduce themselves. Panel Executive Secretary Freddie Poole then read the conflict-of-interest statement. She noted that Kathleen G. Beavis, M.D., and Margo A. Smith, M.D., reported interests in firms at issue, but in matters not related to the topic in today's agenda. The agency determined that they may participate fully in all deliberations. 

### 

### Concerning old business, Ms. Poole stated that on November 28, 2001, Sepsis Inc.'s Endotoxin Activity diagnostic assay had been found not approvable in concurrence with the panel's recommendations in its October 11, 2001, meeting and that the Osmetech urinary tract infection analyzer had been found substantially equivalent but with restrictions for its use. Cellestis Limited's QuantiFERON-TB device had been approved subject to the recommendations made by the panel in its October 12, 2001, meeting.

### 

### Dr. Wilson then stated that the charge to the panel was to classify several pre-1976 amendment devices to identify *Bacillus anthracis* and *Yersinia pestis.* 

### FDA Presentation: *B. anthracis*

**Roxanne Shively, MS,** Sr. Review Scientist, Bacteriology Branch,
Division of Clinical Laboratory Devices, described the *B. anthracis*
preamendment products, which aid in the diagnosis of anthrax in humans.
She noted that the products are distributed primarily to public health
laboratories and other specialty laboratories that perform the tests on
human specimens. Ms. Shively emphasized that the panel could choose to
classify the three products separately. She described the three
products, which consist of a specific bacteriophage ("gamma phage"),
antibody conjugates, and antigens for antibody detection, and factors
affecting each. Factors affecting gamma phage results include the
behavior of variant phage strains, phage titer and stability, the media
used, and the length of incubation, the inoculum density, and
technologist experience.

Factors affecting fluorescent antibody conjugate results include the
fact that capsular and cell-surface antigens of *B. anthracis* are
shared by other species, the difficulty of preparing high-titer antisera
in animals, growth conditions affecting encapsulation, and inoculum
density.

Factors that affect the antigen reagent results obtained with the
antigens include purity and concentration of the antigen preparation,
prozone effects, subjective endpoints, nonspecific reactivity, abrogated
antibody response due to antibiotic treatment, inability to
differentiate recent and past infection, and prior vaccination.

In concluding, Ms. Shively provided some information on the historical
use of the antigen test and noted that diagnostic laboratory testing for
*B. anthracis* is limited to specialized and public health laboratories;
the reagents are prepared for and distributed among those laboratories.
She noted that although human disease is rare, *B. anthracis* is
classified as a Category A "critical biological agent" because it can be
easily disseminated and can cause high mortality.

Ms. Shively reviewed the classification process and described the types
of controls that could be placed on devices to minimize risk to public
health. She noted that a variety of regulations exists that apply to
tests on or with *B. anthracis,* such as organism-specific practice
guidelines from the Centers for Disease Control and Prevention (CDC);
local, State, and national reporting requirements; and the Select Agents
Rule, which limits quality-control materials for vaccine strains.

**Dr. Wilson** then invited the panel to question Ms. Shively.
**Carmelita U. Tuazon, M.D.,** asked whether Ms. Shively had any
information on problems with the use of the reagents. Dr. Wilson asked
**John W. Ezzell, Ph.D.,** Chief, Special Pathogens Branch, U.S. Army
Medical Research Institute of Infections Diseases **(**USAMRID), who was
in the audience, to respond. Dr. Ezzell answered that no false-positive
or -negative results had been seen with the gamma phage using isolates
but that low numbers of false positives had been reported with bacilli
not normally associated with those clinical materials. Other criteria,
however, can be used to differentiate results. **Stanley M. Reynolds**
asked whether the gamma phage test was meant to be a stand-alone test,
and Dr. Ezzell replied that it was not. Panel members asked for
clarification on the commercial availability of the tests, the source
for CDC's and USAMRID's strains, and the stability of the strains over
time, which Dr. Ezzell answered to their satisfaction.

**L. Barth Reller, M.D.,** raised the issue of whether laboratories
outside the public health system should have access to the gamma phage.
**Dr. Ezzell** noted that it could be useful for Level A (e.g.,
hospital) laboratories to have access to a quick-screen mechanism. Dr.
Reller asked whether, given some of the pitfalls associated with control
strains, it would be a good idea to put tests in the hands of
inexperienced laboratories. Dr. Ezzell noted that the gamma phage is not
used in any laboratory without proficiency testing and documentation and
thought that it could be used in Level A labs. **Lauri D. Thrupp,
M.D.,** concurred with Dr. Reller; he noted that when dealing with
inexperienced laboratories and a low-prevalence organism, a hazardous
situation could develop. Dr. Ezzell reiterated that the tests are
largely unavailable outside the public health system and are distributed
through CDC. **J. Edward Brown, Ph.D.,** Chief, Quality Systems
Integration, USAMRID**,** added that military laboratories obtain their
reagents from CDC. Panel members continued discussion on whether it
would be appropriate to use the tests in Level A laboratories. Dr. Ezell
noted that certain Level B laboratories can use PCR techniques to
ascertain the presence of *B. anthracis,* but gamma phage tests provide
a quick screen, giving results within 4 to 5 hours; also it is unclear
how widespread PCR techniques ultimately will become.

**Open Public Hearing**

**John Ticehurst, M.D.,** Assistant Professor of Pathology and Medicine,
the Johns Hopkins University School of Medicine**,** asked the panel
members to think about the implications of false or improperly
interpreted results and noted that in a biothreat situation, stand-alone
use would be important because laboratories would be under pressure to
provide rapid results. He noted the unique epidemiology of bioterrorism
events and stated that the number of "worried well" would be likely to
outnumber the number of actual patients. He asked the panel to be wary
of classifying the devices in Class I or III, to insist on manufacturing
consistency, and to restrict clinical use through gate keeping. Dr.
Ticehurst noted that public health labs were overburdened during the
anthrax incidents last fall and that many Level A labs have considerable
expertise.

**Dr. Wilson** then invited the panel to question the speaker. **Dr.
Reller** stated that the public health labs were overwhelmed because
they were undersupported. He suggested strengthening Level B labs and
enlarging their mission. He noted that in North Carolina, selected
laboratories are asked to provide personnel to assist State public
health laboratories and that the State relies on certain Level A labs
for consultation. The panel continued with a spirited discussion of the
role of public health laboratories and the impact of using Level A labs
in bioterrorism events.

### Open Committee Discussion

**Margo A. Smith, M.D.,** stated that she would like the gamma phage to
be available but that controls and clinical guidance would have to be
provided. **Valerie L. Ng, Ph.D., M.D.,** noted that her lab does not do
phage testing and stated that competency and proficiency are important
issues in making the phage available to Level A labs. **Dr. Ezzell**
emphasized that the phage test should not be in the hands of people who
have not been properly trained. **Ronald J. Zabransky, Ph.D.,** asked
for clarification on the controls that could be placed on devices of
different classifications, which **Steven I. Gutman, M.D., M.B.A.,**
Director, Division of Clinical Laboratory Devices, provided. **Drs.
Zabransky** and **Thrupp** suggested that fluorescent antibody testing
might be appropriate for Level A labs because many such labs are used to
conduct those tests, but **Dr. Ezzell** responded that fluorescent
antibody testing for *B. anthracis* has many problems---for example, the
capsule can cause background problems because it is always being
sloughed off, and it is difficult to culture the organism. Panel members
discussed the benefits of having a quick test versus the potential
problems of test performance. **Drs. Ng and Thrupp** pointed out that if
a patient has clinical manifestations of anthrax, treatment should not
be delayed pending laboratory confirmation.

**Panel Questions**

**Dr. Wilson** then directed the Panel to the FDA's Questions. He noted
that these questions are similar to those on the Classification
Questionnaire form.

**Question \# 1:** Are you aware of any other known risks to health
presented by the uses of the types of devices identified by the FDA as
preamendments reagents for the identification of *Bacillus anthracis*?
Dr. Wilson summarized the panel's response in terms of safety around the
issue of how the test was used and the clinical interpretations of the
test.

**Question \# 2:** Are you aware of any additional information which
could affect the safety and effectiveness of the device? Dr. Wilson
again summarized the panel's response as how to use the test results.

**Question #3:** What levels of controls are sufficient to provide
reasonable assurance of the safety and effectiveness of these type
devices? The panel agreed that General and Special Controls would be
sufficient.

**Question #4:** Do you believe that restrictions on sale, distribution
or use are necessary to provide reasonable assurance of safety and
effectiveness?

**Final Recommendations and Vote**

**Marjorie G. Shulman**, Consumer Safety Officer, Center for Devices and
Radiological Health, explained the classification questionnaire to the
panel. Dr. Wilson asked the panel if they preferred to vote on each type
device separately or bundle them. The panel voted 4-3 to consider the
devices together. It voted unanimously to classify the devices in Class
II and to recommend testing guidelines (Questions 1-3b).

Some panel members suggested that special controls could include
reporting requirements. **Dr. Beavis** stated that regulations governing
reporting should be left to the States. **Dr. Thrupp** expressed concern
that if new strains and other problems were not reported, harm could
result.

The panel voted 6-0 (with one abstention) to recommend that FDA partner
with CDC, USAMRID, and other appropriate agencies involved in laboratory
performance issues to develop practical ways to establish performance
standards (Question 3b).

The panel also voted 7-0 for the FDA to place a high priority on
establishing performance standards for the devices (Questions 4a and
4b). It voted 6-0 (with one abstention) that the devices should be
restricted to use only by persons with specific training or experience
in their use and only in certain facilities (i.e., that the devices
should be limited in distribution and that accountability and oversight
should be in the domain of public health laboratories) and that public
health laboratories should be encouraged, in the context of the
Laboratory Response Network, to develop appropriate training and
reporting procedures for the devices (Questions 7a and 7b).

The panel then completed the Supplemental Data Sheet. The panel voted
unanimously to accept the devices' current indications for use, with
further amendments by FDA staff to develop an indication for the antigen
and fluorescent antibody assays and to clarify the wording of the
indication for the gamma phage reagent (Question 4). In response to
question 5, the panel voted 6-1 to specify "as discussed" and to require
that appropriate biosafety handling of the diagnostic specimens be
followed. **Dr. Beavis** pointed out that *B. anthracis* is a Biosafety
Level 2 organism and that it is incumbent upon laboratories to follow
safe-handling procedures; the requirement was, in her opinion,
unnecessary. In response to question 6, the panel voted unanimously to
classify the devices as high priority. For questions 7, 8, and 9, the
panel specified "as discussed," and in response to question 10, the
panel voted unanimously not to exempt the devices from any of the
requirement listed. They responded to question 11 by specifying "as
discussed." In its final vote, the panel voted unanimously to accept
both forms.

### FDA Presentation: *Y. pestis*

Ms. Shively described the *Y. pestis* preamendment products---a specific
bacteriophage, antibody conjugates, and antigens for antibody
detection---all of which aid in the diagnosis of pneumonic plague in
humans. Ms. Shively provided background data on pneumonic plague; she
noted that it is difficult to distinguish *Y. pestis* from *Y.
pseudotuberculosis* in the laboratory.

Ms. Shively described each product and listed the factors affecting the
results obtained with each product. Factors affecting bacteriophage
results are the behavior of variant phage strains, the media used, the
length and temperature of incubation, phage titer and stability,
inoculum density, and the experience of the technologist.

Factors affecting fluorescent antibody test results are F-1 antigen
expression by other species; variation in *Y. pestis* expression of F-1
antigen, which can be reduced as a result of storage and growth
conditions; inoculum density; and the method of fixation.

Antigen preparation purity, concentration of F-1 antigen, the time at
which the serum sample was obtained (i.e., if it was obtained too
early), rare infections with nonencapsulated *Y. pestis,* and prozone
effects can all affect antigen test results. In addition, the test
cannot differentiate between recent and past infection, the endpoints
are subjective, and heterophiles demonstrate nonspecific reactivity.

In concluding, Shively provided some information on the historical use
of the three devices. She noted that although human disease is uncommon,
*Y. pestis* is classified as a Category A critical biological agent: It
can be easily disseminated and causes high mortality. Public health
efforts continue to be important for preventing natural sources of
infection.

**Open Public Hearing**

Rosemary Humes, representing the Association of Public Health
Laboratories, emphasized that during the anthrax incidents last fall,
much of what the public health labs had to deal with was environmental
testing. In any bioterrorism event, people will be hysterical and will
want environmental testing; the panel should consider this likelihood
when discussing labeling and indications for use.

**Dr. Wilson** then invited the panel to ask questions of the speaker.
**Dr. Reller** asked

Ms. Humes several questions concerning the nature of the environmental
testing that public health labs might be expected to conduct and how the
labs dealt with demands from the public during the anthrax incident last
fall. He stated that decisions regarding the role of public health labs
should not be made in the political arena. **Ms. Humes** responded that
in most cases, efforts were made to educate the public and turn them
away from testing. Private environmental labs that did testing for the
public could not rule out anthrax in some cases and thus had to send the
samples to public health laboratories anyway.

**Dr. Reller** noted that *Y. pestis* is a fragile organism unlikely to
generate the same issues of environmental testing as *B. anthracis.* FDA
has an important role in educating everyone about actual risks. It is
important to have competent laboratories, including public health
laboratories that are adequately funded to do the job right, and to
educate everyone, including politicians, on what really protects the
public's health and enables swift diagnosis for individual patients as
well as swift public health responses to real events. **Dr. Thrupp**
noted that Dr. Reller's comment suggested the same restrictions that the
panel recommended for *B. anthracis,* which should serve to minimize the
testing in private laboratories outside of the public health arena.

**Dr. Thrupp** asked who the suppliers of the reagents are, and **Dr.
Ezzell** answered that the reagents are available from the Ft. Collins
CDC laboratory or USAMRIID.

**Irving Nachamkin, Dr. P.H.,** Hospital of the University of
Pennsylvania**,** asked whether any performance data were available for
the antibody and phage devices. **Dr. Ezzell** provided details on some
of the factors that affect performance.

**Open Committee Discussion**

The panel felt that it had covered the main issues during the open
public hearing.

**Questions to the Panel**:

Dr. Wilson then determined that the FDA questions would be answered when
completing the Classification Questionnaire form, so the panel voted to
answer them at that time.

### Final Recommendation and Vote

The panel voted unanimously to consider the devices as a group. Dr.
Wilson then led the panel through the classification questionnaire.

The panel voted unanimously to classify the devices in Class II and to
require special controls like those for the *B. anthracis* devices:
testing guidelines should be derived from available publications and
experience and should be developed for specimens, procedures,
interpretation, and public health reporting (Questions 1-3b). The panel
discussed issues involved in the enforcement of GMPs, in light of the
limited distribution of the devices and FDA's enforcement capabilities,
and voted unanimously to endorse the importance of FDA enforcement of
GMPs for the devices.

Moving to Questions 7a and 7b, the panel voted unanimously that the
devices should be used only by persons with specific training or
experience in their use and only in certain facilities (i.e., that the
devices should be limited in distribution and that accountability and
oversight should be in the domain of public health laboratories). In
addition, the panel voted 5-0, with one abstention, that public health
laboratories should be encouraged to develop appropriate training and
reporting procedures for laboratories using the devices.

The panel then completed the Supplemental Data Sheet. Panel members
raised the issue of environmental testing devices and their relation to
the FDA review process. The panel voted 6-0 to approve the current
indications for use (Question 4); to note "as discussed" in response to
question 5; to classify the devices as Class II with a high priority
(Question 6); to specify "as discussed" in response to questions 7 and
8; to note "as discussed in question 7b of the Product Classification
Questionnaire" in response to question 9; and to allow none of the
exemptions listed in question 10. In its final vote, the panel voted
unanimously to accept both forms.

### 

### Adjournment

### Dr. Wilson thanked the participants and adjourned the meeting at 4:19 p.m. 

> I certify that I attended the meeting of the Microbiology Devices
> Panel on March 7, 2002, and that this summary accurately reflects what
> transpired.
>
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Freddie Mae M. Poole
>
> Panel Executive Secretary

I approve the minutes of this meeting

as recorded in this summary.

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

Michael L. Wilson, M.D.

Panel Chair

Summary minutes prepared by

Caroline Polk

Polk Editorial Services

1112 Lamont Street, NW

Washington, DC 20010

\(202\) 265-8271

Edited by

Freddie M. Poole

Executive Secretary