March 7, 2002
Gaithersburg Holiday Inn
Microbiology Devices Advisory Panel Meeting
March 7, 2002
Wilson, M.D., Chair
Denver Health Medical Center
Cook County Hospital
Washington Hospital Center
Pennsylvania Department of Health
George Washington University Hospital
Ronald J. Zabransky, Ph.D.
Steven I. Gutman,
Director, Division of Clinical Laboratory Devices
Panel Executive Secretary
Sr. Review Scientist, Bacteriology Branch, Division of Clinical Laboratory Devices
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.
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.
Marjorie G. Shulman, Consumer Safety Officer, Center for Devices and
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
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.
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
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
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.
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
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
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
Open Committee Discussion
The panel felt that it had covered the main issues during the open public
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.
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
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.
I certify that I attended the meeting of the Microbiology Devices Panel on March 7, 2002, and that this summary accurately reflects what transpired.
I approve the minutes of this meeting
as recorded in this summary.
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