[Federal Register Volume 65, Number 46 (Wednesday, March 8, 2000)]
[Notices]
[Pages 12268-12271]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-5523]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 00B-0108]


Microbiology Devices; Reclassification of Fully Automated Short-
Term Incubation Cycle Antimicrobial Susceptibility Devices From Class 
III to Class II

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of panel recommendation.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is announcing for 
public comment the recommendation of the Microbiology Devices Panel 
(the Panel) to reclassify the fully automated short-term incubation 
cycle antimicrobial susceptibility devices from class III to class II. 
The Panel made this recommendation after reviewing the reclassification 
petition submitted by bioMeAE1rieux Vitek, Inc., and other publicly 
available information. FDA is also announcing for public comment its 
tentative findings on the Panel's recommendation. After considering any 
public comments on the Panel's recommendation and FDA's tentative 
findings, FDA will approve or deny the reclassification petition by 
order in the form of a letter to the petitioner. FDA's decision on the 
reclassification petition will be announced in the Federal Register. 
Elsewhere in this issue of the Federal Register, FDA is publishing a 
notice of availability of a guidance document that would serve as a 
special control for the reclassified device.

DATES: Submit written comments by June 7, 2000.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Joseph L. Hackett, Center for Devices 
and Radiological Health (HFZ-440), Food and Drug Administration, 9200 
Corporate Blvd., Rockville, MD 20850, 301-594-3084.

SUPPLEMENTARY INFORMATION:

I. Background (Regulatory Authorities)

    The Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 301 
et seq.), as amended by the Medical Device Amendments of 1976 (the 1976 
amendments) (Pub. L. 94-295), the Safe Medical Devices Act of 1990 
(Pub. L. 101-629), and the FDA Modernization Act of 1997 (Pub. L. 105-
115), established a comprehensive system for the regulation of medical 
devices intended for human use. Section 513 of the act (21 U.S.C. 360c) 
established three categories (classes) of devices, depending on the 
regulatory controls needed to provide reasonable assurance of their 
safety and effectiveness. The three categories of devices are class I 
(general controls), class II (special controls), and class III 
(premarket approval).
    Under section 513 of the act, devices that were in commercial 
distribution before May 28, 1976 (the date of enactment of the 1976 
amendments), generally referred to as preamendments devices, are 
classified after FDA has: (1) Received a recommendation from a device 
classification panel (an FDA advisory committee); (2) published the 
panel's recommendation for comment, along with a proposed regulation 
classifying the device; and (3) published a final regulation 
classifying the device. FDA has classified most preamendments devices 
under these procedures.
    Devices that were not in commercial distribution prior to May 28, 
1976, generally referred to as postamendments devices, are classified 
automatically by statute (section 513(f) of the act) into class III 
without any FDA rulemaking process. Those devices remain in class III 
and require premarket approval, unless and until the device is 
reclassified into class I or II or FDA issues an order finding the 
device to be substantially equivalent, under section 513(i) of the act, 
to a predicate device that does not require premarket approval. The 
agency determines whether new devices are substantially equivalent to 
previously offered devices by means of premarket notification 
procedures in section 510(k) of the act (21 U.S.C. 360(k)) and 21 CFR 
part 807 of the regulations.
    A preamendments device that has been classified into class III may 
be marketed, by means of premarket notification procedures, without 
submission of a premarket approval application until FDA issues a final 
regulation under section 515(b) of the act (21 U.S.C. 360e(b)) 
requiring premarket approval.
    Reclassification of classified postamendments devices is governed 
by section 513(f)(2) of the act. This section provides that FDA may 
initiate the reclassification of a device classified into class III 
under section 513(f)(1) of the act, or the manufacturer or importer of 
a device may petition the Secretary of Health and Human Services (the 
Secretary) for the issuance of an order classifying the device in class 
I or class II. FDA's regulations in Sec. 860.134 (21 CFR 860.134) set 
forth the procedures for the filing and review of a petition for 
reclassification of such class III devices. In order to change the 
classification of the device, it is necessary that the

[[Page 12269]]

proposed new class have sufficient regulatory controls to provide 
reasonable assurance of the safety and effectiveness of the device for 
its intended use.
    Under section 513(f)(2)(B)(i) of the act, the Secretary may, for 
good cause shown, refer a petition to a device classification panel. 
The Panel shall make a recommendation to the Secretary respecting 
approval or denial of the petition. Any such recommendation shall 
contain: (1) A summary of the reasons for the recommendation, (2) a 
summary of the data upon which the recommendation is based, and (3) an 
identification of the risks to health (if any) presented by the device 
with respect to which the petition was filed.

II. Regulatory History of the Device

    The fully automated short-term incubation cycle antimicrobial 
susceptibility device intended for determining the susceptibility 
patterns of microorganisms to various antimicrobial agents is a 
postamendments device classified into class III under section 513(f)(1) 
of the act. Prior to 1976, antimicrobial susceptibility disks were 
regulated as drugs. In 1976, with the passage of the 1976 amendments, 
all antimicrobial susceptibility products were considered transitional 
devices and automatically classified into class III. In 1978, the Vitek 
system for antimicrobial susceptibility testing was approved. In 1980, 
the antimicrobial susceptibility test (AST) disks device and the AST 
powder device were classified into class II. The semi-automated and 
automated methodologies were subject to class III controls because they 
were not substantially equivalent to traditional antibiotic disks and 
powders. In 1983, FDA denied a petition requesting the AST disks 
devices to be reclassified into class I. In 1984, the semi-automated 
and automated AST methodologies were reclassified into class II. The 
petition did not address the fully automated short-term incubation 
cycle methodologies. On July 2, 1997, FDA received a petition from 
bioMeAE1rieux Vitek, Inc., requesting reclassification of the fully 
automated short-term incubation cycle antimicrobial susceptibility 
devices from class III to class II under section 513(f)(2) of the act 
and Sec. 860.134, based on information submitted in the petition.
    Consistent with the act and the regulation, FDA referred the 
petition to the Panel for its recommendation on the requested change in 
classification.

III. Device Description

    The fully automated short-term incubation cycle antimicrobial 
susceptibility device is intended to determine, in less than 16 hours, 
the antimicrobial susceptibility of nonfastidious aerobic and/or 
facultative anaerobic bacteria to FDA-approved antimicrobial agents. 
These devices are based on optical detection of growth of bacterial 
isolates in media with selected antimicrobial concentrations during a 
short term, less than 16 hours, incubation cycle. Test results are used 
as an aid for the physician in making therapeutic decisions involving 
the administration of antimicrobial drugs.

IV. Recommendations of the Panel

    At a public meeting on February 13, 1998, the Panel unanimously 
recommended that the fully automated short-term incubation cycle 
antimicrobial susceptibility devices be reclassified from class III to 
class II. The Panel believes that class II with special controls would 
provide reasonable assurance of the safety and effectiveness of the 
device. Those special controls include: (1) The use of updated and 
appropriate ``challenge strains,'' (2) the use of a nephelometer for 
preparing the inoculum, (3) application of ``acceptable error'' as a 
range with confidence intervals, (4) identification of a predicate 
device for comparative clinical performance testing, and (5) guidelines 
in the FDA guidance document entitled ``Review Criteria for Assessment 
of Antimicrobial Susceptibility Devices.'' In addition, the Panel 
believes there is the need for a postmarketing action plan, which the 
Panel called ``postmarket surveillance,'' to review problems as they 
arise. (See further discussion under section IX of this document).
    The Panel stated that special controls will diminish some of the 
risks associated with the inappropriate use of antimicrobial agents, 
including the potential risk of death associated with an ineffective 
antimicrobial agent.

V. Risks to Health

    After considering the information discussed by the Panel during the 
meeting on February 13, 1998, the published literature, and the Medical 
Device Reporting (MDR) system reports, FDA believes the following risks 
are associated with the use of fully automated short-term incubation 
cycle antimicrobial susceptibility devices.
    When an antimicrobial agent result is erroneously reported to the 
clinician as ``sensitive'' and in reality is ``resistant,'' the patient 
may be treated inappropriately and inadvertently subjected to an 
exacerbation of the infection, drug reaction, an extended hospital 
stay, collateral infections, or possibly death.
    When an antimicrobial agent result is erroneously reported to the 
clinician as ``resistant'' and in reality is ``sensitive,'' the 
appropriate treatment may be delayed with a similar potential of severe 
sequelae.

VI. Summary of Reasons for Recommendation

    Based on the Panel members' personal knowledge and clinical 
experience with the device, the data and information contained in the 
petition, the information provided by FDA, and the open discussions 
during the Panel meeting, the following reasons were given by the Panel 
in support of its recommendation to reclassify the fully automated 
short-term incubation cycle antimicrobial susceptibility device for use 
in the rapid determination of the in vitro susceptibility of 
nonfastidious aerobic and facultative anaerobic organisms to 
antimicrobial agents from class III into class II:
    1. The safety and effectiveness of the fully automated short-term 
incubation cycle antimicrobial susceptibility device has become well-
established since approval of the first device in 1978.
    2. The establishment of special controls, in addition to general 
controls, provides reasonable assurance of the safety and effectiveness 
of the fully automated short-term incubation cycle antimicrobial 
susceptibility device.
    3. The rate of serious complications from the fully automated 
short-term incubation cycle antimicrobial susceptibility device is low 
and can be effectively minimized by: (a) Evaluating the system with 
updated challenge strains of organisms, as well as those organisms that 
are appropriate to the antimicrobial being tested; (b) using a 
nephelometer for preparing the inoculum; (c) using application of 
``acceptable error'' as a range with confidence intervals; (d) 
conducting adequate and appropriate clinical testing; and (e) enforcing 
labeling restrictions and ensuring adherence to the guidelines 
described in the FDA guidance document entitled ``Review Criteria for 
Assessment of Antimicrobial Susceptibility Devices.''
    The Panel has identified the risks to health regarding the use of 
the fully automated short-term incubation cycle AST system as the 
reporting of erroneous results. Insufficient testing of each unique 
antimicrobial agent with an inappropriate clinical and challenge 
organism, the use of an uncalibrated

[[Page 12270]]

inoculum, or a nonstandardized acceptable error endpoint can result in 
such erroneous reports.
    The Panel believes that the fully automated short-term incubation 
cycle AST device should be reclassified into class II because special 
controls provide reasonable assurance of the safety and effectiveness 
of the device, and there is sufficient information to establish special 
controls to provide such assurance.

VII. Summary of Data Upon Which the Panel Recommendation is Based

    Based on the information discussed by the Panel during the February 
13, 1998, Panel meeting, the published literature, the information 
presented in the petition, and the literature searches done by FDA, the 
Panel believes that there is reasonable knowledge of the benefits of 
the device when used for the determination of antimicrobial 
susceptibilities. The fully automated short-term incubation cycle 
antimicrobial susceptibility device provides a more timely laboratory 
report and clinical intervention. The sooner the clinician has the 
results of susceptibility testing, providing controls are in place to 
minimize erroneous results, the sooner the patient can be placed on 
appropriate therapy, thereby increasing the probability of faster 
recovery.
    Automated antimicrobial susceptibility devices have been in the 
marketplace over 25 years. There is significant scientific and medical 
information available regarding the nature, complexity, and problems 
associated with these devices. With the short-term incubation cycle 
devices, the error rate tends to be higher because of decreased 
incubation times and the use of algorithms to determine resistance. 
Because of this, the results can more profoundly affect the clinical 
decision. This occurs frequently with certain organisms pneumoniae, and 
specific antimicrobial agent-bacterial pathogen combinations.
    FDA believes that the special controls discussed in section VIII of 
this document are capable of providing reasonable assurance of the 
safety and effectiveness of the fully automated short-term incubation 
cycle antimicrobial susceptibility device with regard to the identified 
risks to health with the use of this device.

VIII. Special Controls

    In addition to general controls, FDA believes that a special 
control should be established to minimize the risks to health 
identified with the use of this device. The special control will be an 
FDA guidance document as described below.

A. FDA Guidance Document

    The FDA guidance document that would serve as a special control 
provides information to help manufacturers address the risks identified 
by the Panel. The guidance document describes a means by which fully 
automated short-term incubation cycle antimicrobial susceptibility 
devices may comply with the requirement of special controls for class 
II devices. Designation of this guidance document as a special control 
means that manufacturers attempting to establish that their device is 
substantially equivalent to a predicate device must demonstrate that 
the proposed device complies with either the specific recommendations 
of this guidance or some alternative control that provides equivalent 
assurances of safety and effectiveness. Fully automated short-term 
incubation cycle antimicrobial susceptibility devices remain subject to 
premarket approval unless and until reclassified by FDA.
    Adherence to the revised FDA guidance document entitled ``Review 
Criteria for Assessment of Antimicrobial Susceptibility Devices'' (Ref. 
1) can control the risks associated with inappropriate challenge 
strains being used in clinical testing, nonstandardized preparation of 
inoculum, varying interpretations of error ranges, and clinical 
performance testing. Each of these risks is addressed in the guidance 
document.
1. Appropriate Challenge Strains
    Inappropriate testing, too few samples, and lack of attention to 
the specific antimicrobial/organism relationships that were approved by 
the Center for Drug Evaluation and Research, should be avoided. In the 
process of doing preclinical and clinical studies, testing of the 
device with well-characterized strains may detect possible areas where 
the device needs improvement, as well as providing a greater confidence 
in the reporting of results with the use of the device.
2. Standardized Preparation of Inoculum
    An acknowledged source of error in all systems is the use of an 
inappropriate inoculum. If the inoculum density falls outside of the 
established range, the results may provide inaccurate reports of 
``sensitive'' or ``resistant.'' The use of a nephelometer alleviates 
visual acuity and ambiguity in determining a specific turbidity 
endpoint. As discussed in the guidance, the National Committee for 
Clinical Laboratory Standards (NCCLS) Methods for Dilution 
Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically 
(M7-A4), recommends use of a nephelometer as an option for preparing 
the inoculum.
3. Application of ``Acceptable Error'' as a Range With Confidence 
Intervals
    By using an acknowledged standard (e.g., 95 percent confidence 
intervals for agreement and error rates that must fall within specified 
bounds), a consistent threshold can be universally applied.
4. Appropriate Clinical Performance Testing
    FDA approves antimicrobial agents with specific indications for 
use. Many antimicrobial agents will show activity with only 
``selected'' organisms. When manufacturers are performing clinical 
tests on their systems, it is essential to test only those organisms 
specifically identified in the ``Indication for Use'' statement of the 
approved drug. These are the organisms for which the clinician will 
require susceptibility results for treating the patient.
5. Reference to the Current Guidelines Established in Standards 
Published by the NCCLS
    The quality of the device is enhanced by conforming to accepted 
standards. Standards listed in the FDA guidance document include the 
most recent version of Performance Standards for Antimicrobial Disk 
Susceptibility Tests (M2-A-), Methods for Dilution Antimicrobial 
Susceptibility Tests for Bacteria that Grow Aerobically     (M7-A-), 
Development of In Vitro Susceptibility Criteria and Quality Control 
Parameters (M23-A-), and Performance Standards for Antimicrobial 
Susceptibility Testing (M100-A-).

IX. FDA's Tentative Findings

    FDA agrees with the Panel's recommendation. However, FDA interprets 
the term, ``postmarket surveillance,'' as used by the Panel, to mean 
continuation of the industry-wide activity already in place to review 
any problems with these devices as they develop. Many laboratories 
participate in various recognized surveys, which are widely subscribed 
to and sent out regularly. The results of these surveys are reviewed, 
tabulated, often listed by device, and published. For example, the 
College of American Pathology provides an extensive survey program. The 
Centers for Disease Control and Prevention do periodic testing to 
evaluate potential problems with susceptibility testing and disseminate

[[Page 12271]]

the results of that research. There is also the Med-Watch program as 
well as the Medical Device Reporting system to identify problems or 
trends associated with these devices. The agency believes the above 
survey, testing, and reporting programs provide adequate postmarket 
surveillance. The development of an FDA guidance as a special control 
will minimize the major sources of erroneous reporting associated with 
the fully automated short-term incubation cycle antimicrobial 
susceptibility device. Because special controls, in addition to general 
controls, would provide reasonable assurance of safety and 
effectiveness, the device should be classified into class II. There is 
sufficient information to establish special controls to provide such 
assurance.

X. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday:
    1. FDA Guidance Document, ``Review Criteria for Assessment of 
Antimicrobial Susceptibility Devices,'' 2000 revision.
    2. NCCLS Approved Standard, M2 (most recent approved supplement), 
Performance Standards for Antimicrobial Disk Susceptibility Tests, 
Wayne, PA.
    3. NCCLS Approved Standard, M7 (most recent approved supplement), 
Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria 
That Grow Aerobically, Wayne, PA.
    4. NCCLS Approved Standard, M100 (most recent approved supplement), 
Performance Standards for Antimicrobial Susceptibility Testing, Wayne, 
PA.
    5. NCCLS Approved Standard, M23 (most recent approved supplement), 
Development of In Vitro Susceptibility Testing Criteria and Quality 
Control Parameters, Wayne, PA.
    6. Transcript of the Microbiology Devices Panel Meeting, February 
13, 1998.

XI. Environmental Impact

    The agency has determined under 21 CFR 25.34(b) that this 
reclassification action is of a type that does not individually or 
cumulatively have a significant effect on the human environment. 
Therefore, neither an environmental assessment nor an environmental 
impact statement is required.

XII. Analysis of Impacts

    FDA has examined the impacts of the notice under Executive Order 
12866 and the Regulatory Flexibility Act (Public Law 96-354) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Public Law 104-121), and the Unfunded Mandates Reform Act of 1995 
(Public Law 104-4)). Executive Order 12866 directs agencies to assess 
all costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). The agency believes that this reclassification action is 
consistent with the regulatory philosophy and principles identified in 
the Executive Order. In addition, the reclassification action is not a 
significant regulatory action as defined by the Executive Order and so 
is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Reclassification of the device from class III to 
class II will relieve manufacturers of the cost of complying with the 
premarket approval requirements in section 515 of the act. Because 
reclassification will reduce regulatory costs with respect to this 
device, it will impose no significant economic impact on any small 
entities, and it may permit small potential competitors to enter the 
marketplace by lowering their costs. The agency therefore certifies 
that this reclassification action, if finalized, will not have a 
significant economic impact on a substantial number of small entities. 
In addition, this reclassification action will not impose costs of $100 
million or more on either the private sector or State, local, and 
tribal governments in the aggregate, and therefore a summary statement 
of analysis under section 202(a) of the Unfunded Mandates Reform Act of 
1995 is not required.

XIII. Request for Comments

    Interested persons may, on or before June 7, 2000, submit to the 
Dockets Management Branch (address above) written comments regarding 
this document. Two copies of any comments are to be submitted, except 
that individuals may submit one copy. Comments are to be identified 
with the docket number found in brackets in the heading of this 
document. A copy of the document and received comments may be seen in 
the Dockets Management Branch between 9 a.m. and 4 p.m., Monday through 
Friday.

    Dated: February 14, 2000.
Linda S. Kahan,
Deputy Director for Regulations Policy, Center for Devices and 
Radiological Health.
[FR Doc. 00-5523 Filed 3-7-00; 8:45 am]
BILLING CODE 4160-01-F