Microbiology Devices; Reclassification of Influenza Virus Antigen Detection Test Systems Intended for Use Directly With Clinical Specimens, 29387-29392 [2014-11635]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 79, Number 99 (Thursday, May 22, 2014)]
[Proposed Rules]
[Pages 29387-29392]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-11635]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2014-N-0440]


Microbiology Devices; Reclassification of Influenza Virus Antigen 
Detection Test Systems Intended for Use Directly With Clinical 
Specimens

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed order.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to 
reclassify antigen based rapid influenza virus antigen detection test 
systems intended to detect influenza virus directly from clinical 
specimens that are currently regulated as influenza virus serological 
reagents from class I into class II with special controls and into a 
new device classification regulation.

DATES: Submit either electronic or written comments on the proposed 
order by August 20, 2014. See section XI for the proposed effective 
date of any final order that may publish based on this proposed order.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2014-
N-0440, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper submissions): 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and Docket No. FDA-2014-N-0440 for this rulemaking. All comments 
received may be posted without change to https://www.regulations.gov, 
including any personal information provided. For additional information 
on submitting comments, see the ``Comments'' heading of the 
SUPPLEMENTARY INFORMATION section.
    Docket: For access to the docket to read background documents or 
comments received, go to https://www.regulations.gov and insert the 
docket number, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Stefanie Akselrod, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, Rm. 5517, Silver Spring, MD 20993-0002, 301-
796-6188.

SUPPLEMENTARY INFORMATION:

I. Regulatory Authorities

    The Federal Food, Drug, and Cosmetic Act (the FD&C Act), 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 Food and Drug Administration Modernization Act of 1997 (FDAMA) 
(Pub. L. 105-115), the Medical Device User Fee and Modernization Act of 
2002 (Pub. L. 107-250), the Medical Devices Technical Corrections Act 
(Pub. L. 108-214), the Food and Drug Administration Amendments Act of 
2007 (Pub. L. 110-85), and the Food and Drug Administration Safety and 
Innovation Act (FDASIA) (Pub. L. 112-144), among other amendments, 
established a comprehensive system for the regulation of medical 
devices intended for human use. Section 513 of the FD&C Act (21 U.S.C. 
360c) established three categories (classes) of devices, reflecting 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 the FD&C Act, FDA clears or approves the three classes of 
medical devices for commercial distribution in the United States 
through three regulatory processes: Premarket approval (PMA), product 
development protocol, and premarket notification (a premarket 
notification is generally referred to as a ``510(k)'' after the section 
of the FD&C Act where the requirement is found). The purpose of a 
premarket notification is to demonstrate that the new device is 
substantially equivalent to a legally marketed predicate device. Under 
section 513(i) of the FD&C Act, a device is substantially equivalent if 
it has the same intended use and technological characteristics as a 
predicate device, or has different technological characteristics but 
data demonstrate that the new device is as safe and effective as the 
predicate device and does not raise different issues of safety or 
effectiveness.
    FDA determines whether new devices are substantially equivalent to 
previously offered devices by means of premarket notification 
procedures in section 510(k) of the FD&C Act (21 U.S.C. 360(k)) and 
part 807 of the regulations (21 CFR part 807). Section 510(k) of the 
FD&C Act and the implementing regulations in part 807, subpart E, 
require a person who intends to market a medical device to submit a 
premarket notification submission to FDA before proposing to begin the 
introduction, or delivery for introduction into interstate commerce, 
for commercial distribution of a device intended for human use.
    In accordance with section 513(f)(1) of the FD&C Act, devices that 
were not in commercial distribution before May 28, 1976, the date of 
enactment of the 1976 amendments, generally referred to as 
postamendment devices, are classified automatically by statute into 
class III without any FDA rulemaking process. These devices remain in 
class III and require premarket approval, unless FDA classifies the 
device into class I or class II by issuing an order finding the device 
to be substantially equivalent, in accordance with section 513(i) of 
the FD&C Act, to a predicate device that does not require premarket 
approval or the device is reclassified into class I or class II. The 
Agency determines whether new devices are substantially equivalent to 
predicate devices by means of premarket notification procedures in 
section 510(k) of the FD&C Act and part 807 of FDA's regulations.
    Section 513(f)(2) of the FD&C Act establishes procedures for ``de 
novo'' risk-based review and classification of postamendment devices 
automatically classified into class III by section

[[Page 29388]]

513(f)(1). Under these procedures, any person whose device is 
automatically classified into class III by section 513(f)(1) of the 
FD&C Act may seek reclassification into class I or II, either after 
receipt of an order finding the device to be not substantially 
equivalent, in accordance with section 513(i), to a predicate device 
that does not require premarket approval, or at any time after 
determining there is no legally marketed device upon which to base a 
determination of substantial equivalence. In addition, under section 
513(f)(3) of the FD&C Act, FDA may initiate, or the manufacturer or 
importer of a device may petition for, the reclassification of a device 
classified into class III under section 513(f)(1).
    On July 9, 2012, FDASIA was enacted. Section 608(a) of FDASIA (126 
Stat. 1056) amended section 513(e) of the FD&C Act, changing the 
process for reclassifying a device from rulemaking to an administrative 
order. Section 608(b) of FDASIA (126 Stat. 1056) amended section 515(b) 
of the FD&C Act (21 U.S.C. 360e(b)), changing the process for requiring 
premarket approval for a preamendments class III device from rulemaking 
to an administrative order.

Reclassification

    FDA is publishing this document to propose the reclassification of 
antigen based rapid influenza detection test (RIDT) systems intended to 
detect influenza virus antigen directly from clinical specimens that 
are currently regulated as influenza virus serological reagents under 
Sec.  866.3330 (21 CFR 866.3330) from class I into class II with 
special controls and into a new device classification regulation.
    Section 513(e) of the FD&C Act governs reclassification of 
classified preamendments device types and postamendments devices that 
have been classified into class I or II under section 513(f)(2) or 
(f)(3) of the FD&C Act. This section provides that FDA may, by 
administrative order, reclassify a device based upon ``new 
information.'' FDA can initiate a reclassification under section 513(e) 
of the FD&C Act or an interested person may petition FDA to reclassify 
an eligible device type. The term ``new information,'' as used in 
section 513(e) of the FD&C Act, includes information developed as a 
result of a reevaluation of the data before the Agency when the device 
was originally classified, as well as information not presented, not 
available, or not developed at that time. (See, e.g., Holland-Rantos 
Co. v. United States Department of Health, Education, and Welfare, 587 
F.2d 1173, 1174 n.1 (D.C. Cir. 1978); Upjohn v. Finch, 422 F.2d 944 
(6th Cir. 1970); Bell v. Goddard, 366 F.2d 177 (7th Cir. 1966).)
    Reevaluation of the data previously before the Agency is an 
appropriate basis for subsequent action where the reevaluation is made 
in light of newly available authority (see Bell, 366 F.2d at 181; 
Ethicon, Inc. v. FDA, 762 F.Supp. 382, 388-391 (D.D.C. 1991)), or in 
light of changes in ``medical science'' (Upjohn, 422 F.2d at 951). 
Whether data before the Agency are old or new data, the ``new 
information'' to support reclassification under section 513(e) of the 
FD&C Act must be ``valid scientific evidence,'' as defined in section 
513(a)(3) and 21 CFR 860.7(c)(2). (See, e.g., General Medical Co. v. 
FDA, 770 F.2d 214 (D.C. Cir. 1985); Contact Lens Association v. FDA, 
766 F.2d 592 (D.C. Cir.), cert. denied, 474 U.S. 1062 (1986).)
    FDA relies upon ``valid scientific evidence'' in the classification 
process to determine the level of regulation for devices. To be 
considered in the reclassification process, the ``valid scientific 
evidence'' upon which the Agency relies must be publicly available. 
Publicly available information excludes trade secret and/or 
confidential commercial information, e.g., the contents of a pending 
PMA. (See section 520(c) of the FD&C Act (21 U.S.C. 360j(c)).) Section 
520(h)(4) of the FD&C Act, added by FDAMA, provides that FDA may use, 
for reclassification of a device, certain information in a PMA 6 years 
after the application has been approved. This can include information 
from clinical and preclinical tests or studies that demonstrate the 
safety or effectiveness of the device but does not include descriptions 
of methods of manufacture or product composition and other trade 
secrets.
    Section 513(e)(1) of the FD&C Act sets forth the process for 
issuing a final order for reclassifying a device. Specifically, prior 
to the issuance of a final order reclassifying a device, the following 
must occur: (1) Publication of a proposed order in the Federal 
Register; (2) a meeting of a device classification panel described in 
section 513(b) of the FD&C Act; and (3) consideration of comments to a 
public docket. FDA has held a meeting of a device classification panel 
described in section 513(b) of the FD&C Act with respect to rapid 
influenza diagnostic tests, and therefore, has met this requirement 
under section 513(e).
    FDAMA added section 510(m) to the FD&C Act. Section 510(m) of the 
FD&C Act provides that a class II device may be exempted from the 
premarket notification requirements under section 510(k) of the FD&C 
Act, if the Agency determines that premarket notification is not 
necessary to assure the safety and effectiveness of the device.

II. Regulatory Background of the Device

    In the Federal Register of April 22, 1980 (45 FR 27204), FDA 
published proposed regulations containing general provisions applicable 
to the classification of immunology and microbiology devices and 
individual proposed regulations to classify 161 immunology and 
microbiology devices into one or more of three regulatory classes: 
Class I (general controls), class II (performance standards), and class 
III (premarket approval). These regulations included the April 22, 
1980, proposed rule (45 FR 27204 at 27261) to classify influenza virus 
serological reagents into class I under Sec.  866.3330 (21 CFR 
866.3330) Influenza virus serological reagents. In a final rule, on 
November 9, 1982 (47 FR 50814 at 50823), under the authority of the 
Medical Device Amendments of 1976, FDA classified influenza virus 
serological reagents into class I under Sec.  866.3330. At that time, 
influenza tests conceived to fall under this regulation were laboratory 
methods to detect antibodies that develop in response to influenza 
infection while the detection of the influenza virus itself was done 
primarily by viral culture. As enzyme immunoassay technology developed, 
tests capable of detecting viral proteins (antigens) directly in human 
respiratory samples began to come to FDA for clearance. Since then, 
numerous influenza detection tests based on antigen-antibody binding 
properties have been developed and cleared for the market. The first 
RIDT for use directly from clinical specimens was cleared in 1990 and 
followed by others in the late 1990s. To date, methods utilizing 
antigens and antibodies as components of an influenza detection device 
have been regulated under Sec.  866.3330 as class I devices exempt from 
the premarket notification (510(k)) requirement subject to the 
limitations in Sec.  866.9 (21 CFR 866.9). RIDTs found under Sec.  
866.3330 exceed the limitations to the exemption from premarket 
notification for influenza virus serological reagents under Sec.  
866.9(c)(6) and thus require a 510(k) submission.
    There are approximately 12 RIDTs classified under Sec.  866.3330 
actively marketed today. Because these devices are easy to use and 
provide results within 15 to 30 minutes, they are widely used in point-
of-care settings where rapid diagnosis of influenza is important for 
early case identification.

[[Page 29389]]

III. Identification

    We are proposing that RIDTs classified under Sec.  866.3330 be 
identified under the new name of influenza virus antigen detection test 
system. An influenza virus antigen detection test system is a device 
intended for the qualitative detection of influenza viral antigens 
directly from clinical specimens in patients with signs and symptoms of 
respiratory infection. The test aids in the diagnosis of influenza 
infection and provides epidemiological information on influenza. Due to 
the propensity of the virus to mutate, new strains emerge over time 
that may potentially affect the performance of these devices. Because 
influenza is highly contagious and may lead to an acute respiratory 
tract infection causing severe illness and even death, the accuracy of 
these devices has serious public health implications.

IV. Background for Proposed Reclassification Decision

    On June 13, 2013, FDA convened a meeting of the Microbiology 
Advisory Panel to discuss the regulation of RIDTs that are currently 
regulated as class I devices. The primary reasons for convening the 
panel to discuss this topic were continued reports of poor real world 
RIDT performance by the RIDTs in the field compounded by the emergence 
of new influenza strains with a potential to create a public health 
emergency. The occurrence of the 2009 flu pandemic emphasized that 
these RIDTs, while widely used by clinicians in point of care settings, 
performed poorly resulting in misdiagnosed cases and, according to 
anecdotal reports, sometimes with serious or even fatal consequences.
    The panel discussion included a discussion of the labeled 
performance of the currently available RIDTs and presentations by 
representatives from the Centers for Disease Control and Prevention 
(CDC) and the Association of Public Health Laboratories (APHL) citing 
the evidence of performance of these tests in real life settings. One 
of the important issues raised was that the performance of an influenza 
antigen detecting test is subject to the changes in the virus as it 
mutates over time. The panel members were asked to discuss whether 
there is sufficient evidence to suggest that general controls under 
class I regulation are or are not sufficient to provide a reasonable 
assurance that current and future RIDTs are safe and effective and 
whether the addition of special controls would provide reasonable 
assurance of the device's safety and effectiveness if the general 
controls alone do not. Panel members provided the opinion that 
sufficient data and information exist to indicate that special controls 
are needed to mitigate the risks of false positive and false negative 
results from RIDTs and provide a reasonable assurance of safety and 
effectiveness of the device and to identify the special controls 
needed. The panel members indicated that placing RIDTs into class II 
with special controls was appropriate.

V. Classification Recommendation

    FDA is proposing that all RIDTs currently regulated under Sec.  
866.3330 be reclassified into class II with special controls under the 
new device name ``influenza virus antigen detection test system.'' FDA 
believes that special controls that: (1) Identify the minimum 
acceptable performance criteria; (2) identify the appropriate 
comparator for establishing performance of new assays; and (3) call for 
mandatory annual analytical reactivity testing of contemporary 
influenza strains, including testing of newly emerging strains that 
pose a danger of public health emergency, would provide reasonable 
assurance of safety and effectiveness of these devices.
    Section 510(m) of the FD&C Act provides that a class II device may 
be exempt from the premarket notification requirements under section 
510(k), if the Agency determines that premarket notification is not 
necessary to provide reasonable assurance of the safety and 
effectiveness of the device. For this device, FDA believes that 
premarket notification is necessary to provide reasonable assurance of 
safety and effectiveness and, therefore, does not intend to exempt the 
device from the premarket notification requirements.

VI. Risks to Health

    Although an RIDT is intended for use as an aid in the diagnosis of 
influenza infection in conjunction with clinical symptoms and other 
laboratory findings, failure of the device to perform as indicated 
(producing erroneous or inaccurate results) could mislead the physician 
and cause inappropriate or delayed medical treatment of a patient. 
Failure of the test to produce accurate test results can also lead to 
inaccurate epidemiological information that may contribute to 
inappropriate public health responses and to facilitate spread of the 
infection in a community. After considering the information discussed 
by the Microbiology Devices Panel during the June 13, 2013, meeting in 
conjunction with the published literature on the subject and the FDA 
Medical Device Reporting system reports, FDA believes the following 
risks are associated with RIDTs:
     A false negative result may lead to failure to provide a 
correct diagnosis and the appropriate treatment of infection caused by 
influenza virus and may contribute to unnecessary treatment for another 
suspected condition.
     A false negative result will also provide incorrect 
epidemiological information leading to failure to initiate appropriate 
corrective measures to control and prevent additional infections.
     A false positive result on the other hand may lead to 
delayed treatment of a respiratory infection caused by another 
etiologic agent, which could potentially result in a more serious 
patient outcome.
     A false positive result will also provide incorrect 
epidemiological information on the presence of influenza in a 
community, which may result in unnecessary patient isolation or contact 
limitations and in unnecessary close contact investigations.
     A lack of result due to a device malfunction also may lead 
to a delayed diagnosis and an inadequate treatment regime and, again, 
lead to delayed epidemiological information on the presence of 
influenza in a community, contributing to the spread of the infection.

VII. Summary of the Reasons for Reclassification

    Due to the mounting evidence and reports from the scientific 
community about the poor sensitivity of the RIDTs currently on the 
market and the corresponding risks to health associated with low 
sensitivity in combination with a rapidly evolving influenza genome 
with the potential for a public health emergency, FDA convened a 
meeting of the Microbiology Devices Panel of the Medical Devices 
Advisory Committee in order to discuss a proposal to reclassify RIDTs 
in Sec.  866.3330 from class I to class II with special controls. 
Consistent with the opinions expressed by the experts on the panel, FDA 
believes that the establishment of special controls, in addition to 
general controls, is necessary to mitigate the risks to health not 
mitigated by the general controls and provide a reasonable assurance of 
safety and effectiveness for these devices. While we believe that 
general controls continue to adequately address the risk to health 
caused by a lack of result due to a device malfunction we believe 
special controls, in addition to general controls, are needed to 
control

[[Page 29390]]

the other risks of this device, which are: (1) A false negative result 
may lead to failure to provide a correct diagnosis and the appropriate 
treatment of infection caused by influenza virus and may contribute to 
unnecessary treatment for another suspected condition; (2) a false 
negative result will also provide incorrect epidemiological information 
leading to failure to initiate appropriate corrective measures to 
control and prevent additional infections; (3) a false positive result 
on the other hand may lead to delayed treatment of a respiratory 
infection caused by another etiologic agent, which could potentially 
result in a more serious patient outcome; and (4) a false positive 
result will also provide incorrect epidemiological information on the 
presence of influenza in a community, which may result in unnecessary 
patient isolation or contact limitations and in unnecessary close 
contact investigations.

VIII. Special Controls

    FDA believes that the following special controls are necessary, in 
addition to general controls, to mitigate the risks to health described 
in section VI.
    1. The device's sensitivity and specificity performance 
characteristics must meet one of the following two minimum clinical 
performance criteria in order to be cleared for marketing and to remain 
on the market:
     If the manufacturer chooses to compare the device to viral 
culture:
    [cir] The sensitivity estimate for the device when testing for 
Influenza A must be at least at the 90 percent point estimate with a 
lower bound of the 95 percent confidence interval that is greater than 
or equal to 80 percent. The sensitivity estimate for the device when 
testing for Influenza B must be at least at the 80 percent point 
estimate with a lower bound of the 95 percent confidence interval that 
is greater than or equal to 70 percent.
    [cir] The specificity estimate for the device when testing for 
Influenza A and Influenza B must be at least at the 95 percent point 
estimate with a lower bound of the 95 percent confidence interval that 
is greater than or equal to 90 percent.
     If the manufacturer chooses to compare the device to an 
appropriate molecular comparator method:
    [cir] The positive percent agreement for the device when testing 
for Influenza A and Influenza B must be at least at the 80 percent 
point estimate with a lower bound of the 95 percent confidence interval 
that is greater than or equal to 70 percent.
    [cir] The negative percent agreement for the device when testing 
for Influenza A and Influenza B must be at least at the 95 percent 
point estimate with a lower bound of the 95 percent confidence interval 
that is greater than or equal to 90 percent.
    2. When performing testing to demonstrate the device meets the 
requirements in paragraph 1 of this section, a currently appropriate 
and FDA accepted comparator method must be used to establish assay 
performance in clinical studies.
    3. Annual analytical reactivity testing of the device must be 
performed with contemporary influenza strains. This annual analytical 
reactivity testing must meet the following criteria:
     The appropriate strains to be tested will be identified by 
FDA in consultation with CDC and sourced from CDC or a CDC-designated 
source. If the annual strains are not available from CDC, FDA will 
identify an alternative source for obtaining the requisite strains.
    [cir] The testing must be conducted according to a standardized 
protocol considered and determined by FDA to be acceptable and 
appropriate.
    [cir] By July 31 of each calendar year, the results of the last 3 
years of annual analytical reactivity testing must be included as part 
of the device's labeling. If a device has not been on the market long 
enough for 3 years of annual reactivity testing since the device was 
given marketing authorization, then the results of every designated 
annual reactivity testing since the device was given marketing 
authorization by FDA, including the results of annual analytical 
reactivity testing performed on the viral strains provided that 
calendar year, must be included. The results must be presented as part 
of the device's labeling in a tabular format, which includes the 
detailed information for each virus tested as described in the 
certificate of authentication, either by:
    [cir] Placing the results directly in the device's Sec.  809.10(b) 
(21 CFR 809.10(b)) compliant labeling in a section of the labeling 
devoted to annual analytical reactivity testing; or
    [cir] Providing a hyperlink in a section of the device's labeling 
to the manufacturer's public Web site where the annual analytical 
reactivity testing data can be found. If this option is chosen, the 
manufacturer's home page must publicly provide a hyperlink, which can 
easily be found and executed, to the annual analytical reactivity 
testing results and the Web page containing those annual analytical 
reactivity testing results must allow unrestricted viewing access. This 
includes being easy to locate the results from the primary part of the 
manufacturer's Web site that discusses the device.
    4. If an emergency, or a potential emergency, is declared by the 
Secretary of Health and Human Services (HHS) for an influenza viral 
strain:
     Within 30 days from the date that FDA notifies 
manufacturers that characterized viral samples are available for test 
evaluation, the manufacturer must have testing performed on the device 
with that viral strain in accordance with a standardized protocol 
considered and determined by FDA to be acceptable and appropriate. The 
procedure and location of testing may depend on the nature of the 
emerging virus.
     Within 60 days from the date that CDC first makes 
characterized viral samples available to manufacturers and continuing 
until the emergency, or potential emergency, is declared by the 
Secretary of HHS to be over, the results of the influenza emergency 
analytical reactivity testing, including the detailed information for 
the virus tested as described in the certificate of authentication, 
must be included as part of the device's labeling in a tabular format, 
either by:
    [cir] Placing the table directly in the device's Sec.  809.10(b) 
compliant labeling in the section of the labeling devoted to annual 
analytical reactivity testing and influenza emergency analytical 
reactivity testing but separate from the annual analytical reactivity 
testing tables; or
    [cir] Providing a hyperlink in a section of the device's labeling 
devoted to annual analytical reactivity testing and influenza emergency 
analytical reactivity testing to a part of the manufacturer's public 
Web site where the annual and the emergency analytical reactivity 
testing data can be found. If this option is chosen, the manufacturer's 
home page must publicly provide a hyperlink, which can easily be found 
and executed, to the analytical reactivity and emergency testing 
results and the Web page containing those annual analytical reactivity 
testing results must allow unrestricted viewing access.
    Table 1 shows the special controls set forth in this order that are 
needed to address the identified risks for this device not sufficiently 
addressed by the general controls to provide a reasonable assurance of 
safety and effectiveness of the device.

[[Page 29391]]



  Table 1--Identified Risks to Health and Required Mitigation Measures
------------------------------------------------------------------------
     Identified risks to health          Required mitigation measures
------------------------------------------------------------------------
1. A false negative result may lead  Special Controls 1-4.
 to failure to provide a correct
 diagnosis and the appropriate
 treatment of infection caused by
 influenza virus and may contribute
 to unnecessary treatment for
 another suspected condition..
2. A false negative result will      Special Controls 1-4.
 also provide incorrect
 epidemiological information
 leading to failure to initiate
 appropriate corrective measures to
 control and prevent additional
 infections..
3. A false positive result on the    Special Controls 1-4.
 other hand may lead to delayed
 treatment of a respiratory
 infection caused by another
 etiologic agent, which could
 potentially result in a more
 serious patient outcome..
4. A false positive result will      Special Controls 1-4.
 also provide incorrect
 epidemiological information on the
 presence of influenza in a
 community, which may result in
 unnecessary patient isolation or
 contact limitations and in
 unnecessary close contact
 investigations..
------------------------------------------------------------------------

    If this proposed order is finalized, RIDTs in Sec.  866.3330 will 
be reclassified into class II with special controls in a new 
classification regulation at 21 CFR 866.3328. Adherence to the special 
controls, when finalized, in addition to the general controls, is 
necessary to provide a reasonable assurance of the safety and 
effectiveness of the device.

IX. Environmental Impact

    The Agency has determined under 21 CFR 25.34(b) that this action is 
of 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.

X. Paperwork Reduction Act of 1995

    This proposed administrative order establishes special controls 
that refer to previously approved collections of information found in 
other FDA regulations. These collections of information are subject to 
review by the Office of Management and Budget (OMB) under the Paperwork 
Reduction Act of 1995 (44 U.S.C. 3501-3520). The collections of 
information in part 807, subpart E, regarding premarket notification 
submissions have been approved under OMB control number 0910-0120; and 
the collections of information in 21 CFR part 801 and 21 CFR 809.10 
have been approved under OMB control number 0910-0485.

XI. Proposed Effective Date

    FDA proposes that any final order based on this proposed order 
become effective 1 year after its date of publication in the Federal 
Register.

XII. Comments

    Interested persons may submit either electronic comments regarding 
this document or the associated Special Controls guideline to https://www.regulations.gov or written comments to the Division of Dockets 
Management (see ADDRESSES). It is only necessary to send one set of 
comments. Identify comments with the docket number found in brackets in 
the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday, and will be posted to the docket at https://www.regulations.gov.

XIII. Reference

    The following reference has been placed on display in the Division 
of Dockets Management (see ADDRESSES) and may be seen by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday, and is 
available electronically at https://www.regulations.gov. (FDA has 
verified the Web site address in this reference section, but we are not 
responsible for any subsequent changes to the Web site after this 
document publishes in the Federal Register.)
    1. Transcript of FDA's Microbiology Devices Panel Meeting, June 13, 
2013. (Available at: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/MicrobiologyDevicesPanel/UCM359554.pdf.)

List of Subjects in 21 CFR Part 866

    Biologics, Laboratories, Medical devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 866 be amended as follows:

PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES

0
1. The authority citation for part 866 continues to read as follows:

    Authority:  21 U.S.C. 351, 360, 360c, 360e, 360j, 371.

0
2. Add Sec.  866.3328 to subpart D to read as follows:


Sec.  866.3328  Influenza virus antigen detection test system.

    (a) Identification. An influenza virus antigen detection test 
system is a device intended for the qualitative detection of influenza 
viral antigens directly from clinical specimens in patients with signs 
and symptoms of respiratory infection. The test aids in the diagnosis 
of influenza infection and provides epidemiological information on 
influenza. Due to the propensity of the virus to mutate, new strains 
emerge over time which may potentially affect the performance of these 
devices. Because influenza is highly contagious and may lead to an 
acute respiratory tract infection causing severe illness and even 
death, the accuracy of these devices has serious public health 
implications.
    (b) Classification. Class II. The special controls for this device 
are:
    (1) The device's sensitivity and specificity performance 
characteristics must meet one of the following two minimum clinical 
performance criteria in order to be cleared for marketing and to remain 
on the market:
    (i) If the manufacturer chooses to compare the device to viral 
culture:
    (A) The sensitivity estimate for the device when testing for 
Influenza A must be at least at the 90 percent point estimate with a 
lower bound of the 95 percent confidence interval that is greater than 
or equal to 80 percent. The sensitivity estimate for the device when 
testing for Influenza B must be at least at the 80 percent point 
estimate with a lower bound of the 95 percent confidence interval that 
is greater than or equal to 70 percent.
    (B) The specificity estimate for the device when testing for 
Influenza A and Influenza B must be at least at the 95 percent point 
estimate with a lower bound of the 95 percent confidence interval that 
is greater than or equal to 90 percent.
    (ii) If the manufacturer chooses to compare the device to an 
appropriate molecular comparator method:

[[Page 29392]]

    (A) The positive percent agreement for the device when testing for 
Influenza A and Influenza B must be at least at the 80 percent point 
estimate with a lower bound of the 95 percent confidence interval that 
is greater than or equal to 70 percent.
    (B) The negative percent agreement estimate for the device when 
testing for Influenza A and Influenza B must be at least at the 95 
percent point estimate with a lower bound of the 95 percent confidence 
interval that is greater than or equal to 90 percent.
    (2) When performing testing to demonstrate the device meets the 
requirements in paragraph (b)(1) of this section, a currently 
appropriate and FDA accepted comparator method must be used to 
establish assay performance in clinical studies.
    (3) Annual analytical reactivity testing of the device must be 
performed with contemporary influenza strains. This annual analytical 
reactivity testing must meet the following criteria:
    (i) The appropriate strains to be tested will be identified by FDA 
in consultation with the Centers for Disease Control and Prevention 
(CDC) and sourced from CDC or a CDC-designated source. If the annual 
strains are not available from CDC, FDA will identify an alternative 
source for obtaining the requisite strains.
    (ii) The testing must be conducted according to a standardized 
protocol considered and determined by FDA to be acceptable and 
appropriate.
    (iii) By July 31 of each calendar year, the results of the last 3 
years of annual analytical reactivity testing must be included as part 
of the device's labeling. If a device has not been on the market long 
enough for 3 years of annual reactivity testing since the device was 
given marketing authorization, then the results of every designated 
annual reactivity testing since the device was given marketing 
authorization by FDA, including the results of annual analytical 
reactivity testing performed on the viral strains provided that 
calendar year, must be included. The results must be presented as part 
of the device's labeling in a tabular format, which includes the 
detailed information for each virus tested as described in the 
certificate of authentication, either by:
    (A) Placing the results directly in the device's Sec.  809.10(b) of 
this chapter compliant labeling in a section of the labeling devoted to 
annual analytical reactivity testing; or
    (B) Providing a hyperlink in a section of the device's labeling to 
the manufacturer's public Web site where the annual analytical 
reactivity testing data can be found. If this option is chosen, the 
manufacturer's home page must publicly provide a hyperlink, which can 
easily be found and executed, to the annual analytical reactivity 
testing results and the Web page containing those annual analytical 
reactivity testing results must allow unrestricted viewing access. This 
includes being easy to locate the results from the primary part of the 
manufacturer's Web site that discusses the device.
    (4) If an emergency, or a potential emergency, is declared by the 
Secretary of Health and Human Services (HHS) for an influenza viral 
strain:
    (i) Within 30 days from the date that FDA notifies manufacturers 
that characterized viral samples are available for test evaluation, the 
manufacturer must have testing performed on the device with that viral 
strain according to a standardized protocol considered and determined 
by FDA to be acceptable and appropriate. The procedure and location of 
testing may depend on the nature of the emerging virus.
    (ii) Within 60 days from the date that CDC first makes 
characterized viral samples available to manufacturers and continuing 
until the emergency, or potential emergency, is declared by the 
Secretary of HHS to be over, the results of the influenza emergency 
analytical reactivity testing, including the detailed information for 
the virus tested as described in the certificate of authentication, 
must be included as part of the device's labeling in a tabular format, 
either by:
    (A) Placing the table directly in the device's Sec.  809.10(b) of 
this chapter compliant labeling in the section of the labeling devoted 
to annual analytical reactivity testing and influenza emergency 
analytical reactivity testing but separate from the annual analytical 
reactivity testing tables; or
    (B) Providing a hyperlink in a section of the device's labeling 
devoted to annual analytical reactivity testing and influenza emergency 
analytical reactivity testing to a part of the manufacturer's public 
Web site where the annual and the emergency analytical reactivity 
testing data can be found. If this option is chosen, the manufacturer's 
home page must publicly provide a hyperlink, which can easily be found 
and executed, to the analytical reactivity and emergency testing 
results and the Web page containing those annual analytical reactivity 
testing results must allow unrestricted viewing access.

    Dated: May 14, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-11635 Filed 5-21-14; 8:45 am]
BILLING CODE 4160-01-P