[Federal Register Volume 82, Number 8 (Thursday, January 12, 2017)]
[Rules and Regulations]
[Pages 3609-3619]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-00199]


=======================================================================
-----------------------------------------------------------------------

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: Final order.

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

SUMMARY: The Food and Drug Administration (FDA) is reclassifying 
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.

[[Page 3610]]


DATES: This order is effective February 13, 2017. See further 
discussion in section IV, ``Implementation Strategy.''

FOR FURTHER INFORMATION CONTACT: Stefanie Akselrod, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, Rm. 5438, 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), 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 section 513(d) of the FD&C Act, devices that were in 
commercial distribution before the enactment of the 1976 amendments on 
May 28, 1976 (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 
automatically classified by section 513(f) of the FD&C 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, in accordance with section 
513(i) of the FD&C Act, to a predicate device that does not require 
premarket approval.
    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 the same intended use as 
the predicate device and 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 questions of safety 
or effectiveness than the predicate device. The Agency determines 
whether new devices are substantially equivalent to predicate devices 
by means of premarket notification (510(k)) procedures in section 
510(k) of the FD&C Act (21 U.S.C. 360(k)) and part 807 (21 CFR part 
807).
    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.
    On July 9, 2012, FDASIA was enacted. Section 608(a) of FDASIA 
amended section 513(e) of the FD&C Act, changing the mechanism for 
reclassifying a device from rulemaking to an administrative order. 
Section 513(e) of the FD&C Act 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. U.S. Dep't of 
Health, Educ., 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, 388-91 (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) of the FD&C Act and 21 CFR 860.7(c)(2). See, e.g., Gen. Med. 
Co. v. FDA, 770 F.2d 214 (D.C. Cir. 1985); Contact Lens Mfrs. Ass'n. v. 
FDA, 766 F.2d 592 (D.C. Cir.), cert. denied, 474 U.S. 1062 (1986).
    Section 513(e)(1) of the FD&C Act sets forth the process for 
issuing a final order for reclassifying a device under that section. 
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 published a proposed order to 
reclassify this device type in the Federal Register of May 22, 2014 (79 
FR 29387). FDA has held a meeting of a device classification panel 
described in section 513(b) of the FD&C Act with respect to antigen 
based rapid influenza diagnostic test (RIDT) systems and has also 
received and considered comments on the proposed order, as discussed in 
section II. Therefore, FDA has met the requirements under section 
513(e)(1) of the FD&C Act.

II. Public Comments in Response to the Proposed Order

    On May 22, 2014, FDA published a proposed order to reclassify 
antigen based RIDTs 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 (79 FR 29387).
    The Agency received comments on the proposed order from several 
entities. Comments were received from device industry manufacturers, a 
consumer group, professional organizations, a health care organization, 
a device manufacturers association, and an individual consumer.
    To make it easier to identify comments and our responses, the word 
``Comment'' and a comment number appear in parentheses before each 
comment's description, and the word ``Response'' in parentheses 
precedes each response. Similar comments are grouped together under the 
same number. Specific issues raised by the comments and the Agency's 
responses follow.

[[Page 3611]]

A. General Comments

    (Comment 1) Commenters expressed support for the proposed order to 
reclassify antigen based RIDTs from class I to class II with special 
controls, noting that there is evidence that the currently available 
antigen based RIDTs, which are widely used in non-clinical laboratory 
settings such as physician office laboratories, are performing poorly, 
resulting in many misdiagnosed cases of influenza. Commenters noted 
that a misdiagnosis of influenza may have serious consequences, 
including: Inappropriate use of antibiotics and failure to use 
antiviral therapy, which may be critical for some patients, following 
false negative results; the unnecessary or inappropriate prescribing of 
antiviral drugs following false positive results; ineffective infection 
control measures; and an overall increased public health burden, such 
as increased rate of hospitalization and return doctor visits. Several 
commenters expressed a concern regarding frequent antigenic changes in 
the circulating strains as the influenza virus evolves and agreed with 
the new requirement that manufacturers conduct annual analytical 
testing of circulating strains in an effort to monitor the performance 
of these tests over time. Overall, there was a general consensus among 
the commenters that the proposed special controls address and mitigate 
the risks to health.
    (Response) FDA agrees that reclassification of antigen based RIDTs 
into class II as outlined in this order will help to improve the 
overall quality of testing for influenza. The new minimum performance 
requirements for these tests detecting influenza virus antigens are 
expected to lower the number of misdiagnosed influenza infections by 
increasing the number of devices that can reliably detect the influenza 
virus. In addition, the special controls requiring annual and emergency 
analytical reactivity testing provide a process for continued 
monitoring of the performance of antigen based RIDTs. As part of that 
process, the Centers for Disease Control and Prevention (CDC) and FDA 
will collaborate in efforts to ensure that there is an influenza virus 
analytical reactivity test panel available to all manufacturers of 
antigen based RIDTs for evaluation of the analytical reactivity of 
their assays with circulating viruses on an annual basis.
    (Comment 2) One commenter noted that under the FD&C Act, as amended 
by FDASIA, FDA is able to reclassify a device via an ``order rather 
than rulemaking,'' but the commenter expressed a concern that FDA seems 
to consider holding a panel meeting after the issuance of a proposed 
order as ``discretionary rather than mandatory.'' The commenter urged 
FDA to hold panel meetings after the issuance of proposed 
reclassification orders in order to allow the panel to discuss the 
proposal after it has been issued. The commenter stated that holding a 
panel meeting following issuance of a proposed reclassification order 
is a critical element of the process reforms enacted by Congress. In 
addition, the commenter expressed a concern that the Agency has not 
obtained sufficient feedback from physicians who commonly use the rapid 
influenza tests in their practice. Therefore, the commenter suggested 
that FDA should convene another panel meeting and include these 
physicians to provide critical expertise and perspective on the overall 
evaluation of FDA's proposed plans on test reclassification, including 
the analytical reactivity testing protocol, specifications, and 
qualification of specimens.
    (Response) The June 13, 2013, Microbiology Advisory Panel 
(``Panel'') meeting considered all relevant scientific issues 
associated with the proposed order for the antigen based RIDTs and 
recommended reclassifying these devices into class II (special 
controls). The Panel included six physicians and seven researchers who 
provided input that FDA considered for purposes of the proposed order, 
including the proposed special controls. Each of the Panel members is 
considered an authority on matters of influenza infection, treatment, 
epidemiology, and/or biology. Representatives from CDC and the 
Association of Public Health Laboratories presented extensive data on 
the use of the currently available antigen based RIDTs and the outcomes 
related to patients that support the conclusion that there has been 
poor performance of antigen based RIDTs in the medical practice. The 
Panel recommended the reclassification of antigen based RIDTs. FDA is 
not aware of any significant changes in benefits or risks relating to 
the antigen based RIDTs that have been identified since the June 13, 
2013, Panel meeting. Stakeholders had an opportunity to provide 
feedback to the proposed order in their comments, and that feedback has 
been largely positive. The public comments are addressed here and are 
also available to view by request or on https://www.regulations.gov.
    The process followed by FDA in reclassifying antigen based RIDTs is 
in accordance with the applicable statutory provisions, which were 
amended by FDASIA. Section 608 of FDASIA amended section 513(e) of the 
FD&C Act by changing the reclassification process from rulemaking to an 
administrative order process. The amendments to section 513(e) of the 
FD&C Act made by FDASIA require, in relevant part, that issuance of an 
administrative order reclassifying a device be preceded by a proposed 
order and a meeting of a device classification panel.
    As amended, section 513(e) of the FD&C Act does not prescribe when 
these two events (the panel meeting and proposed order) must occur in 
relation to each other. Therefore, under this provision, the Agency may 
hold a panel meeting either before or after the issuance of a proposed 
reclassification order. This approach is consistent with the prior 
panel provision in section 513(e) of the FD&C Act, which provided for 
FDA, at its discretion, to secure a panel recommendation prior to the 
promulgation of a reclassification rule. Generally, for future 
reclassifications under section 513(e) of the FD&C Act for which a 
meeting of a device classification panel has not yet occurred, FDA 
expects a proposed reclassification order will be issued prior to the 
panel meeting required under section 513(e).

B. Transition Period

    (Comment 3) While one commenter expressed agreement that the 
proposed 1 year timeframe should be sufficient for manufacturers to 
bring devices already on the market into compliance with the special 
controls, another commenter suggested that FDA consider providing 
additional transition time for the implementation of the final order. 
The commenter suggested that this would assist manufacturers who are 
working in good faith to meet the new requirements to prepare 
submissions in advance of the influenza season and would provide for 
product continuity among health care providers. The commenter did not 
identify why 1 year would be an insufficient period of transition time.
    (Response) The Panel recommended and FDA made the determination 
that special controls, including the new minimum performance 
requirements, are needed, in addition to general controls, to provide 
reasonable assurance of safety and effectiveness for antigen based 
RIDTs. We, therefore, do not believe, given the risk that poor 
performance of antigen based RIDTs pose to public health, a delay in 
implementation of more than 1 year is appropriate. FDA also understands 
the need for a balanced approach that takes into account the time it 
will take for

[[Page 3612]]

manufacturers to come into compliance with the special controls and 
seeks to avoid disruption of access to these devices. With these 
considerations in mind, FDA believes that a period of 1 year from the 
publication date of this final order is appropriate for manufacturers 
to come into compliance with the special controls and for those 
manufacturers whose currently legally marketed devices do not meet the 
minimum performance criteria to prepare and submit a 510(k) for a new 
or significantly changed or modified device. Therefore, FDA does not 
intend to enforce compliance with the special controls with respect to 
currently legally marketed antigen based RIDT devices until 1 year 
after the date of publication of this final order. FDA believes this 
approach will help ensure the efficient and effective implementation of 
the final order.

C. Clinical Performance Standards and Comparator Methods

    (Comment 4) One comment recommended a transition to one common 
reference method comparator: A molecular nucleic acid-based method. The 
reasons cited for this recommendation included: (1) A level playing 
field for all manufacturers and (2) better clarity for users, industry, 
and the Agency. Another comment raised concerns about the unreliability 
of the culture results due to non-standardized culture practices. In 
addition, a commenter cautioned that providing two minimum performance 
standards, one when compared to viral culture and another when compared 
to a nucleic acid-based method, may have unintended consequences: (1) 
Users may make false assumptions and choose a method based strictly on 
the presented estimates of sensitivity and specificity without noting 
the comparator reference method that was used to derive the performance 
measures and (2) manufacturers may elect to conduct the method 
comparison using both types of reference methods and submit the results 
in support of a 510(k) even if only one of the comparisons meets the 
minimum performance bar.
    (Response) FDA appreciates the concern over the potential 
consequences of allowing for the two performance levels based on 
different comparator methods. The Agency carefully considered the 
public feedback as well as the implications of eliminating the viral 
culture comparator method as an acceptable comparator method used in 
the evaluation of clinical performance of antigen based RIDTs. Some 
important considerations were: (1) A lack of standardization of viral 
culture methods among various laboratories, (2) an increasing 
difficulty in procuring the services of a laboratory that is equipped 
to perform viral culture procedures, (3) the wide availability of FDA-
cleared nucleic acid-based comparator methods among laboratories, (4) 
the demonstrated high sensitivity of the nucleic acid-based methods 
when compared to viral culture method (when properly performed) for the 
detection of the influenza viruses, and (5) the reliability of the 
viral culture method when performed properly.
    In addition, we recognize that performance evaluation based on two 
different comparators where each detects a different analyte (viral 
culture methods detect viable virus particles while nucleic acid-based 
methods detect the viral ribonucleic acids) requires two sets of 
performance criteria resulting in performance measures that may not 
allow for direct comparison between some devices. However, viral 
culture method, when performed correctly, has been shown historically 
to be accurate and remains a valid reference method for the detection 
of influenza viruses. There are many influenza detecting devices 
currently on the market that have been evaluated based on comparison 
with viral culture comparator methods and met the performance criteria 
set forth in Sec.  866.3328(b)(1)(ii) (21 CFR 866.3328). FDA has also 
stated expressly in the special controls that a viral culture 
comparator method used to demonstrate that a device meets the minimum 
performance criteria at Sec.  866.3328(b)(1)(ii) must be correctly 
performed.
    At this time, the only currently appropriate and FDA accepted 
comparator methods are: (1) An FDA-cleared nucleic acid-based test or 
(2) a correctly performed viral culture method. However, FDA recognizes 
that a comparator method at least as accurate as FDA-cleared nucleic 
acid-based tests in the detection of the influenza viruses may be 
established in the future. Based on that recognition and the available 
information, the final order clarifies that other comparator methods, 
if currently appropriate and FDA accepted, could be used to demonstrate 
that the performance criteria requirements in Sec.  866.3328(b)(1)(i) 
have been met. Therefore, if FDA determines at some point in the future 
that another comparator method at least as accurate as FDA-cleared 
nucleic acid-based tests has been established as a currently 
appropriate comparator method, sponsors of premarket submissions for 
antigen based RIDTs would have the option of demonstrating that their 
devices meet the minimum performance criteria at Sec.  
866.3328(b)(1)(i) based on a comparison to that additional currently 
appropriate and FDA-accepted comparator method.
    (Comment 5) Another commenter cautioned that the performance 
estimates shown in the package inserts for these tests may be biased 
due to the fact that the data have been generated under closely 
controlled clinical trial procedures that use optimal sample types, a 
time of sample collection post onset of symptoms, proper sample 
storage, and time to testing. Because these conditions are often not 
maintained in daily clinical use, the true performance of these assays 
in ``real life'' settings may be different.
    (Response) FDA acknowledges that the performance data in the device 
labeling are estimates. All assays are subject to variation under real-
life circumstances when the assays are used in clinical practice. 
However, FDA believes that premarket studies demonstrating performance 
for these devices should include a variety of testing sites 
representative of the settings in which the device will be used and 
that a sufficient number of clinical specimens should be tested to 
arrive at reasonable measures of confidence in the calculated 
performance estimates (i.e., the lower bound of the two-sided 95 
percent confidence interval (calculated by the Score method)), as 
outlined in the guidance document entitled ``Establishing the 
Performance Characteristics of In Vitro Diagnostic Devices for the 
Detection or Detection and Differentiation of Influenza Viruses'' 
(http://www.fda.gov/RegulatoryInformation/Guidances/ucm079171.htm) 
(``2011 Influenza Guidance document'').
    (Comment 6) One commenter suggested that the proposed sensitivity 
criteria for influenza A for antigen based RIDTs, when using a 
molecular method as a comparator method, are less stringent than those 
recorded in the 2011 Influenza Guidance document. The commenter stated 
that it:

    [I]s not clear . . . why the Special Controls for comparison to 
a molecular method has become less stringent (sensitivity/PPA 
estimate for Influenza A reduced from a point estimate of 90 percent 
with a 95 percent CI lower bound of 80 percent, to a point estimate 
of 80 percent with a 95 percent CI lower bound of 70 percent) when 
the intention of a Special Controls document would presumably be 
thought to make comparative criteria tighter overall.

    The commenter made a reference to the statement in section 9.B.iii, 
pages 26-27 of the 2011 Influenza Guidance

[[Page 3613]]

document (3d bullet), that states: ``Nucleic acid-based tests should 
demonstrate at least 90% sensitivity for each analyte and each specimen 
type with a lower bound of the two-sided 95% CI greater than 80%.'' The 
commenter also questioned whether this determination was discussed and 
used to scientifically justify the different criteria for sensitive 
molecular methods, including polymerase chain reaction, which detect 
inactive virus in the absence of viable viral particles in a sample, 
and for viral detection in general when using a molecular comparative 
method.
    (Response) The quoted statement from the 2011 Influenza Guidance 
document refers to the performance of nucleic acid-based devices, while 
the performance criteria stated in the May 22, 2014, proposed order (79 
FR 29387 at 29390) (Section VIII. Special Controls: . . . If the 
manufacturer chooses to compare the device to an appropriate molecular 
comparator method: 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) refer to RIDTs 
based on antigen detection, which are historically known to have a more 
limited sensitivity due to the properties of the enzyme immunoassay 
(EIA) technology. The relevant citation pertaining to the performance 
of the rapid devices detecting influenza virus antigens may be found in 
section 9.B.iii, pages 26-27 (1st and 2d bullet) of the 2011 Influenza 
Guidance document, which states:

    For rapid devices detecting influenza A virus antigen, we 
recommend that you include a sufficient number of prospectively 
collected samples for each specimen type claimed to generate a 
sensitivity result with a lower bound of the two-sided 95% CI 
greater than 60%. . . . For rapid devices detecting influenza B 
virus antigen, we recommend that you include a sufficient number of 
samples for each claimed specimen type to generate a result for 
sensitivity with a lower bound of the two-sided 95% CI greater than 
55%.

    Nucleic acid-based assays that test for influenza are regulated 
under Sec.  866.3980, Respiratory viral panel multiplex nucleic acid 
assay, and have been held to higher performance criteria than antigen 
based RIDTs because of their demonstrated ability to reach higher 
sensitivity for viral detection. By establishing special controls with 
minimum performance criteria for antigen based RIDTs, this final order 
raises the required minimum performance criteria for viral detection by 
the EIA based tests beyond the recommendations set forth in the 2011 
Influenza Guidance Document. Nucleic acid-based tests continue to be 
subject to the document entitled ``Class II Special Controls Guidance: 
Respiratory Viral Panel Multiplex Nucleic Acid Assay'' (http://www.fda.gov/RegulatoryInformation/Guidances/ucm180307.htm), except when 
the device detects and differentiates Influenza A subtype H1 and 
subtype H3, in which case they are also subject to the document 
entitled ``Class II Special Controls Guidance Document: Testing for 
Detection and Differentiation of Influenza A Virus Subtypes Using 
Multiplex Nucleic Acid Assays'' (http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm180310.pdf).
    (Comment 7) One commenter criticized FDA for providing no 
specifications for how to design a clinical performance study for 
antigen based RIDT systems in terms of the proportion of samples that 
should be presented for each age group. In addition, the comment 
suggested that the performance estimates of different devices presented 
in their package inserts may be biased due to the actual proportions of 
age groups in the study (i.e., children vs. adults) and may not be 
truly reflective of the performance in the population overall. The 
commenter further suggested that the number of positive samples as well 
as sensitivity and specificity (or positive percent agreement (PPA)/
negative percent agreement (NPA)) for each age group be presented in 
each device's Instructions for Use to ensure transparency.
    (Response) FDA's current recommendations for appropriate study 
design can be found in the 2011 Influenza Guidance document, where 
section 9.B.ii mentions that there should be a representative number of 
positive samples (determined by the reference method) from each age 
group and [the data should be presented] stratified by age (e.g., 
pediatric populations aged birth to 5 years, 6 to 21 years, . . . 
adults aged 22-59, and greater than 60 years old) in addition to the 
overall data summary table.
    In addition, the 2011 Influenza Guidance document recommends 
diversifying the location of the selected clinical sites and the 
anticipated prevalence of influenza at the time of the study. Depending 
on the site selection, the age composition of the subjects will vary, 
but it is difficult to predict the different age groups at the outset 
of a study. FDA evaluates assay performance estimates stratified by age 
groups and determines whether the performance among different age 
groups is similar before making the final decision regarding 510(k) 
clearance. FDA encourages sponsors to use the pre-submission program to 
discuss the premarket submission strategy and study design for their 
specific devices. The pre-submission program is described in the 
guidance document titled ``Requests for Feedback on Medical Device 
Submissions: The Pre-Submission Program and Meetings with Food and Drug 
Administration Staff'' found on FDA's Web site at http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm311176.pdf.
    (Comment 8) A commenter also suggested that the proposed special 
controls do not clearly state that data demonstrating that a device 
meets the clinical performance criteria be obtained using prospective, 
fresh samples and that this may be easily remedied by adding a 
statement in the final special controls document indicating that 
``clinical performance studies should be carried out on fresh, 
prospective samples.''
    (Response) The 2011 Influenza Guidance Document, in section 9.B.iii 
Specimens, on p. 27, states that: ``[w]e recommend that you assess the 
ability of your device to detect influenza viruses in fresh specimens 
collected from patients suspected of having an influenza infection who 
have been sequentially enrolled in the study (all-comers study)''. The 
guidance further states that ``[f]rozen archived specimens may be 
useful for analytical performance evaluations, but are not recommended 
for studies to calculate clinical sensitivity or specificity''.
    As the incidence of influenza varies from year to year and also 
from region to region, testing of archived specimens may be acceptable 
where fresh positive specimens are difficult to obtain. Performance 
data obtained from testing retrospective archived samples are generally 
evaluated and presented separately from data obtained with 
prospectively collected specimens in the final device labeling.
    (Comment 9) A further recommendation was made that the proposed 
special controls include explicit wording to clarify that clinical 
performance criteria must be met for each sample type claimed in the 
proposed labeling submitted for clearance.
    (Response) FDA agrees with this recommendation. The proposed 
special controls have been modified to clarify that clinical 
performance criteria must be met for each specimen type claimed in the 
intended use of the device.

[[Page 3614]]

    (Comment 10) One commenter asserted that the proposed acceptance 
criteria for devices choosing to use viral culture as a comparator have 
been determined using certain generalizations that can confound the 
data. Referring to the Executive Summary document prepared for the 
Panel meeting (Ref. 1), the commenter states that, for example, all 
sample types and age ranges were included in the overall presentation 
of sensitivity for various devices. The commenter objected that the 
performance criteria, as presented in the Executive Summary document, 
appear to have been subjectively defined. The commenter further 
suggested that the purpose of tables 1 and 2 in the Executive Summary 
was to imply that any device cleared prior to 2008 is assumed to have 
variable and unacceptable performance, and that the performance 
criteria for antigen based RIDTs were chosen specifically with the 
intention of removing those devices from use. Additionally, the 
commenter stated that the information, as presented in the publicly 
available Executive Summary, did not make it clear that the data were 
confounded and created an unfair marketing advantage for some 
manufacturers.
    (Response) The summary data tables presented in the Executive 
Summary document submitted to the Panel in June 2013 were compiled to 
illustrate the range in clinical performance among the antigen based 
RIDTs available on the market in support of the reclassification effort 
and were not aimed to remove devices cleared before 2008 from the 
market, as the commenter suggests. The data for each assay presented in 
table 1 in the Executive Summary document were based on the information 
provided to FDA in support of the 510(k) submissions for those devices 
and included results from all prospectively collected samples during 
the clinical study conducted by the manufacturer, regardless of the 
specimen type or the age of the patient (Ref. 1). The information in 
this table shows a wide range of assay performances.
    The data presented in table 2 in the Executive Summary document 
were intended to illustrate the even broader range in sensitivity of 
these assays as reported in the scientific literature and derived from 
postmarket studies conducted in the field. The data in table 2 were 
also based on combined results, regardless of sample type, patient age 
and even influenza virus type. Although the commenter may consider the 
data ``confounded,'' they were not meant to demonstrate statistical 
validity but rather to illustrate that some of the currently available 
antigen based RIDTs have clinically poor sensitivity even under the 
controlled conditions of a clinical study conducted in support of a 
regulatory submission. More importantly, the clinical performance of 
these assays in the field, as reported in peer reviewed publications, 
is considerably worse for some of these assays than was demonstrated in 
the studies submitted to FDA to support their clearance. Overall, the 
data contained in the two tables were intended to help illustrate the 
sensitivity of the antigen based RIDTs available on the market, taking 
into consideration the limitations of the available technology. The 
data presented in both tables in the Executive Summary document support 
that improved influenza detection devices are needed to benefit public 
health in detection, treatment, and infection control with regard to 
the influenza viruses.
    (Comment 11) Some commenters inquired about the process for 
notifying manufacturers that their assays do not meet the new 
performance criteria and expressed concern that manufacturers should be 
allowed sufficient transition time to develop new or modified influenza 
detection devices and to submit new 510(k)s for those products.
    (Response) A manufacturer will not be individually notified that 
its product does not comply with the new special controls; each 
manufacturer of an antigen based RIDT is responsible for compliance 
with these special controls, including the minimum performance 
criteria. If an antigen based RIDT device does not meet the new 
performance criteria set forth in this final order, the device may be 
considered adulterated under section 501(f)(1)(B) of the FD&C Act (21 
U.S.C. 351(f)(1)(B)), and manufacturers must cease marketing of the 
device. However, as outlined in section IV, ``Implementation 
Strategy,'' FDA does not intend to enforce compliance with the special 
controls with respect to currently legally marketed antigen based RIDT 
devices until 1 year after the date of publication of this final order. 
A manufacturer may contact the Center for Devices and Radiological 
Health's (CDRH) Division of Microbiology Devices in the Office of In 
Vitro Diagnostics and Radiological Health (OIR) with any specific 
questions.
    (Comment 12) One commenter inquired whether there will be an 
appeals mechanism for manufacturers and what specific steps would be 
available for manufacturers.
    (Response) No new appeals mechanisms will be implemented for those 
manufacturers whose assays do not comply with the new special controls. 
However, there are processes available to outside stakeholders to 
request additional review of decisions or actions by the CDRH. For more 
information, see the FDA guidance document entitled ``Center for 
Devices and Radiological Health Appeals Processes--Guidance for 
Industry and Food and Drug Administration Staff'' (http://www.fda.gov/RegulatoryInformation/Guidances/ucm284651.htm).

D. Annual Analytical Reactivity Testing

1. Access to Strains
    (Comment 13) Commenters expressed concerns about whether all 
manufacturers, regardless of their size or resources, will have equal 
access to the samples needed to conduct the annual analytical 
reactivity testing in compliance with the new special controls. One of 
the commenters noted that there may be challenges to specimen access 
for some manufacturers under the World Health Organization (WHO) 
Pandemic Influenza Preparedness (PIP) Framework as well as potential 
impact on accessing the influenza strains sourced by the WHO Global 
Influenza Surveillance and Response System (GISRS). The commenter asked 
if manufacturers required to perform the annual testing would need to 
participate in the PIP framework to access GISRS specimens. The 
commenter further stated that unless all companies are able to access 
specimens in a fair, timely and non-cost restrictive manner to comply 
with the new postmarket requirements, some innovators may be unable to 
continue to develop new influenza diagnostics.
    (Response) CDC intends to make available an annual analytical 
reactivity test panel, which is an annual standardized seasonal 
influenza virus test panel, so that manufacturers can comply with the 
annual analytical reactivity testing requirement. If the annual strains 
are not available from CDC, FDA will identify an alternative source for 
obtaining the requisite strains. The selection of viruses in the CDC 
annual analytical reactivity test panels is expected to be largely 
based on the strains selected by WHO for the annual vaccine and will be 
distributed for annual analytical reactivity testing or analytical 
validation in support of new 510(k) submissions for antigen based RIDT 
devices. We expect that the panel will primarily consist of human 
viruses that circulated in the recent influenza seasons. FDA and CDC do 
not believe that manufacturers will need to enter

[[Page 3615]]

agreements under the PIP Framework to access influenza viral strains in 
the manner described in this final order for the sole purpose of 
conducting testing to comply with the special controls at Sec.  
866.3328(b)(3) and (4). The annual analytical reactivity test panel 
will be made available to manufacturers at the same time, including 
those that require it for the annual analytical reactivity testing as 
well as those who are developing new or modified influenza assays. CDC 
and FDA are committed to facilitating equal access for manufacturers to 
the annual analytical reactivity test panel and are prepared to 
consider any unforeseen circumstances in an equitable manner.
    (Comment 14) Another commenter expressed a concern regarding 
whether the requisite strain(s) will be made available in sufficient 
time to allow manufacturers to conduct the studies and have the data 
available in the labeling or on the manufacturer's Web site within the 
timeframe specified for both annual and emergency analytical reactivity 
testing. The comment stated that for most manufacturers, the process of 
testing and making a change in labeling would take a minimum of 90 days 
from receipt of samples.
    (Response) Under the new special controls, the results of the last 
3 years of annual analytical reactivity testing conducted from the date 
that the device was given marketing authorization by FDA must be 
incorporated into the device's labeling in the manner discussed in 
Sec.  866.3328(b)(3)(iii) by July 31 of each calendar year. CDC and FDA 
are committed to making available or designating an alternative source 
for the annual analytical reactivity test panel with sufficient time 
for all manufacturers to conduct the testing and include the results in 
their device's labeling within the required timeframe.
    Similarly, in the case of emergency analytical reactivity testing, 
as described in the special controls at Sec.  866.3328(b)(4), after CDC 
makes the viral samples available for testing, FDA will notify the 
manufacturers of the availability of the samples. The manufacturers 
will have 60 days to perform the testing of the viral samples and to 
incorporate the results into the device's labeling in the manner 
discussed in Sec.  866.3328(b)(4)(ii). If a manufacturer is concerned 
about meeting these timelines due to time needed to amend device 
labeling that physically accompanies the device, the manufacturer may 
pursue the Sec.  866.3328(b)(3)(iii)(B) and (b)(4)(ii)(B) alternatives, 
which allow manufacturers to provide the results as electronic labeling 
via the manufacturer's public Web site that can be reached via a 
hyperlink found in the device's label or in other labeling that 
physically accompanies the device. If a manufacturer chooses the option 
to post analytical reactivity testing results on its Web site, it would 
be subject to the requirements of section 502(f) of the FD&C Act (21 
U.S.C. 352(f)) that provides that required labeling for prescription 
devices intended for use in health care facilities or by a health care 
professional and required labeling for in vitro diagnostic devices 
intended for use by health care professionals or in blood 
establishments may be made available solely by electronic means as long 
as the labeling complies with the law, and that the manufacturer 
affords users the opportunity to request the labeling in paper form, 
and that after a request, promptly provides the requested information 
without additional cost.
    If a manufacturer provides the hyperlink to a public Web site at 
which annual analytical reactivity and emergency testing data may be 
viewed, generally no updates would be needed to the labeling that 
physically accompanies the device when meeting the annual analytical 
reactivity testing requirements under Sec.  866.3328(b)(3) or the 
emergency analytical reactivity testing requirements under Sec.  
866.3328(b)(4). If annual or emergency analytical reactivity testing 
reveals that the device is unable to detect one or more strains, the 
manufacturer would need to include a limitation in the device labeling, 
as further discussed in our response to Comment 21.
2. Acquisition of the Annual Analytical Reactivity Test Panel and 
Reporting of Results
    (Comment 15) Commenters expressed concern about the logistics of 
the implementation of the new requirement for the annual analytical 
reactivity testing. One commenter stated that a clear mechanism was not 
outlined in the proposed order for activities leading to the reporting 
of results.
    (Response) The activities leading to the reporting of results will 
include acquisition of the annual analytical reactivity test panel and 
analytical reactivity testing following the standardized protocol 
included with the test panel, which will be a standardized protocol 
considered and determined by FDA to be acceptable and appropriate. 
Results must be reported by updating the device's labeling in 
accordance with Sec.  866.3328(b)(3)(iii). As previously stated, CDC 
and FDA are committed to working with the manufacturers of the 
influenza tests to facilitate timely and equitable access to the 
influenza virus annual analytical reactivity test panel. CDC has 
developed a Web site (http://www.cdc.gov/flu/dxfluviruspanel/index.htm) 
where the manufacturers can affirm their need for the annual analytical 
reactivity test panel, referred to by CDC as the ``CDC Influenza Virus 
Panel,'' to comply with the annual analytical reactivity testing 
requirement. The CDC panel will be distributed along with certificates 
of analyses for the viruses and a standardized testing protocol, 
considered and determined by FDA to be acceptable and appropriate, 
instructing the user on handling and testing of the provided virus 
stocks in the test panel. There are currently no plans to post the 
analytical reactivity testing data generated by the manufacturers on 
the CDC Web site. For any questions related to the test procedure, 
manufacturers may contact CDC or FDA as specified in the information 
included with the influenza virus analytical reactivity test panel. CDC 
will serve as the contact for questions pertaining to viruses, and FDA 
will serve as the contact for all regulatory and reporting issues.
    (Comment 16) Commenters expressed concern about the continued 
availability of the test panel from CDC due to the future potential for 
limited resources at CDC or FDA.
    (Response) In a case where the influenza virus analytical 
reactivity test panel is not available from CDC due to unforeseen 
limitations in resources, an alternate source of influenza strains for 
use in conducting the annual analytical reactivity testing will be 
identified by FDA, in consultation with CDC. An example of an alternate 
source could be a commercial vendor that specializes in acquisition, 
authentication, production, and preservation of microorganisms.
    (Comment 17) Commenters suggested that the industry should be 
engaged for feedback in the development of the standardized testing 
protocol.
    (Response) A standardized protocol has been developed by CDC in 
consultation with FDA and will be provided to manufacturers with the 
annual analytical reactivity test panel. The protocol uses basic 
principles for working with virus stocks and is general enough to allow 
for use with various devices. For any questions related to the testing 
procedure, manufacturers can contact CDC or FDA. CDC will serve as the 
contact for questions pertaining to viruses, and FDA will serve as the 
contact for all regulatory and reporting issues.
    (Comment 18) One commenter inquired whether the analytical 
reactivity testing could be conducted using a modified limit of 
detection

[[Page 3616]]

(LoD) protocol, where 60 replicates are tested over 3 dilutions with 
positivity rates between 80 and 99 percent followed by linear 
regression to calculate the specific concentration that corresponds to 
a positivity rate of 95 percent.
    (Response) This approach is acceptable to use in the determination 
of a LoD of an antigen based RIDT assay. However, manufacturers must 
follow the protocol included with the influenza virus analytical 
reactivity test panel, which will be a standardized protocol considered 
and determined by FDA to be acceptable and appropriate. We believe the 
standardized protocol will be less burdensome than this commenter's 
proposal and will help ensure that the results generated allow for 
comparability between different devices, as all devices will have 
followed a common standardized testing protocol.
    (Comment 19) One commenter asked whether interested manufacturers 
would have an option to have the testing conducted by an independent 
laboratory, such as a laboratory at a university.
    (Response) Yes, a manufacturer may contract an outside laboratory 
to conduct the testing on its behalf.
    (Comment 20) One commenter raised a concern that customers without 
access to a manufacturer's Web site may not be able to access the 
annual and/or emergency analytical reactivity testing information; 
therefore, the commenter suggested that an alternate method of contact 
should be provided in the product labeling.
    (Response) All in vitro diagnostic devices are required by 
regulation to state on the label and in the product labeling the name 
and place of business of the manufacturer, packer, or distributor Sec.  
809.10(a)(8) and (b)(14) (21 CFR 809.10(a)(8) and (b)(14)), except 
where such information is not applicable, or as otherwise specified in 
a standard for a particular product class.
    In addition, in accordance with Sec.  866.3328(b)(3)(iii) the 
results of the annual analytical reactivity testing must either be in 
the Sec.  809.10(b) compliant labeling that physically accompanies the 
device or be provided as electronic labeling via the manufacturer's 
public Web site that can be reached via a hyperlink prominently found 
in the device's label or in other labeling that physically accompanies 
the device. If the manufacturer chooses the Web site option, it would 
be subject to the requirements of section 502(f) of the FD&C Act, which 
provides that required labeling for prescription devices intended for 
use in health care facilities or by a health care professional and 
required labeling for in vitro diagnostic devices intended for use by 
health care professionals or in blood establishments may be made 
available solely by electronic means, as long as the labeling complies 
with the law, and that the manufacturer affords users the opportunity 
to request the labeling in paper form, and that after a request, 
promptly provides the requested information without additional cost. 
Therefore, a manufacturer is already required to provide an opportunity 
for a health care professional to request the annual analytical 
reactivity test results in paper form.
    (Comment 21) One commenter raised a question about notifying the 
public when a test is non-reactive with any of the strains included in 
the influenza virus analytical reactivity test panel provided by CDC 
and whether the product labeling will be updated annually. In 
particular, the commenter questioned how labeling changes to reflect 
absence of reactivity would be communicated to users who have already 
purchased the test.
    (Response) This final order requires that the results of the last 3 
years of annual analytical reactivity testing conducted from the date 
that the device was given marketing authorization by FDA be included as 
part of the device's labeling by July 31 of each calendar year. 
Modification of the labeling solely to incorporate analytical 
reactivity testing results required under Sec.  866.3328(b)(3)(iii) or 
(b)(4)(ii) can be made without an official submission to FDA. In a case 
where one or more strains are shown not to be detected by the device 
during annual analytical reactivity testing under Sec.  866.3328(b)(3) 
or emergency analytical reactivity testing under Sec.  866.3328(b)(4), 
the manufacturer will need to include a limitation in the device 
labeling regarding reactivity with the specific strain(s) that were not 
detected by the device. Without such a limitation, the device would not 
meet the labeling requirements of Sec.  809.10(b).
    (Comment 22) One commenter raised a question about whether there 
will be a guidance document issued on a yearly basis to interpret the 
results of the analytical reactivity testing for that year.
    (Response) FDA does not intend to issue a guidance document on how 
to interpret the results of the analytical reactivity testing each 
year, as the result interpretations are stated in the CDC information 
sheet that will be distributed with the CDC annual analytical 
reactivity test panel. The annual analytical reactivity testing is 
intended to evaluate whether the assay detects each strain included in 
the annual analytical reactivity test panel; however, that testing does 
not provide direct information about how the assay performs when used 
with clinical specimens that are collected directly from patients. Any 
positive result obtained during analytical reactivity testing performed 
with the annual influenza virus analytical reactivity test panel, at 
any viral concentration/dilution, indicates that the assay is reactive 
with that virus; however, the minimal concentration of the virus that 
is needed for the detection (assay sensitivity) may vary. Since the 
difference in analytical reactivity does not necessarily translate into 
an appreciable difference in performance when testing clinical 
specimens, it is important to emphasize that the results should not be 
over-interpreted for clinical purposes.
    (Comment 23) One commenter suggested further collaboration between 
the Agency and influenza test manufacturers in establishing the 
regulatory process for implementing the labeling change before a final 
``Notice to Industry'' or other document is published. The commenter 
further recommended that FDA specify an interactive process, whereby 
individual manufacturers can seek guidance, particularly if they 
encounter issues that may impede timely publication of annual and 
emergency analytical reactivity testing data (e.g., if the matrix used 
in the preparation of the virus strains in the test panel causes 
invalid results with a particular device).
    (Response) Interactive communication with manufacturers is common 
practice among the reviewers and the managers in CDRH. Manufacturers 
are encouraged to contact CDRH's OIR with questions or about issues 
related to the new requirements. In addition, the CDRH pre-submission 
program is designed to allow sponsors the opportunity to obtain 
targeted FDA feedback in response to specific questions related to 
product development, including planned non-clinical evaluations, 
proposed clinical study protocols, or data requirements prior to making 
a submission to the Agency.

E. Timely Testing of Newly Emergent Strains

    (Comment 24) Similar concerns to those surrounding the annual 
reactivity testing requirement were raised in regard to the emergency 
testing of emergent strains. In addition, one comment expressed support 
for specifying a timeline for reporting the results after the samples 
become available.

[[Page 3617]]

    (Response) Section 866.3328(b)(4)(ii) requires that, in certain 
emergency or potential emergency situations involving an influenza 
viral strain, the results of analytical reactivity testing with the 
emerging virus(es) must be made available within 60 days from the date 
that FDA notifies antigen based RIDT manufacturers that characterized 
viral samples are available. The results of the influenza emergency 
analytical reactivity testing must be disclosed in a tabular format in 
a similar manner as the results of the annual analytical reactivity 
testing (i.e., either by placing the table directly in the device's 
Sec.  809.10(b) compliant labeling that physically accompanies the 
device in the section of the labeling devoted to analytical reactivity 
testing, or in a section of the device's label or in labeling that 
physically accompanies the device, by prominently providing a hyperlink 
to a part of the manufacturer's Web site where the analytical 
reactivity testing data can be found). As previously discussed, 
modification of the labeling solely to incorporate annual analytical 
reactivity testing results under Sec.  866.3328(b)(3)(iii) or emergency 
analytical reactivity testing results under Sec.  866.3328(b)(4)(ii) 
can be made without an official submission to FDA. In a case where one 
or more strains are shown not to be detected by the device during 
annual analytical reactivity testing under Sec.  866.3328(b)(3) or 
emergency analytical reactivity testing under Sec.  866.3328(b)(4), the 
manufacturer will need to include a limitation in the device labeling 
regarding reactivity with the specific strain(s) that were not detected 
by the device. Without such a limitation the device would not meet the 
labeling requirements of Sec.  809.10(b).
    FDA is also clarifying the special controls to be more precise 
regarding the situations in which emergency analytical reactivity 
testing is required. Under section 564(a)-(b) of the FD&C Act (21 
U.S.C. 360bbb-3(a)-(b)), the Secretary of Health and Human Services 
(HHS) may authorize the introduction into interstate commerce of a 
drug, device, or biologic product intended for use in an actual or 
potential emergency (referred to as ``emergency use'') after making a 
declaration, under section 564(b)(1) of the FD&C Act, that 
circumstances exist justifying the authorization. Such a declaration 
must be based on one of the following actions listed at section 
564(b)(1)(A)-(D) of the FD&C Act:
     A determination by the Secretary of Homeland Security that 
there is a domestic emergency, or a significant potential for a 
domestic emergency, involving a heightened risk of attack with a 
chemical, biological, radiological, or nuclear (CBRN) agent or agents;
     A determination by the Secretary of Defense that there is 
a military emergency, or a significant potential for a military 
emergency, involving a heightened risk to U.S. military forces of 
attack with a CBRN agent or agents;
     A determination by the Secretary of HHS that there is a 
public health emergency, or a significant potential for a public health 
emergency, that affects, or has a significant potential to affect, 
national security or the health and security of U.S. citizens living 
abroad, and that involves a CBRN agent or agents, or a disease or 
condition that may be attributable to such agent or agents; or
     The identification of a material threat, by the Secretary 
of Homeland Security under section 319F-2 of the Public Health Service 
(PHS) Act, that is sufficient to affect national security or the health 
and security of U.S. citizens living abroad.
    If one of these four actions that can provide the basis for the 
Secretary of HHS to make a declaration under section 564(b)(1) of the 
FD&C Act occurs with respect to an influenza viral strain, then, after 
being notified that characterized viral samples are available from CDC, 
antigen based RIDT manufacturers must conduct analytical reactivity 
testing with those samples and make the results available in their 
device labeling within the timeframes set forth in Sec.  
866.3328(b)(4).
    In addition, the Secretary of HHS may determine under section 
319(a) of the PHS Act (42 U.S.C. 247d(a)) that a disease or disorder 
presents a public health emergency or that a public health emergency 
otherwise exists. In the event of such a determination under section 
319(a) of the PHS Act with respect to an influenza viral strain, then, 
after being notified that characterized viral samples are available 
from CDC, antigen based RIDT manufacturers would also need to conduct 
analytical reactivity testing with those samples and make the results 
available in their device labeling within the timeframes set forth in 
Sec.  866.3328(b)(4).
    The final order also modifies the special controls to require that 
any emergency reactivity test results added to antigen based RIDT 
device labeling under Sec.  866.3328(b)(4)(ii) remain in the labeling 
for a period of 3 years. Emerging influenza strains may still be 
circulating after the statutory actions described under section 
564(b)(1)(A)-(D) of the FD&C Act and section 319(a) of the PHS Act have 
terminated. The change will align the period that emergency analytical 
reactivity test results must remain in device labeling with the 
requirement in Sec.  866.3328(b)(3)(iii) that manufacturers provide the 
last 3 years of annual analytical reactivity testing in the device 
labeling. FDA believes that this makes the labeling requirements in the 
special controls more clear and consistent for industry.
    As discussed previously, after reviewing the comments received 
along with the proposed order and the Panel's recommendations, FDA is 
making a few clarifications and modifications to the special controls 
for antigen based RIDTs. These include: (1) Clarifying that clinical 
performance criteria must be met for each specimen type claimed in the 
intended use of the device; (2) clarifying that manufacturers of future 
antigen based RIDT devices may use a currently appropriate and FDA 
accepted comparator method other than comparison to an FDA-cleared 
nucleic acid based-test or viral culture methods to demonstrate that 
those devices meet the clinical performance criteria, if such a 
comparator method is established; (3) clarifying that a manufacturer 
choosing to provide analytical reactivity testing results via its 
public Web site must prominently provide hyperlink to that Web site in 
the device's label or in other labeling that physically accompanies the 
device; (4) clarifying the circumstances in which emergency analytical 
reactivity testing is required under Sec.  866.3328(b)(4); and (5) 
requiring results of such emergency analytical reactivity testing to 
remain in the device labeling for a period of 3 years.

III. The Final Order

    Under section 513(e) of the FD&C Act, FDA is adopting its findings 
as published in the preamble to the proposed order, with the 
modifications discussed in section II of this final order. FDA is 
issuing this final order to reclassify antigen based rapid influenza 
virus antigen detection test systems intended to detect influenza virus 
antigen directly from clinical specimens that are currently regulated 
as influenza virus serological reagents under Sec.  866.3330 from class 
I into class II with special controls and into a new device 
classification regulation for ``influenza virus antigen detection test 
systems.'' Currently, antigen based RIDTs are mostly found under 
product codes GNX and GNT. However, any antigen based rapid influenza 
virus antigen detection test system intended to detect influenza virus 
antigen directly from clinical specimens that is currently regulated as 
influenza virus serological reagents under Sec.  866.3330 is subject to 
this

[[Page 3618]]

reclassification regardless of the product code to which it is 
currently assigned.
    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) of the FD&C Act, 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. Therefore, this type of device 
is not exempt from premarket notification requirements.
    In addition, FDA believes that special controls that: (1) Identify 
the minimum acceptable performance criteria; (2) require use of a 
currently appropriate and FDA accepted comparator method for 
establishing performance of new antigen based RIDTs; (3) require annual 
analytical reactivity testing of contemporary influenza strains; and 
(4) require analytical reactivity testing of newly emerging strains 
under certain situations involving an emergency or potential for an 
emergency, are necessary to provide reasonable assurance of safety and 
effectiveness of these devices.

IV. Implementation Strategy

    The special controls identified in this final order are effective 
February 13, 2017.
     For antigen based RIDTs that have not been legally 
marketed prior to February 13, 2017, or that have been legally marketed 
but are required to submit a 510(k) under 21 CFR 807.81(a)(3) because 
the device is about to be significantly changed or modified, 
manufacturers must obtain 510(k) clearance, among other relevant 
requirements, and demonstrate compliance with the special controls 
included in this final order, before marketing their new or changed 
device. If a manufacturer markets such a device after February 13, 2017 
without obtaining 510(k) clearance and demonstrating compliance with 
the special controls included in this final order, then FDA would 
consider taking action against such a manufacturer under its usual 
enforcement policies.
     For antigen based RIDTs that have been legally marketed 
prior to February 13, 2017, FDA does not intend to enforce compliance 
with the special controls until January 12, 2018. If a manufacturer 
markets such a device after January 12, 2018, and that device does not 
comply with the special controls, then FDA would consider taking action 
against such a manufacturer under its usual enforcement policies.
    FDA believes that a period of 1 year from the publication date of 
this final order is appropriate for manufacturers to come into 
compliance with the special controls and for those manufacturers whose 
currently legally marketed devices do not meet the minimum performance 
criteria to prepare and submit a 510(k) for a new or significantly 
changed or modified device. FDA believes this approach will help ensure 
the efficient and effective implementation of the order.

V. Analysis of 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.

VI. Paperwork Reduction Act of 1995

    This administrative order establishes special controls that refer 
to previously approved collections of information found in other FDA 
regulations and guidance. 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; the 
collections of information in 21 CFR part 812 regarding investigational 
device exemptions have been approved under OMB control number 0910-
0078; the collections of information in 21 CFR part 801 and Sec.  
809.10 have been approved under OMB control number 0910-0485; and the 
collections of information regarding pre-submissions have been approved 
under OMB control number 0910-0756.

VII. Codification of Orders

    Prior to the amendments by FDASIA, section 513(e) of the FD&C Act 
provided for FDA to issue regulations to reclassify devices. Although 
section 513(e) of the FD&C Act, as amended, requires FDA to issue final 
orders rather than regulations, FDASIA also provides for FDA to revoke 
previously issued regulations by order. FDA will continue to codify 
classifications and reclassifications in the Code of Federal 
Regulations (CFR). Changes resulting from final orders will appear in 
the CFR as changes to codified classification determinations or as 
newly codified orders. Therefore, under section 513(e)(1)(A)(i) of the 
FD&C Act, as amended by FDASIA, in this final order, we are codifying 
the reclassification of antigen based RIDTs into class II (special 
controls).

VIII. Reference

    The following reference is on display in the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, and is available for viewing by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday; it 
is also available electronically at https://www.regulations.gov. FDA 
has verified the Web site addresses, as of the date this document 
publishes in the Federal Register, but Web sites are subject to change 
over time.

1. Transcript and other meeting materials of FDA's Microbiology 
Devices Panel Meeting held on June 13, 2013, are available on FDA's 
Web site at: http://www.fda.gov/AdvisoryCommittees/ucm351035.htm.

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, 21 CFR part 
866 is 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

[[Page 3619]]

devices has serious public health implications.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) The device's sensitivity and specificity performance 
characteristics or positive percent agreement and negative percent 
agreement, for each specimen type claimed in the intended use of the 
device, must meet one of the following two minimum clinical performance 
criteria:
    (i) For devices evaluated as compared to an FDA-cleared nucleic 
acid based-test or other currently appropriate and FDA accepted 
comparator method other than correctly performed viral culture method:
    (A) The positive percent agreement estimate for the device when 
testing for influenza A and influenza B must be at the point estimate 
of at least 80 percent 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 the point estimate 
of at least 95 percent with a lower bound of the 95 percent confidence 
interval that is greater than or equal to 90 percent.
    (ii) For devices evaluated as compared to correctly performed viral 
culture method as the comparator method:
    (A) The sensitivity estimate for the device when testing for 
influenza A must be at the point estimate of at least 90 percent 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 the point estimate of at least 80 
percent 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 the point estimate of at least 
95 percent 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 an FDA-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 analytical reactivity testing to have been 
conducted since the device received marketing authorization from FDA, 
then the results of every annual analytical reactivity testing since 
the device received marketing authorization from FDA 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 that physically accompanies the device 
in a separate section of the labeling where the analytical reactivity 
testing data can be found; or
    (B) In the device's label or in other labeling that physically 
accompanies the device, prominently providing a hyperlink to the 
manufacturer's public Web site where the analytical reactivity testing 
data can be found. The manufacturer's home page, as well as the primary 
part of the manufacturer's Web site that discusses the device, must 
provide a prominently placed hyperlink to the Web page containing this 
information and must allow unrestricted viewing access.
    (4) If one of the actions listed at section 564(b)(1)(A)-(D) of the 
Federal Food, Drug, and Cosmetic Act occurs with respect to an 
influenza viral strain, or if the Secretary of Health and Human 
Services (HHS) determines, under section 319(a) of the Public Health 
Service Act, that a disease or disorder presents a public health 
emergency, or that a public health emergency otherwise exists, with 
respect to 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 those viral 
samples 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.
    (ii) Within 60 days from the date that FDA notifies manufacturers 
that characterized viral samples are available for test evaluation and 
continuing until 3 years from that date, 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 results directly in the device's Sec.  809.10(b) of 
this chapter compliant labeling that physically accompanies the device 
in a separate section of the labeling where analytical reactivity 
testing data can be found, but separate from the annual analytical 
reactivity testing results; or
    (B) In a section of the device's label or in other labeling that 
physically accompanies the device, prominently providing a hyperlink to 
the manufacturer's public Web site where the analytical reactivity 
testing data can be found. The manufacturer's home page, as well as the 
primary part of the manufacturer's Web site that discusses the device, 
must provide a prominently placed hyperlink to the Web page containing 
this information and must allow unrestricted viewing access.

    Dated: January 4, 2017.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2017-00199 Filed 1-11-17; 8:45 am]
 BILLING CODE 4164-01-P