[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]
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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: Final order.
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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