[Federal Register Volume 85, Number 35 (Friday, February 21, 2020)]
[Proposed Rules]
[Pages 10110-10118]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-03515]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2019-N-5192]
Microbiology Devices; Reclassification of Human Immunodeficiency
Virus Serological Diagnostic and Supplemental Tests and Human
Immunodeficiency Virus Nucleic Acid Diagnostic and Supplemental Tests
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed amendment; proposed order.
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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
proposing to reclassify certain human immunodeficiency virus (HIV)
serological diagnostic and supplemental tests and HIV nucleic acid
(NAT) diagnostic and supplemental tests, postamendments class III
devices with the product code MZF, into class II (special controls),
subject to premarket notification. FDA is also proposing new device
classification regulations along with special controls that the Agency
believes are necessary to provide a reasonable assurance of safety and
effectiveness for these devices. FDA is proposing this reclassification
on its own initiative. If finalized, this order will reclassify these
types of devices from class III (premarket approval) to class II
(special controls) and reduce the regulatory burdens associated with
these devices, as these types of devices will no longer be required to
submit a premarket approval application (PMA) but can instead submit a
premarket notification (510(k)) and receive clearance before marketing
their device.
DATES: Submit either electronic or written comments by April 21, 2020.
Please see section XI of this document for the proposed effective date
when the new requirements apply and for the proposed effective date of
a final order based on this proposed order.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before April 21, 2020. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of April 21, 2020. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are postmarked or the delivery service
acceptance receipt is on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed below (see ``Written/Paper Submissions'' and
``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2019-N-5192 for ``Microbiology Devices; Reclassification of human
immunodeficiency virus serological diagnostic and supplemental tests
and human immunodeficiency virus nucleic acid diagnostic and
supplemental tests''. Received comments, those filed in a timely manner
(see ADDRESSES), will be placed in the docket and, except for those
submitted as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
[[Page 10111]]
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Jenifer Roe, Center for Biologics
Evaluation and Review, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 240-
402-7911.
SUPPLEMENTARY INFORMATION:
I. Background--Regulatory Authorities
The Federal Food, Drug, and Cosmetic Act (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), Food
and Drug Administration Modernization Act of 1997 (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
(Pub. L. 112-144), among other amendments, establishes 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 (general controls and special controls), and class
III (general controls and premarket approval).
Section 513(a)(1) of the FD&C Act defines the three classes of
devices. Class I devices are those devices for which the general
controls of the FD&C Act (controls authorized by or under sections 501,
502, 510, 516, 518, 519, or 520 (21 U.S.C. 351, 352, 360, 360f, 360h,
360i, or 360j) or any combination of such sections) are sufficient to
provide reasonable assurance of safety and effectiveness; or those
devices for which insufficient information exists to determine that
general controls are sufficient to provide reasonable assurance of
safety and effectiveness or to establish special controls to provide
such assurance, but because the devices are not purported or
represented to be for a use in supporting or sustaining human life or
for a use which is of substantial importance in preventing impairment
of human health, and do not present a potential unreasonable risk of
illness or injury, are to be regulated by general controls (section
513(a)(1)(A) of the FD&C Act). Class II devices are those devices for
which general controls by themselves are insufficient to provide
reasonable assurance of safety and effectiveness, and for which there
is sufficient information to establish special controls to provide such
assurance, including the promulgation of performance standards,
postmarket surveillance, patient registries, development and
dissemination of guidelines, recommendations, and other appropriate
actions the Agency deems necessary to provide such assurance (section
513(a)(1)(B) of the FD&C Act). Class III devices are those devices for
which insufficient information exists to determine that general
controls and special controls would provide a reasonable assurance of
safety and effectiveness, and are purported or represented to be for a
use in supporting or sustaining human life or for a use which is of
substantial importance in preventing impairment of human health, or
present a potential unreasonable risk of illness or injury (section
513(a)(1)(C) of the FD&C Act).
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)(1) 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, (1) FDA
reclassifies the device into class I or class II, or (2) 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. FDA determines whether new devices are
substantially equivalent to predicate devices by means of premarket
notification procedures in section 510(k) of the FD&C Act and part 807
(21 CFR part 807), subpart E, of the regulations.
A postamendments device that has been initially classified in class
III under section 513(f)(1) of the FD&C Act may be reclassified into
class I or II under section 513(f)(3) of the FD&C Act. Section
513(f)(3) of the FD&C Act provides that FDA, acting by administrative
order, can reclassify the device into class I or class II on its own
initiative, or in response to a petition from the manufacturer or
importer of the device. To change the classification of the device, the
proposed new class must have sufficient regulatory controls to provide
a reasonable assurance of the safety and effectiveness of the device
for its intended use.
FDA relies upon ``valid scientific evidence,'' as defined in
section 513(a)(3) and 21 CFR 860.7(c)(2), in the classification process
to determine the level of regulation for devices. To be considered in
the reclassification process, the ``valid scientific evidence'' upon
which the Agency relies must be publicly available (see section 520(c)
of the FD&C Act). Publicly available information excludes trade secret
and/or confidential commercial information, e.g., the contents of a
pending PMA (see section 520(c) of the FD&C Act).
In accordance with section 513(f)(3) of the FD&C Act, the Agency is
issuing this proposed order to reclassify HIV serological diagnostic
and supplemental tests and HIV NAT diagnostic and supplemental tests,
postamendments class III devices, into class II (special controls),
subject to premarket notification because the Agency believes the
standard in section 513(a)(1)(B) of the FD&C Act is met because there
is sufficient information to establish special controls, in addition to
general controls, to provide reasonable assurance of the safety and
effectiveness of the device.\1\
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\1\ In December 2019, FDA began adding the term ``Proposed
amendment'' to the ``ACTION'' caption for these documents, typically
styled ``Proposed order'', to indicate that they ``propose to
amend'' the Code of Federal Regulations. This editorial change was
made in accordance with the Office of Federal Register's (OFR)
interpretations of the Federal Register Act (44 U.S.C. chapter 15),
its implementing regulations (1 CFR 5.9 and parts 21 and 22), and
the Document Drafting Handbook.
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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 provide reasonable assurance of the
safety and effectiveness of the device. FDA has determined that
premarket notification is necessary to reasonably assure the safety and
effectiveness of HIV serological diagnostic and supplemental tests and
HIV NAT diagnostic and supplemental tests. Therefore, the Agency does
not
[[Page 10112]]
intend to exempt this proposed class II device from premarket
notification (510(k)) submission under section 510(m) of the FD&C Act.
II. Regulatory History of the Devices
This proposed order covers HIV serological diagnostic and
supplemental tests and HIV NAT diagnostic and supplemental tests. These
are prescription tests that are assigned product code MZF. These
postamendments devices are currently regulated as class III devices
under section 513(f)(1) of the FD&C Act. Based on our review experience
and consistent with the FD&C Act and FDA's regulations in 21 CFR
860.134, FDA believes that these devices should be reclassified from
class III into class II with special controls because there is
sufficient information for these devices to establish special controls
that can provide a reasonable assurance of the device's safety and
effectiveness.
FDA has regulated the devices subject to this proposed order for
many years. The first serological test intended for use as an aid in
the diagnosis of infection with HIV was approved in 1987. The first
supplemental test intended for use as an aid in confirming diagnosis of
infection with HIV was approved in 1992. Currently there are 11
diagnostic serological tests and 6 supplemental serological tests on
the market in the United States. In 2006, FDA approved one NAT test
that is intended for use as an aid in the diagnosis of infection with
HIV. This device is also approved as a supplemental NAT test.
A review of the medical device reporting databases indicates that
there is a low number of reported events for HIV serological diagnostic
and supplemental tests and HIV NAT diagnostic tests. Over 100 million
HIV tests subject to this proposed reclassification have been sold
since 2000, with less than 1,000 reported events as of September 2019.
Of these, fewer than 40 are reported to involve injuries due to false
results; the remainder are malfunctions, user errors, or incorrect
results that had no reported effect on the individual being tested.
There have been less than 10 recalls specific to these tests, and no
class I recalls, indicating a good safety record for this device class.
III. Device Description
This proposed order applies to certain HIV serological diagnostic
and supplemental tests that are prescription devices for the
qualitative detection of HIV antigens and/or antibodies against HIV in
human body fluids or tissues. As such, the prescription device must
satisfy prescription labeling requirements for in vitro diagnostic
products (see 21 CFR 809.10(a)(4) and (b)(5)(ii)). The tests are
intended for use as an aid in the diagnosis of infection with HIV.
These devices are not intended for monitoring patient status or for
screening donors of blood, plasma, or human cells, tissues, or cellular
or tissue-based products (HCT/Ps). HIV serological tests detect the
presence of HIV by using anti-HIV antibodies and/or HIV antigens to
detect the presence of HIV antigens and/or anti-HIV antibodies in human
fluids. The analytes are detected by chemical, fluorescent,
luminescent, or other methods to produce a qualitative output that
determines the presence or absence of HIV in the sample. Supplemental
serological tests are intended to be used as an additional test to
confirm the presence of HIV antibodies or antigens in specimens found
to be repeatedly reactive by a diagnostic screening device. These tests
are intended for professional use only.
This proposed order also applies to certain HIV NAT diagnostic and
supplemental tests that are prescription devices for the detection of
HIV nucleic acid in human body fluids or tissues. The tests are
intended for use as an aid in the diagnosis of infection with HIV.
These devices are not intended for monitoring patient status, or for
screening donors of blood, plasma, or HCT/Ps. HIV NAT tests detect the
presence of HIV by detecting HIV nucleic acid in human body fluids or
from solutions after isolation of nucleic acid from cells or tissues.
The nucleic acids are amplified and detected by labeled probes that
produce a qualitative signal that indicates the presence or absence of
HIV nucleic acid in the sample. Supplemental NAT tests are intended to
be used as an additional test to confirm the presence of HIV nucleic
acid in specimens found to be repeatedly reactive by a diagnostic
screening device. These tests are intended for professional use only.
IV. Proposed Reclassification
FDA is proposing to reclassify HIV serological diagnostic and
supplemental tests and HIV NAT diagnostic and supplemental tests. FDA
held a public meeting on July 19, 2018, of the Blood Products Advisory
Committee, convened as a medical device Panel (``the Panel''), which
unanimously agreed that special controls, in addition to general
controls, are sufficient to mitigate the risks to health from HIV
serological diagnostic and supplemental tests and HIV NAT diagnostic
and supplemental tests. The Panel believed that class II with special
controls would provide reasonable assurance of the safety and
effectiveness of the device. The Panel discussed the proposed special
controls (see section VII), especially the performance criteria and
number of samples that would be required for testing. The Panel also
recommended that FDA consider reclassification from class III to class
II of HIV viral load tests indicated for use for monitoring patient
status.
The Agency believes that, at this time, sufficient data and
information exist such that the risks to health identified in section V
can be mitigated by establishing special controls that, together with
general controls, can provide a reasonable assurance of the safety and
effectiveness of these devices. Therefore, FDA proposes these devices
be reclassified from class III to class II.
In accordance with section 513(f)(3) of the FD&C Act and 21 CFR
part 860, subpart C, FDA is proposing to reclassify postamendments HIV
serological diagnostic and supplemental tests and NAT diagnostic and
supplemental tests from class III into class II. FDA believes that
there are sufficient data and information available through FDA's
accumulated experience with these devices from review submissions,
recommendations provided by the Panel, and from published literature to
demonstrate that the proposed special controls, along with general
controls, would effectively mitigate the risks to health identified in
section V and provide a reasonable assurance of safety and
effectiveness of these devices. Absent the special controls identified
in this proposed order, general controls applicable to the device are
insufficient to provide reasonable assurance of the safety and
effectiveness of the device. FDA expects that the reclassification of
these devices would enable more manufacturers to develop HIV
serological diagnostic and supplemental and NAT diagnostic and
supplemental tests such that patients would benefit from increased
access to safe and effective tests.
FDA is proposing to create separate classification regulations for
HIV serological diagnostic and supplemental tests and HIV NAT
diagnostic and supplemental tests that will be reclassified from class
III to class II. Under this proposed order, if finalized, HIV
serological diagnostic and supplemental tests and HIV NAT diagnostic
and supplemental tests will be identified as prescription devices. In
this proposed order the Agency has proposed the special controls under
section 513(a)(1)(B) of the FD&C Act
[[Page 10113]]
that, together with general controls, would provide a reasonable
assurance of the safety and effectiveness of HIV serological and NAT
diagnostic and supplemental tests.
Section 510(m) of the FD&C Act provides that FDA may exempt a class
II device from the premarket notification requirements under section
510(k) of the FD&C Act if FDA determines that premarket notification is
not necessary to provide reasonable assurance of the safety and
effectiveness of the device. For these HIV serological diagnostic and
supplemental tests and HIV NAT diagnostic and supplemental tests, FDA
has determined that premarket notification is necessary to provide a
reasonable assurance of the safety and effectiveness of the devices.
Therefore, FDA does not intend to exempt these proposed class II
devices from the 510(k) requirements. If this proposed order is
finalized, persons who intend to market this type of device must submit
to FDA a 510(k) and receive clearance prior to marketing the device.
This proposal, if finalized, will decrease regulatory burden on
industry, as manufacturers will no longer have to submit a PMA for
these types of devices but can instead submit a 510(k) to the Agency
for review prior to marketing their device. A 510(k) is a less
burdensome pathway to market a device, which typically results in a
shorter premarket review timeline compared to a PMA. This ultimately
provides more timely access of these types of devices to patients.
V. Risks to Health
HIV can be transmitted to others by blood transfusion, sex, sharing
of contaminated needles by intravenous drug users, and from mother to
child during pregnancy, childbirth, and breast feeding (Ref. 1). Left
untreated, a significant proportion of those infected with HIV will
develop acquired immunodeficiency syndrome (AIDS), which causes
significant morbidity and mortality. However, with consistent anti-
retroviral treatment, HIV infection is a treatable, chronic condition
with significantly improved survival and quality of life for people
living with HIV and significantly decreased risk of transmission to
others (Ref. 2). The Centers for Disease Control and Prevention (CDC)
recommends that all persons ages 13 through 64 and pregnant women be
tested at least once, with more frequent testing for individuals at
high risk of infection. Nevertheless, at the present time, only about
85 percent of people infected with HIV in the United States know that
they are infected, and those who do not know their status are many
times more likely to transmit the virus to others (Ref. 3). Therefore,
improving access to HIV diagnostic devices is an urgent public health
priority. After considering the recommendations of the panel, FDA's
accumulated experience with these devices from review submissions, and
the published literature, FDA has identified the following probable
risks to health associated with HIV serological diagnostic and
supplemental tests:
(1) A false negative/false non-reactive test result may influence
patient management decisions, such as the withholding or
discontinuation of antiretroviral therapy, which can lead to serious
injury including death. A false negative/false non-reactive test result
also may contribute to public health risk by leading to inadvertent
transmission of virus by an infected person. Factors that may cause
decreased test sensitivity and/or increased rate of false negative/
false non-reactive test reporting include, but are not limited to,
strain variability, acquisition of de novo mutations in genomic regions
of HIV targeted by the device, the presence of interfering substances
in the sample, acute infection at a stage that is too early for a
device to detect the infection, and analyte concentrations that are too
low to be detected by the device due to suppression of analyte
expression by drugs used to treat or prevent HIV infection. False
negative/false non-reactive results also can be caused by improper
sample collection or sample handling, loss of sensitivity of the
device, failure of detection reagents, and failure of instruments. They
also can be caused by misinterpretation of invalid results as negative.
(2) A false positive/false reactive test result may contribute to
unnecessary initiation of treatment. It can also lead to unnecessary
interventions such as an unnecessary Caesarian section for women during
childbirth, unnecessary treatment of infants with anti-retroviral
medications, withholding of breastfeeding, and significant emotional
stress. Factors that may lead to false positive/false reactive results
include cross-reactivity with other substances in the sample,
contamination of the sample, patient participation in vaccine trials,
and improper sample handling and instrument use.
VI. Summary of the Reasons for Reclassification
FDA believes that HIV serological diagnostic and supplemental tests
and HIV NAT diagnostic and supplemental tests should be reclassified
from class III (PMA) into class II (special controls) because special
controls, in addition to general controls, can be established to
mitigate the risks to health identified in section V and provide
reasonable assurance of the safety and effectiveness of these device
types. The proposed special controls are identified by FDA in section
VII. FDA's reasons for reclassification are as follows:
(1) There is substantial scientific and medical information
available regarding the nature, complexity, and risks associated with
HIV serological diagnostic and supplemental tests and NAT diagnostic
and supplemental tests. The safety and effectiveness of this device
type has been well-established by the performance of the more than 20
devices currently available (Ref. 4).
(2) Risks associated with the failure of the device to perform as
indicated (e.g., false negative/false non-reactive or false positive/
false reactive test results) can be mitigated through a combination of
special controls, including performance criteria and requirements for
submission of certain aspects of labeling, submission of certain
manufacturing information, and submission of a complaint log.
Performance criteria will consist primarily of analytical and clinical
study design specifications and performance criteria that are based on
public information regarding the performance and validation of
previously approved devices. Examples of labeling mitigations include
appropriate limitations, including that results should be confirmed
according to current guidelines as promulgated by the CDC and other
public health authorities, which are necessary to ensure that the
devices are used and the results are interpreted appropriately, given
the diversity of environments in which they are intended to be used.
Manufacturing information submitted will include summaries of
strategies to detect new types, subtypes, genotypes and mutations to
ensure the tests continue to detect clinically relevant forms of HIV, a
summary of the design matrix that determines the severity of events to
ensure appropriate adverse event reporting, protocols for assessing
stability, evaluation of test performance at the extremes of
specifications to ensure the tests have been validated to function
correctly under diverse conditions. The complaint log that will be
submitted annually for 5 years following clearance of a traditional
510(k) is the log required to be maintained by device manufacturers
under 21 CFR 820.198(a). We are proposing as a special control to
require submission of all complaints, whether or not the complaint was
reported under part 803 (21 CFR part 803). We are not
[[Page 10114]]
requiring submission of an annual report as described in 21 CFR 814.84.
Review of the complaint log will allow FDA to closely monitor issues
with manufacturing and implementation of new devices that may not rise
to the level of adverse event reporting required under 21 CFR
820.198(a) but that may have an effect on the performance of the
devices.
Taking into account the probable health benefits of the use of the
device and the nature and known incidence of the risk of the device,
FDA, on its own initiative, is proposing to reclassify these
postamendments devices from class III into class II. FDA believes that,
when used as indicated, HIV serological and NAT diagnostic and
supplemental tests can provide significant benefits to clinicians and
patients.
VII. Proposed Special Controls
FDA believes that these devices can be classified into class II
with the establishment of special controls. FDA believes that these
special controls, in addition to general controls, will provide a
reasonable assurance of the safety and efficacy of these devices.
Tables 1 and 2 demonstrate how these proposed special controls will
mitigate each of the identified risks to health in section V.
Table 1--Risks to Health and Mitigation Measures for HIV Serological
Diagnostic and Supplemental Tests
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Identified risks to health Mitigation measures
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A false negative/false non- Labeling limitations, warnings, and
reactive test result may interpretation requirements.
influence patient management Analytical and clinical sensitivity
decisions, such as the performance criteria.
withholding of antiviral therapy, Clinical testing on appropriate
which can lead to serious injury populations.
including death. Acceptable strategies for monitoring
emergence of and ability of the
test to detect new or altered
circulating forms of HIV.
A false negative/false non- Acceptable processes for failure
reactive test result may mode analysis, testing performance
contribute to public health risk at extremes of specifications,
by leading to inadvertent determining severity of adverse
transmission of virus by an events and malfunctions.
infected person. Submission of a complaint log to
monitor decreases in test
performance or manufacturing
failures.
A false positive/false reactive Labeling instructions for
test result may contribute to appropriate confirmation of
unnecessary initiation of results.
treatment or other medical Analytical and clinical specificity
interventions, which increases performance criteria.
patient risk to the potential Clinical testing on appropriate
adverse effects of such populations.
treatments or medical Acceptable validation of
interventions. susceptibility to interference and
cross-reactivity.
Acceptable processes for failure
mode analysis, testing performance
at extremes of specifications,
determining severity of adverse
events and malfunctions.
Submission of a complaint log to
monitor trends in false positive
results.
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Table 2--Risks to Health and Mitigation Measures for HIV NAT Diagnostic
and Supplemental Tests
------------------------------------------------------------------------
Identified risks to health Mitigation measures
------------------------------------------------------------------------
A false negative/false non- Labeling limitations, warnings, and
reactive test result may interpretation requirements.
influence patient management Analytical and clinical sensitivity
decisions, such as the performance criteria.
withholding of antiviral therapy, Clinical testing on appropriate
which can lead to serious injury populations.
including death.
A false negative/false non- Acceptable strategies for monitoring
reactive test result may emergence of and ability of the
contribute to public health risk test to detect new or altered
by leading to inadvertent circulating forms of HIV.
transmission of virus by an Acceptable processes for failure
infected person. mode analysis, testing performance
at extremes of specifications,
determining severity of adverse
events and malfunctions.
Submission of a complaint log to
monitor decreases in test
performance or manufacturing
failures.
A false positive/false reactive Labeling instructions for
result may contribute to appropriate confirmation of
unnecessary initiation of results.
treatment or other medical Analytical and clinical specificity
intervention, which increases performance criteria.
patient risk to the potential Clinical testing on appropriate
adverse effects of such populations.
treatments or medical Acceptable validation of
interventions. susceptibility to interference and
cross-reactivity.
Acceptable processes for failure
mode analysis, testing performance
at extremes of specifications,
determining severity of adverse
events and malfunctions.
Submission of a complaint log to
monitor trends in false positive
results.
------------------------------------------------------------------------
If this proposed order is finalized, HIV serological diagnostic and
supplemental tests and HIV NAT diagnostic and supplemental tests will
be reclassified into class II (special controls). As discussed below,
the reclassification will be codified in 21 CFR 866.3956 (serological)
and 21 CFR 866.3957 (NAT) tests. Firms submitting a 510(k) for an HIV
serological diagnostic and/or supplemental or HIV NAT diagnostic and/or
supplemental test will be required to comply with the particular
mitigation measures set forth in the special controls. Adherence to the
special controls, in addition to the general controls, is necessary to
provide a reasonable assurance of the safety and effectiveness of the
devices.
VIII. Analysis of Environmental Impact
The Agency has determined under 21 CFR 25.34(b) that this 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.
IX. Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed rule contains no new
collection of information. Therefore, clearance by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1995
(PRA) (44 U.S.C. 3501-3521) is not required. This proposed order refers
to previously approved FDA collections of information. These
collections of
[[Page 10115]]
information are subject to review by the OMB under the PRA. 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 820 have been
approved under OMB control number 0910-0073; and the collections of
information in 21 CFR parts 801 and 809 have been approved under OMB
control number 0910-0485.
X. Codification of Orders
Under section 513(f)(3) of the FD&C Act, FDA may issue final orders
to reclassify devices. 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 newly codified
orders. Therefore, under section 513(f)(3), in the proposed order, we
are proposing to codify HIV serological diagnostic and/or supplemental
tests in the new 21 CFR 866.3956, under which HIV serological
diagnostic and/or supplemental tests would be reclassified from class
III to class II, and HIV NAT diagnostic and/or supplemental tests in
the new 21 CFR 866.3957, under which HIV NAT diagnostic and/or
supplemental tests would be reclassified from class III to class II.
XI. Proposed Effective Date
FDA proposes that any final order based on this proposed order
become effective 30 days after its date of publication in the Federal
Register.
XII. References
The following references have been placed on display in the Dockets
Management Staff (see ADDRESSES) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at https://www.regulations.gov. FDA has
verified the website addresses, as of the date this document publishes
in the Federal Register, but websites are subject to change over time.
1. Branson, B.M., H.H. Handsfield, M.A. Lampe, et al., ``Revised
Recommendations for HIV Testing of Adults, Adolescents, and Pregnant
Women in Health-Care Settings,'' MMWR. Recommendations and Reports:
Morbidity and Mortality Weekly Report, 55(RR14): 1-17, 2007.
2. Collaboration, T.A.T.C., ``Survival of HIV-Positive Patients
Starting Antiretroviral Therapy Between 1996 and 2013: A
Collaborative Analysis of Cohort Studies,'' Lancet HIV, 2017.
3. Dailey, A.F., B.E. Hoots, H.I. Hall, et al., ``Vital Signs:
Human Immunodeficiency Virus Testing and Diagnosis Delays--United
States,'' MMWR. Recommendations and Reports: Morbidity and Mortality
Weekly Report, 66: 1300-1306, 2017.
4. ``Reclassification of HIV Point of Care and Laboratory-Based
Serological and NAT Diagnostic Devices from Class III (PMA) to Class
II 510(k); Issue Summary; Prepared for the July 19, 2018, Meeting of
the Blood Products Advisory Committee (BPAC)).'' Available at:
https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/ucm597841.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, it is
proposed that 21 CFR part 866 be amended as follows:
PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES
0
1. The authority citation for part 866 continues to read as follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.
0
2. Add Sec. 866.3956 to subpart D to read as follows:
Sec. 866.3956 Human immunodeficiency virus (HIV) serological
diagnostic and/or supplemental test.
(a) Identification. Human immunodeficiency virus (HIV) serological
diagnostic and supplemental tests are prescription devices for the
qualitative detection of HIV antigen(s) and/or detection of antibodies
against HIV in human body fluids or tissues. The tests are intended for
use as an aid in the diagnosis of infection with HIV. The test results
are intended to be interpreted in conjunction with other relevant
clinical and laboratory findings. For professional use only. These
tests are not intended to be used for monitoring patient status, or for
screening donors of blood, plasma, or human cells, tissues, and
cellular and tissue-based products (HCT/Ps).
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) For all HIV serological diagnostic and supplemental tests
(i) The labeling must include:
(A) An intended use that states that the device is not intended for
use for screening donors of blood, plasma, or HCT/Ps.
(B) A detailed explanation of the principles of operation and
procedures used for performing the assay.
(C) A detailed explanation of the interpretation of results and
recommended actions to take based on results.
(D) Limitations, which must be updated to reflect current clinical
practice and disease presentation and management. The limitations must
include, but are not limited to, statements that indicate:
(1) The matrices with which the device has been cleared, and that
use of this test kit with specimen types other than those specifically
cleared for this device may result in inaccurate test results.
(2) The test is not intended to be used to monitor individuals who
are undergoing treatment for HIV infection.
(3) A specimen with a reactive result should be investigated
further following current guidelines.
(4) All test results should be interpreted in conjunction with the
individual's clinical presentation, history, and other laboratory
results.
(5) A test result that is nonreactive does not exclude the
possibility of exposure to or infection with HIV. Nonreactive results
in this assay may be due to analyte levels that are below the limit of
detection of this assay.
(ii) Device verification and validation must include:
(A) Detailed device description, including the device components,
ancillary reagents required but not provided, and an explanation of the
methodology. Additional information appropriate to the technology must
be included such as the amino acid sequence of antigen(s) and design of
capture antibodies.
(B) For devices with assay calibrators, the design of all primary,
secondary, and subsequent quantitation standards used for calibration
as well as their traceability to a reference material. In addition,
analytical testing must be performed following the release of a new lot
of the standard material that was used for device clearance, or when
there is a transition to a new calibration standard.
(C) Detailed documentation of analytical performance studies
conducted as appropriate to the technology, specimen types tested, and
intended use of the device, including, but not limited to, limit of
blank, limit of detection, cutoff determination, precision, endogenous
and exogenous interferences, cross reactivity, carry-over, quality
control, matrix equivalency, and sample and reagent stability. Samples
selected for use in analytical studies or used to prepare samples for
use in analytical studies must be from subjects with clinically
relevant circulating genotypes in the United States.
[[Page 10116]]
(D) Multisite reproducibility study that includes the testing of
three independent production lots.
(E) Analytical sensitivity of the test must be the same as or
better than that of other cleared or approved tests. Samples tested
must include appropriate numbers and types of samples, including real
clinical samples near the lower limit of detection. Analytical
specificity of the test must be the same as or better than that of
other cleared or approved tests. Samples must include appropriate
numbers and types of samples from patients with different underlying
illnesses or infections and from patients with potential endogenous
interfering substances.
(F) Detailed documentation of performance from a multisite clinical
study. Performance must be analyzed relative to an FDA-cleared or
approved comparator. This study must be conducted using patient
samples, with an appropriate number of HIV positive and HIV negative
samples in applicable risk categories. Additional subgroups or types
must be validated using appropriate numbers and types of samples. The
samples may be a combination of fresh and repository samples, sourced
from within and outside the United States, as appropriate. The study
designs, including number of samples tested, must be sufficient to meet
the following criteria:
(1) Clinical sensitivity of the test must have a lower bound of the
95 percent confidence interval of greater than or equal to 99 percent.
(2) Clinical specificity of the test must have a lower bound of the
95 percent confidence interval of greater than or equal to 99 percent.
(G) Strategies for detection of new strains, types, subtypes,
genotypes, and genetic mutations as they emerge.
(H) Risk analysis and management strategies, such as Failure Modes
Effects Analysis and/or Hazard Analysis and Critical Control Points
summaries and their impact on test performance.
(I) Final release criteria to be used for manufactured test lots
with appropriate evidence that lots released at the extremes of the
specifications will meet the claimed analytical and clinical
performance characteristics as well as the stability claims.
(J) All stability protocols, including acceptance criteria.
(K) Proposed procedure(s) for evaluating customer complaints and
other device information that determines when to submit a medical
device report.
(L) Premarket notification submissions must include the information
contained in paragraph (b)(1)(ii)(A) through (K) of this section.
(iii) Manufacturers must submit a log of all complaints. The log
must include the following information regarding each complaint: The
type of event (false negative/false non-reactive or false positive/
false reactive), lot, date, population, and whether or not the
complaint was reported under part 803 of this chapter (Medical Device
Reporting). The log must be submitted annually on the anniversary of
clearance, for 5 years following initial clearance of a new traditional
510(k).
(2) If the test is intended for Point of Care (PoC) use, the
following special controls, in addition to those listed in paragraph
(b)(1) of this section apply:
(i) The intended use must include a statement that the test is for
PoC use.
(ii) The PoC intended use must include the following information:
(A) That distribution of the test is limited to clinical
laboratories that have an adequate quality assurance program, including
planned systematic activities that provide adequate confidence that
requirements for quality will be met and where there is assurance that
operators will receive and use the instructional materials.
(B) That the test is for use only by an agent of a clinical
laboratory.
(C) That individuals must receive the ``Subject Information
Notice'' prior to specimen collection and appropriate information when
test results are provided.
(iii) PoC labeling must include instructions to follow current
guidelines for informing the individual of the test result and its
interpretation.
(iv) The instructions must state that reactive results are
considered preliminary and should be confirmed following current
guidelines.
(v) Device verification and validation for the PoC claim must
include:
(A) Detailed documentation of performance from a multisite clinical
study. Performance must be analyzed relative to an FDA cleared or
approved comparator. This study must be conducted using patient
samples, with appropriate numbers of HIV positive and HIV negative
samples in applicable risk categories. Additional subgroup or type
claims must be validated using appropriate numbers and types of
samples. The samples may be a combination of fresh and repository
samples, sourced from within and outside the United States, as
appropriate. If the test is intended solely for PoC use, the test must
meet only the performance criteria in paragraph (b)(2)(v)(A)(1) and (2)
of this section and not the criteria in paragraph (b)(1)(ii)(F) of this
section:
(1) Clinical sensitivity of the test must have a lower bound of the
95 percent confidence interval of greater than or equal to 98 percent.
(2) Clinical specificity of the test must have a lower bound of the
95 percent confidence interval of greater than or equal to 98 percent.
(B) Premarket notification submissions must include the information
contained in paragraph (b)(2)(v)(A) of this section.
(3) If the test is intended for supplemental use in addition to use
as an aid in initial diagnosis, the following special controls, in
addition to those listed in paragraphs (b)(1) and (2) of this section,
as appropriate, apply:
(i) For the additional supplemental claim, a clinical study must be
performed that includes samples that were initially reactive and
repeatedly reactive on a diagnostic test but were negative or
indeterminate on a different confirmatory test.
(ii) The intended use must include a statement that the test is
intended for use as an additional test to confirm the presence of HIV
antibodies or antigens in specimens found to be repeatedly reactive by
a diagnostic screening test.
(4) If the test is intended solely as a supplemental test, the
following special controls, in addition to those listed in paragraphs
(b)(1) and (2) of this section, except those in paragraphs
(b)(1)(ii)(F) and (b)(2)(v)(A) of this section, as appropriate, apply:
(i) The labeling must include a statement that the test is intended
for use as an additional test to confirm the presence of HIV antibodies
or antigens in specimens found to be repeatedly reactive by a
diagnostic screening test.
(ii) The labeling must clearly state that the test is not for use
for initial diagnosis or is not intended as a first-line test.
(iii) A clinical study must be performed that includes samples that
were initially reactive and repeatedly reactive on a diagnostic test
but were negative or indeterminate on a confirmatory test.
(5) If the test is intended to differentiate different HIV types,
the following special controls, in addition to those listed in
paragraphs(b)(1) through (4) of this section, as appropriate, apply:
(i) The labeling must include the statement that the test is
intended for the confirmation of initial results from a diagnostic test
and differentiation of different HIV types.
(ii) Analytical and clinical sensitivity and specificity for each
of the HIV
[[Page 10117]]
types, strains, and subtypes of HIV intended to be differentiated must
be evaluated.
(iii) The results interpretation must include instructions for the
user on how to interpret the results, including un-typeable and co-
infection results.
0
3. Add Sec. 866.3957 to subpart D to read as follows:
Sec. 866.3957 Human immunodeficiency virus (HIV) nucleic acid (NAT)
diagnostic and/or supplemental test.
(a) Identification. Human immunodeficiency virus (HIV) nucleic acid
(NAT) diagnostic and supplemental tests are prescription devices for
the qualitative detection of HIV nucleic acid in human body fluids or
tissues. The tests are intended for use as an aid in the diagnosis of
infection with HIV. The test results are intended to be interpreted in
conjunction with other relevant clinical and laboratory findings. For
prescription use only. These tests are not intended to be used for
monitoring patient status, or for screening donors of blood, plasma, or
human cells, tissues, or cellular or tissue-based products (HCT/Ps).
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) For all HIV NAT diagnostic and/or supplemental tests
(i) The labeling must include:
(A) An intended use that states that the device is not intended for
use for screening donors of blood, plasma, or HCT/Ps.
(B) A detailed explanation of the principles of operation and
procedures used for performing the assay.
(C) A detailed explanation of the interpretation of results and
recommended actions to take based on results.
(D) Limitations, which must be updated to reflect current clinical
practice and disease presentation and management. The limitations must
include, but are not limited to, statements that indicate:
(1) The matrices with which the device has been cleared, and that
use of this test kit with specimen types other than those specifically
cleared for this device may result in inaccurate test results.
(2) The test is not intended to be used to monitor individuals who
are undergoing treatment for HIV infection.
(3) A specimen with a reactive result should be investigated
further following current guidelines.
(4) All test results should be interpreted in conjunction with the
individual's clinical presentation, history, and other laboratory
results.
(5) A test result that is nonreactive does not exclude the
possibility of exposure to or infection with HIV. Nonreactive results
in this assay may be due to analyte levels that are below the limit of
detection of this assay.
(ii) Device verification and validation must include:
(A) Detailed device description, including the device components,
ancillary reagents required but not provided, and an explanation of the
methodology. Additional information appropriate to the technology must
be included such as design of primers and probes.
(B) For devices with assay calibrators, the design and nature of
all primary, secondary, and subsequent quantitation standards used for
calibration as well as their traceability to a reference material. In
addition, analytical testing must be performed following the release of
a new lot of the standard material that was used for device clearance,
or when there is a transition to a new calibration standard.
(C) Detailed documentation of analytical performance studies
conducted as appropriate to the technology, specimen types tested, and
intended use of the device, including, but not limited to, limit of
blank, limit of detection, cutoff determination, precision, endogenous
and exogenous interferences, cross reactivity, carry-over, quality
control, matrix equivalency, and sample and reagent stability. Samples
selected for use in analytical studies or used to prepare samples for
use in analytical studies must be from subjects with clinically
relevant circulating genotypes in the United States. The effect of each
claimed nucleic-acid isolation and purification procedure on detection
must be evaluated.
(D) Multisite reproducibility study that includes the testing of
three independent production lots.
(E) Analytical sensitivity of the test must be the same as or
better than that of other cleared or approved tests. Samples tested
must include appropriate numbers and types of samples, including real
clinical samples near the lower limit of detection. Analytical
specificity of the test must be as the same as or better than that of
other cleared or approved tests. Samples must include appropriate
numbers and types of samples from patients with different underlying
illnesses or infections and from patients with potential endogenous
interfering substances.
(F) Detailed documentation of performance from a multisite clinical
study. Performance must be analyzed relative to an FDA cleared or
approved comparator. This study must be conducted using appropriate
patient samples, with appropriate numbers of HIV positive and negative
samples in applicable risk categories. Additional subtype, strain, or
types must be validated using appropriate numbers and types of samples.
The samples may be a combination of fresh and repository samples,
sourced from within and outside the United States, as appropriate. The
study designs, including number of samples tested, must be sufficient
to meet the following criteria:
(1) Clinical sensitivity of the test must have a lower bound of the
95 percent confidence interval of greater than or equal to 99 percent.
(2) Clinical specificity of the test must have a lower bound of the
95 percent confidence interval of greater than or equal to 99 percent.
(G) Strategies for detection of new strains, types, subtypes,
genotypes, and genetic mutations as they emerge.
(H) Risk analysis and management strategies, such as Failure Modes
Effects Analysis and/or Hazard Analysis and Critical Control Points
summaries and their impact on test performance.
(I) Final release criteria to be used for manufactured test lots
with appropriate evidence that lots released at the extremes of the
specifications will meet the claimed analytical and clinical
performance characteristics as well as the stability claims.
(J) All stability protocols, including acceptance criteria.
(K) Proposed procedure(s) for evaluating customer complaints and
other device information that determine when to submit a medical device
report.
(L) Premarket notification submissions must include the information
contained in paragraph (b)(1)(ii)(A) through (K) of this section.
(iii) Manufacturers must submit a log of all complaints. The log
must include the following information regarding each complaint: The
type of event (false negative/false non-reactive or false positive/
false reactive), lot, date, population, and whether or not the
complaint was reported under part 803 of this chapter (Medical Device
Reporting). The log must be submitted annually on the anniversary of
clearance, for 5 years following initial clearance of a new traditional
510(k).
(2) If the test is intended for Point of Care (PoC) use, the
following special controls, in addition to those listed in paragraph
(b)(1) of this section, apply:
(i) The intended use must include a statement that the test is for
PoC use.
[[Page 10118]]
(ii) The PoC intended use must include the following information:
(A) That distribution of the test is limited to clinical
laboratories that have an adequate quality assurance program, including
planned systematic activities that provide adequate confidence that
requirements for quality will be met and where there is assurance that
operators will receive and use the instructional materials.
(B) That the test is for use only by an agent of a clinical
laboratory.
(C) That individuals must receive the ``Subject Information
Notice'' prior to specimen collection and appropriate information when
test results are provided.
(iii) PoC labeling must include instructions to follow current
guidelines for informing the individual of the test result and its
interpretation.
(iv) The instructions must state that reactive results are
considered preliminary and should be confirmed following current
guidelines.
(v) Device verification and validation for the PoC claim must
include:
(A) Detailed documentation from a well-conducted multisite clinical
study. Performance must be analyzed relative to an FDA cleared or
approved comparator. This study must be conducted using patient
samples, with appropriate numbers of HIV positive and HIV negative
samples in applicable risk categories. Additional subgroup or type
claims must be validated using appropriate numbers and types of
samples. The samples may be a combination of fresh and repository
samples, sourced from within and outside the United States, as
appropriate. If the test is intended solely for PoC use, the test must
meet only the performance criteria in paragraphs (b)(2)(v)(A)(1) and
(2) of this section and not the criteria in paragraph (b)(2)(ii)(F) of
this section:
(1) Clinical sensitivity of the test must have a lower bound of the
95 percent confidence interval of greater than or equal to 98 percent.
(2) Clinical specificity of the test must have a lower bound of the
95 percent confidence interval of greater than or equal to 98 percent.
(B) Premarket notification submissions must include the information
contained in paragraph (b)(2)(v)(A) of this section.
(3) If the test is intended for supplemental use in addition to use
as an aid in initial diagnosis, the following special controls, in
addition to those listed in paragraphs (b)(1) and (2) of this section,
as appropriate, apply:
(i) For the additional supplemental claim, a clinical study must be
performed that includes samples that were initially reactive and
repeatedly reactive on a diagnostic test but were negative or
indeterminate on a confirmatory test.
(ii) The intended use must include a statement that the test is
intended for use as an additional test to confirm the presence of HIV
viral nucleic acid in specimens found to be repeatedly reactive by a
diagnostic screening test.
(4) If the test is intended solely as a supplemental test, the
following special controls, in addition to those listed in paragraphs
(b)(1) and (2) of this section, except those in paragraphs(b)(1)(ii)(F)
and (b)(2)(v)(A) of this section, as appropriate, apply:
(i) The labeling must include a statement that the test is intended
for use as an additional test to confirm the presence of HIV viral
nucleic acid in specimens found to be repeatedly reactive by a
diagnostic screening test.
(ii) The labeling must clearly state that the test is not for use
for initial diagnosis or is not intended as a first-line test.
(iii) A clinical study must be performed that includes samples that
were initially reactive and repeatedly reactive on a diagnostic test
but were negative or indeterminate on a confirmatory test.
(5) If the test is intended to differentiate different HIV types,
the following special controls, in addition to those listed in
paragraphs (b)(1) through (4) of this section, as appropriate, apply:
(i) The labeling must include the statement that the test is
intended for the confirmation of initial results and differentiation of
different HIV types.
(ii) Analytical and clinical sensitivity and specificity for each
of the types, strains, and subtypes of HIV intended to be
differentiated must be evaluated.
(iii) The results interpretation must include instructions for the
user on how to interpret the results, including un-typeable and co-
infection results.
Dated: February 18, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-03515 Filed 2-20-20; 8:45 am]
BILLING CODE 4164-01-P