[Federal Register Volume 87, Number 94 (Monday, May 16, 2022)]
[Rules and Regulations]
[Pages 29661-29668]
[FR Doc No: 2022-10461]

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

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: Final amendment; final order.

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

SUMMARY: The Food and Drug Administration (FDA, we, or the Agency) is
issuing a final order 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. Through this final order,
FDA is also adding two new device classification regulations and
identifying special controls that the Agency believes are necessary to
provide a reasonable assurance of safety and effectiveness for these
device types. This final order will reduce the regulatory burdens
associated with these device types, as manufacturers 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: This order is effective June 15, 2022.

FOR FURTHER INFORMATION CONTACT: Melissa Segal, 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,
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).
    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.
    On February 21, 2020, FDA published in the Federal Register a
proposed order (85 FR 10110) to reclassify certain HIV serological
diagnostic and supplemental tests and HIV NAT diagnostic and
supplemental tests from class III to class II (special controls),
subject to premarket notification. The comment period on the proposed
order closed on April 21, 2020.

II. Comments on the Proposed Order

    In response to the February 21, 2020, proposed order, FDA received
several comments from public health organizations, device
manufacturers, and individuals by the close of the comment period, each
containing one or more comments on one or more issues. We describe and
respond to the comments in this section of the document. The order of
response to the comments is purely for organizational purposes and does
not signify the comment's value or importance nor the order in which
the comments were received.
    (Comment 1) Nearly all comments expressed general support for the
proposed reclassification along with appropriate controls to assure
safety and efficacy. The comments noted that reclassification could
improve access to HIV testing, support earlier diagnosis and facilitate
prevention of HIV, enhance laboratory efficiency and patient
management, and strengthen public health surveillance.
    (Response 1) We acknowledge and appreciate the supportive comments.
We are reclassifying these devices and establishing the special
controls published in the proposed order with some clarifications and
modifications, as summarized in section III.
    (Comment 2) Several comments recommended the reclassification of
HIV viral load monitoring tests, which were not included within the
scope of the proposed order. The comments expressed differing opinions
regarding whether HIV viral load reclassification should be included in
this final order. One comment also noted that, at the 119th meeting of
the Blood Products Advisory Committee (BPAC) held on July 19, 2018 (the
Panel), there was clear support from the committee for reclassification
of HIV viral load monitoring tests.
    (Response 2) We appreciate the comments and note that FDA published

a proposed order to reclassify HIV viral load monitoring tests from
class III into class II on November 24, 2021 (86 FR 66982). HIV viral
load monitoring tests have different intended uses than HIV serological
and NAT diagnostic tests and raise different issues of safety and
effectiveness. We do not think it is appropriate to reclassify HIV
viral load monitoring tests in this final order without providing the
public with the opportunity to comment on the basis of the proposed
reclassification or on the special controls. Thus, we are proceeding
with finalizing reclassification of HIV serological and NAT diagnostic
and supplemental tests and are separately pursuing reclassification of
HIV viral load tests.
    (Comment 3) One comment recommended reclassification of home-use
HIV diagnostic devices and stated that reclassification of such tests
from class III to class II would encourage manufacturers to develop new
tests for home use, which could help address current gaps and barriers
to testing in certain populations. However, another comment did not
support reclassification of HIV tests intended for home use.
    (Response 3) FDA has approved only one home-use HIV diagnostic test
to date, which is indicated as an in vitro diagnostic home-use test for
detecting HIV (HIV-1 and HIV-2) in oral fluid. A positive result is
preliminary and followup confirmatory testing is needed. As noted by
one of the comments, home-use HIV diagnostic tests were not within the
scope of the proposed order, and there are distinct performance
considerations and risks associated with home-use HIV diagnostic tests.
Thus, FDA does not intend to reclassify home-use HIV diagnostic tests
at this time, and such devices are not included in the scope of this
final order.
    (Comment 4) Several comments, while generally expressing support
for the proposed reclassification of HIV serological and NAT diagnostic
and supplemental tests from class III to class II, expressed concerns
regarding the proposed special controls on clinical sensitivity and
specificity:
     Performance of Currently Approved HIV Diagnostic Tests:
The comments stated that currently approved tests may not perform at
the level specified in the special controls. One comment said that
``none of the currently approved assays perform at the level specified
by the special controls.'' Another comment said that during the July
19, 2018, Panel meeting, it was noted that ``many of the currently
approved assays don't actually perform at these levels.''
     Performance Levels--Harmonization with Hepatitis C Virus
(HCV) Tests: Several comments expressed concerns about the proposed
sensitivity and specificity levels for HIV tests being too stringent in
general and not harmonized with those proposed for HCV tests. Others
suggested that the proposed performance levels for sensitivity and
specificity were inconsistent with the discussion at the July 19, 2018,
Panel meeting. One of these comments recommended that the performance
measure level of stringency should be a point estimate of 99 percent
with a 95 percent lower bound of the 95 percent confidence interval and
noted that the proposed special controls currently require a lower
bound of the 95 percent confidence interval greater than or equal to 99
percent.
     Characterization of Performance Measures--Harmonization
with HCV Tests: One comment indicated that, in order to harmonize HCV
test requirements and HIV serologic and nucleic acid test requirements,
the HIV test performance measures should be characterized as Positive
Percent Agreement and Negative Percent Agreement with a predicate
assay, rather than clinical sensitivity and specificity (i.e.,
comparing the performance of antibody tests with other antibody tests,
rather than with the presence or absence of disease).
     Sample Size: Two comments noted the investment needed to
conduct clinical trials with sufficiently large sample size to
demonstrate the required levels of sensitivity and specificity will
serve as a disincentive for manufacturers to develop new assays or to
adapt existing assays and will ultimately not meet the reclassification
goal of improving access to quality HIV testing. The comments noted
that sensitivity and specificity requirements, with related sample size
needs, are one of the main driving forces of clinical trial cost.
    (Response 4) We disagree with the comments regarding the
performance of currently approved diagnostic tests, harmonization with
HCV performance levels, and clinical trial sample size. FDA's
experience with HIV diagnostic and supplemental tests demonstrates that
the proposed criteria are consistent with the performance demonstrated
by currently approved tests, which have a long history of safe and
effective use. There may be, under some circumstances, differences
observed in the performance of a test when used in a real-world setting
and its performance in the more controlled environment of a clinical
study. However, FDA believes that lowering the criteria for clinical
study performance raises the risk that future devices will not provide
the same level of safety and effectiveness as currently approved
devices and, thus, will not provide a reasonable assurance of safety
and effectiveness. The comments indicating that ``none of the currently
approved assays perform at the level specified by the special
controls'' and that ``many of the currently approved assays don't
actually perform at these levels'' are inaccurate; all currently
approved HIV diagnostic tests met or exceeded FDA's proposed criteria
in the primary clinical studies submitted for approval.
    FDA does not consider the sensitivity or specificity of tests
meeting a 95 percent lower bound confidence interval of 95 percent to
be equivalent to the sensitivity or specificity of tests meeting a
lower bound of 99 percent. Tests that are unable to meet FDA's criteria
in the special controls could potentially generate a much higher number
of incorrect results than tests that meet FDA's proposed criteria. This
risk is present with the lower bound of 95 percent even if the point
estimate is constrained to 99 percent. Thus, introduction into the
market of new HIV tests with decreased performance compared with
currently available tests may result in a large increase in the number
individuals who would receive incorrect results. Incorrect test
results, both false positive and false negative results, endanger both
individual and public health because people may undergo unneeded
treatment or may be denied needed treatment and may inadvertently
spread HIV.
    Regarding aligning the proposed performance criteria with the
performance criteria proposed as special controls for certain HCV
antibody tests and nucleic acid-based HCV ribonucleic acid (RNA) tests,
the performance necessary to provide a reasonable assurance of safety
and effectiveness of an in vitro diagnostic device is based on, among
other things, the specific analyte measured, the disease or condition
for which the particular device is intended to be used in diagnosis,
and the conditions of use. This means that the performance criteria
identified in special controls may vary between devices that measure
different analytes (e.g., HIV and HCV) or with different conditions of
use (e.g., point of care (PoC) versus lab-based) because the risks
associated with each device are different.
    The performance criteria FDA proposed and finalized for HCV
antibody tests and nucleic acid-based HCV RNA tests have been
demonstrated to provide a reasonable assurance of

safety and effectiveness of these tests that aid in the diagnosis of
HCV infection (see 85 FR 18483, April 2, 2020, and 86 FR 66173,
November 22, 2021); likewise, the criteria FDA proposed for HIV
diagnostic and supplemental tests have been demonstrated to provide a
reasonable assurance of safety and effectiveness for these tests that
aid in diagnosis of infection with HIV. Lowering performance criteria
for HIV diagnostic and supplemental tests raises the risk that lower-
performing tests, for which there is not a reasonable assurance of
safety and effectiveness, will be on the market. Therefore, the
performance criteria FDA is finalizing in this order do not mirror
those FDA has finalized for HCV tests.
    With respect to the concerns expressed about the number of samples
that will be needed to conduct the clinical studies, we note that the
final special controls do not specify a minimum number of samples that
must be used. The number of samples needed in the study is dependent on
the performance of the assay. Although reclassification of these
devices to class II may not always result in smaller clinical studies
than were conducted for HIV diagnostic and supplemental tests approved
under PMAs, we believe that other effects of the reclassification of
these devices into class II, such as typically shorter review timelines
for 510(k) submissions, will decrease the burden associated with
obtaining marketing authorization of these devices. For all the reasons
mentioned above, FDA is retaining the proposed specificity and
sensitivity performance criteria in this final order.
    (Comment 5) Several comments addressed the special control to
submit a complaint log to FDA. One comment requested clarification on
which devices would be subject to the special control, the timeframe
for submission of the complaint log, and how FDA will act on the
information included in the complaint log. One comment indicated that
this information will duplicate the information submitted under part
803 (21 CFR part 803), which requires the submission of malfunction
reports. Another comment stated that the required submission of a
complaint log to monitor decreases in test performance, manufacturing
failures, or trends in false positive results is redundant and an
unnecessary mitigation measure, and that current postmarket controls
for complaint handling, trending, and safety reporting are sufficient
to mitigate these risks and are subject to routine inspection. The
comment further asserted that this special control would impose
reporting requirements that are typically reserved for class III
devices.
    (Response 5) The submission of the complaint log to FDA is not
intended to act as a replacement for a periodic report that is
submitted for a PMA-approved device under 21 CFR 814.84 or to duplicate
the information submitted to fulfill the requirements for medical
device reports (MDRs) under part 803. Instead, we are requiring the
submission of a log of the complaints a manufacturer receives about
these devices that includes certain available information for each
complaint. These complaints must already be reviewed and evaluated by
manufacturers under 21 CFR 820.198. Therefore, we expect that
submission of this log to FDA should not be burdensome to
manufacturers. We have revised the special controls in this final order
to clarify that the information about each complaint listed at
Sec. Sec.  866.3956(b)(1)(iii) and 866.3957(b)(1)(iii) (21 CFR
866.3956(b)(1)(iii) and 866.3957(b)(1)(iii)) must be included in the
log to the extent it is available and that the types of complaints
listed in the parenthetical are examples of the types of complaints
manufacturers may receive about these devices.
    Manufacturers may submit the information electronically through the
FDA Electronic Submission Gateway or on paper or electronic media
(e.g., CD, DVD) to the Center for Biologics Evaluation and Research
Document Control Center. The complaint log must be submitted only for a
period of 5 years following device clearance. The requirement does not
apply to devices previously approved by FDA following submission of a
PMA application. However, if a manufacturer of a device previously
approved under a PMA subsequently submits a traditional 510(k) for a
change to that device, the requirement in the special controls would
apply. The 5-year period does not restart because of minor changes to a
device that do not necessitate the submission of a new 510(k). FDA
intends to review the information submitted in the complaint logs in a
timely way and engage with manufacturers as necessary.
    The submission of the complaint log to FDA as required in the
special control will alert FDA to potential problems with devices that
may not meet the definition of MDR reportable events under part 803,
but that can potentially affect the safety and effectiveness of these
devices. Such problems may include an unusually high invalid rate or
issues with users conducting the test. The submission of the complaint
log will allow FDA to be alerted earlier to these concerns and to
whether they have been adequately addressed, which we believe is
important to providing reasonable assurance of safety and effectiveness
for these devices. The Agency usually would not evaluate this kind of
complaint information until an FDA inspection, which typically occurs
less frequently than annually.
    (Comment 6) Two comments indicated that the cost of conducting
clinical trials to meet the performance requirements in the proposed
special controls for HIV diagnostic and supplemental tests as compared
to those proposed for HCV tests will be a disincentive for
manufacturers to develop multiplex laboratory assays or dual point-of-
care assays with both analytes. It was noted that, with the high burden
of co-occurring HIV and HCV infection, the capability to fully and
efficiently integrate diagnostic testing for HIV and HCV is essential.
    (Response 6) FDA supports efforts to integrate diagnostic testing
for HIV and HCV. However, as noted in Response 4 of this final order,
the performance necessary to provide a reasonable assurance of safety
and effectiveness of in vitro diagnostic devices is based on, among
other things, the analyte, the disease or condition for which the
particular device is intended to be used in diagnosis, and the
conditions of use. Accordingly, the performance criteria necessary to
provide a reasonable assurance of safety and effectiveness for an HIV
diagnostic or supplemental test are reflected in this final order.
Device manufacturers with questions on their plans for development of
multiplex devices for HIV and HCV, including on the design of clinical
studies, can request FDA feedback through the Q-Submission Program
(Ref. 1).
    (Comment 7) One comment noted that the proposed reclassification of
HIV diagnostic and supplemental tests from class III to class II with
special controls decreases some regulatory burden, including the
reduced costs associated with a 510(k), compared to a PMA and
supplements. However, the comment expressed concern that considerable
burden remains associated with the cost of clinical trials to
demonstrate the required performance criteria and to add a new specimen
type, for example a dried blood spot, to a marketed device. The comment
asserted that the clinical trial required to add a new specimen type
under the proposed regulatory pathway would be equivalent to the
current pathway and would be a disincentive to manufacturers to address
changing needs in the field by

submitting changes to their original submission.
    (Response 7) FDA concurs that reclassification of HIV diagnostic
and supplemental tests from class III to class II with special controls
will reduce regulatory burdens as manufacturers will no longer be
required to submit a PMA but can instead submit a 510(k) and receive
clearance before marketing their device. However, we decline to revise
the special controls necessary to provide a reasonable assurance of
safety and effectiveness of these devices for the reasons discussed in
Response 4 above. FDA remains open to discussions with device
manufacturers about clinical study designs.
    (Comment 8) One comment objected to requiring prescriptions for HIV
diagnostic testing, noting that the requirement would result in more
HIV transmissions.
    (Response 8) FDA believes that the reclassification of HIV
diagnostic and supplemental tests to class II with special controls
will provide a reasonable assurance of safety and effectiveness of
these devices while expanding access to HIV testing and reducing the
regulatory burden on manufacturers. Under this final order, the HIV
serological diagnostic and supplemental tests and HIV NAT diagnostic
and supplemental tests subject to this reclassification are identified
as prescription use only devices. There are different performance
considerations and risks associated with non-prescription HIV
diagnostic and supplemental tests. Although not subject to this final
order, FDA has approved one home-use device for which a prescription is
not required.

III. Final Order

    Based on the information discussed in the preamble to the proposed
order (85 FR 10110), the comments received on the proposed order, the
Panel discussions (Ref. 2), and FDA's experiences over the years with
these device types, FDA concludes that special controls, in conjunction
with general controls, will provide reasonable assurance of the safety
and effectiveness of HIV serological diagnostic and supplemental tests
and HIV NAT diagnostic and supplemental tests. FDA is adopting its
findings under section 513(f)(3) of the FD&C Act, as published in the
preamble to the proposed order (85 FR 10110).
    FDA is issuing this final order to reclassify certain HIV
serological diagnostic and supplemental tests and HIV NAT diagnostic
and supplemental tests from class III into class II and to establish
special controls that will be codified at Sec. Sec.  866.3956 and
866.3957.\1\ In this final order, the Agency has identified special
controls under section 513(a)(1)(B) of the FD&C Act which, together
with general controls, provide a reasonable assurance of the safety and
effectiveness of HIV serological and NAT diagnostic and supplemental
tests.
---------------------------------------------------------------------------

    \1\ FDA notes that the ``ACTION'' caption for this final order
is styled as ``Final amendment; final order,'' rather than ``Final
order.'' Beginning in December 2019, this editorial change was made
to indicate that the document ``amends'' the Code of Federal
Regulations. This 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.
---------------------------------------------------------------------------

    FDA is making a few clarifications and modifications to the special
controls as published in the proposed order after considering public
comments, as discussed above, and on its own initiative. These include:
(1) Correcting a reference to ``prescription use only'' in Sec.
866.3957(a) to read ``for professional use only'' and moving the
placement of the text stating the tests are for professional use only
within both Sec. Sec.  866.3956(a) and 866.3957(a); (2) referring to
``blood products'' instead of ``plasma'' in Sec.  866.3956(a) and
(b)(1)(i)(A) and in Sec.  866.3957(a) and (b)(1)(i)(A) for consistency
with the labeling of more recently approved tests; (3) clarifying in
Sec. Sec.  866.3956(b)(1)(v)(A) and 866.3957(b)(1)(v)(A) that multisite
clinical studies required for devices intended for PoC use must be
conducted at appropriate PoC sites; (4) clarifying that the procedures
for determining when to submit an MDR described in Sec.
866.3956(b)(1)(ii)(K) and in Sec.  866.3957(b)(1)(ii)(K) must be
appropriate and acceptable so that they ensure appropriate adverse
event reporting; (5) clarifying certain aspects of the special controls
regarding submission of complaint log; (6) adding references to
``labeling'' in Sec.  866.3956(b)(2), (b)(3), and (b)(5) and in Sec.
866.3957(b)(2), (b)(3), and (b)(5) to make clearer that certain
required statements must be included in the device labeling and making
other minor wording changes to labeling statements required under
Sec. Sec.  866.3956(b)(2) and 866.3957(b)(2); (7) changing references
to the PoC or supplemental ``claim'' to ``PoC use'' or ``supplemental
use'' for consistency with terminology used elsewhere in the special
controls; and (8) identifying more clearly that certain information
must be included in 510(k) submissions for HIV 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. FDA has determined that premarket
notification is necessary to provide a reasonable assurance of the
safety and effectiveness of HIV serological diagnostic and supplemental
tests and HIV NAT diagnostic and supplemental tests. Therefore, these
device types are not exempt from premarket notification requirements.
Persons who intend to market theses device types must submit and obtain
clearance of a premarket notification and demonstrate compliance with
the special controls in this final order, prior to marketing the
device.
    The devices that are the subject of this reclassification are
assigned the generic names ``human immunodeficiency virus (HIV)
serological diagnostic and supplemental tests'' and ``human
immunodeficiency virus (HIV) nucleic acid (NAT) diagnostic and
supplemental tests.'' HIV serological diagnostic and supplemental tests
are identified as prescription devices for the qualitative detection of
HIV antigen(s) and/or detection of antibodies against HIV in human body
fluids or tissues. HIV NAT diagnostic and supplemental tests are
identified as prescription devices for the qualitative detection of HIV
nucleic acid in human body fluids or tissues. HIV serological
diagnostic and supplemental tests and the NAT diagnostic and
supplemental tests are intended for use as an aid in the diagnosis of
infection with HIV, and their results are intended to be interpreted in
conjunction with other relevant clinical and laboratory findings. These
tests are for professional use only and are not intended to be used for
monitoring patient status or for screening donors of blood or blood
products, or human cells, tissues, and cellular and tissue-based
products (HCT/Ps).
    Under this final order, the HIV serological diagnostic and
supplemental tests and HIV NAT diagnostic and supplemental tests are
identified as prescription use only devices. Prescription in vitro
diagnostic devices are exempt from the requirement for adequate
directions for use under section 502(f)(1) of the FD&C Act (21 U.S.C.
352(f)(1)) and 21 CFR 801.5, as long as all the conditions of 21 CFR
801.109 are met. A premarket notification submission for these devices
will be required in the circumstances described in 21 CFR 807.81.

IV. 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. In accordance with section 513(f)(3) of the FD&C Act, we are
codifying in this final order the classification of HIV serological
diagnostic and supplemental tests in the new Sec.  866.3956, under
which these devices are reclassified from class III to class II. In
addition, we are codifying the classification of HIV NAT diagnostic and
supplemental tests in the new Sec.  866.3957, under which these devices
are reclassified from class III to class II.

V. 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.

VI. Paperwork Reduction Act of 1995

    This final order contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521).
The information collection provisions in Sec. Sec.  866.3956(b)(1)(iii)
and 866.3957(b)(1)(iii) have been approved under OMB control number
0910-0437. This approval expires on March 31, 2025. An Agency may not
conduct or sponsor, and a person is not required to respond to, a
collection of information unless it displays a currently valid OMB
control number.
    This final order also refers to previously approved FDA collections
of information. These collections of 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; the collections of information in part 803 have been
approved under OMB control number 0910-0437; and the collections of
information in 21 CFR parts 801 and 809 have been approved under OMB
control number 0910-0485.

VII. References

    The following references are on display in the Dockets Management
Staff (see ADDRESSES) and are available for viewing 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. FDA, ``Requests for Feedback and Meetings for Medical Device
Submissions: The Q-Submission Program,'' available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program.
2. Transcript of 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, 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, 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 and are for
professional use only. The test results are intended to be interpreted
in conjunction with other relevant clinical and laboratory findings.
These tests are not intended to be used for monitoring patient status,
or for screening donors of blood or blood products, 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 or blood products 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, carryover, 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.
    (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) Appropriate and acceptable 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 if
available: The type of event (e.g., false negative/false nonreactive 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 clearance of a
traditional premarket notification.
    (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 PoC labeling must include a statement that the test is
intended for PoC use.
    (ii) The PoC labeling must include the following information near
the statement of the intended use:
    (A) That the test is for distribution 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) Instructions for individuals to 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 in the labeling must state that reactive
results are considered preliminary and should be confirmed following
current guidelines.
    (v) Device verification and validation for PoC use must include:
    (A) Detailed documentation of performance from a multisite clinical
study conducted at appropriate PoC sites. 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)(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) 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) Device validation and verification for supplemental use must
include a clinical study, including samples that were initially
reactive and repeatedly reactive on a diagnostic test but were negative
or indeterminate on a different confirmatory test. Premarket
notification submissions must include this information.
    (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) Device validation and verification must include a clinical
study including samples that were initially reactive and repeatedly
reactive on a diagnostic test but were negative or indeterminate on a
confirmatory test. Premarket notification submissions must include this
information.
    (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) The results interpretation in the labeling must include
instructions for the user on how to interpret the results, including
un-typeable and co-infection results.
    (iii) Device validation and verification must include evaluation of
analytical and clinical sensitivity and specificity for each of the HIV
types, strains, and subtypes of HIV intended to be differentiated.
Premarket notification submissions must include this information.

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 and are for professional use only. The test results
are intended to be interpreted in conjunction with other relevant
clinical and laboratory findings. These tests are not intended to be
used for monitoring patient status, or for screening donors of blood or
blood products, 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 or blood products, 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, carryover, 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) Appropriate and acceptable 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, if
available: The type of event (e.g., false negative/false nonreactive 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 clearance of a
traditional premarket notification.
    (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 PoC labeling must include a statement that the test is
intended for PoC use.
    (ii) The PoC labeling must include the following information near
the statement of the intended use:
    (A) That the test is for distribution 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) Instructions for individuals to 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 in the labeling must state that reactive
results are considered preliminary and should be confirmed following
current guidelines.
    (v) Device verification and validation for PoC use must include:
    (A) Detailed documentation from a well-conducted multisite clinical
study conducted at appropriate PoC sites. 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)(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) 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) Device validation and verification for supplemental use must
include a clinical study, including samples that were initially
reactive and repeatedly reactive on a diagnostic test but were negative
or indeterminate on a confirmatory test. Premarket notification
submissions must include this information.
    (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) Device validation and verification must include a clinical
study including samples that were initially reactive and repeatedly
reactive on a diagnostic test but were negative or indeterminate on a
confirmatory test. Premarket notification submissions must include this
information.
    (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) The results interpretation in the labeling must include
instructions for the user on how to interpret the results, including
un-typeable and co-infection results.
    (iii) Device validation and verification must include evaluation of
analytical and clinical sensitivity and specificity for each of the
types, strains, and subtypes of HIV intended to be differentiated.
Premarket notification submissions must include this information.

    Dated: May 11, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-10461 Filed 5-13-22; 8:45 am]
BILLING CODE 4164-01-P