[Federal Register Volume 86, Number 222 (Monday, November 22, 2021)]
[Rules and Regulations]
[Pages 66173-66177]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-25374]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2020-N-1082]
Microbiology Devices; Reclassification of Certain Hepatitis C
Virus Antibody Assay Devices, Renamed to Hepatitis C Virus Antibody
Tests
AGENCY: Food and Drug Administration, Department of Health and Human
Services (HHS).
ACTION: Final amendment; final order.
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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
issuing a final order to reclassify certain hepatitis C virus (HCV)
antibody assay devices intended for the qualitative detection of HCV,
postamendments class III devices (product code MZO) into class II
(general controls and special controls), subject to premarket
notification. FDA is renaming and codifying these devices under the
classification regulation named ``hepatitis C virus (HCV) antibody
tests.'' FDA is also identifying the special controls that the Agency
believes are necessary to provide a reasonable assurance of safety and
effectiveness of these devices.
DATES: This order is effective December 22, 2021.
FOR FURTHER INFORMATION CONTACT: Maria Ines Garcia, Center for Devices
and Radiological Health, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 66, Rm. 3104, Silver Spring, MD 20993-0002, 301-
796-7017, [email protected].
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 classes of devices, reflecting the regulatory
controls needed to provide reasonable assurance of their safety and
effectiveness. The three classes of devices are class I (general
controls), class II (general 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.\1\ Those devices remain
in class III and require premarket approval unless, and until, (1) FDA
reclassifies the device into class I or 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 (21 U.S.C.
360(k)) and part 807 (21 CFR part 807), subpart E, of the regulations.
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\1\ HCV antibody assay devices for the qualitative detection of
HCV with intended uses outside the scope of the classification under
21 CFR 866.3169 are considered postamendments devices that are
subject to classification under section 513(f)(1) of the FD&C Act
or, if the relevant requirements are met, under section 513(f)(2) of
the FD&C Act.
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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 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) of the FD&C Act and
[[Page 66174]]
Sec. 860.7(c)(2) (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 (21 U.S.C. 360j(c))). Publicly available information
excludes trade secret and/or confidential commercial information, e.g.,
the contents of a pending premarket approval application (PMA) (see
section 520(c) of the FD&C Act).
FDA published a proposed order in the Federal Register of April 2,
2020 (85 FR 18490), to reclassify these device types from class III
into class II (general controls and special controls), subject to
premarket notification. FDA has considered the information available to
the Agency, including the deliberations of the March 22, 2018,
Microbiology Devices Panel (2018 Panel), and comments from the public
docket to determine that there is sufficient information to establish
special controls to effectively mitigate the risks to the health
identified in section V of the proposed order, and that these special
controls, together with general controls, provide a reasonable
assurance of safety and effectiveness when applied to certain HCV
antibody assay devices intended for the qualitative detection of HCV.
Therefore, in accordance with section 513(f)(3) of the FD&C Act,
FDA, on its own initiative, is issuing this final order to reclassify
certain HCV antibody assay devices intended for the qualitative
detection of HCV from class III to class II (general and special
controls).\2\
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\2\ 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. The change was made in accordance with the Office of
the Federal Register's (OFR) interpretation 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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II. Comments on the Proposed Order
On April 2, 2020, FDA published in the Federal Register a proposed
order (85 FR 18490) to reclassify certain HCV antibody assay devices
intended for the qualitative detection of HCV from class III to class
II, subject to premarket notification. The comment period on the
proposed order closed on June 1, 2020. In response to the proposed
order, FDA received comments from industry, healthcare associations,
public health departments, and individual consumers by the close of the
comment period, some of which contained one or more comments on one or
more issues. We describe and respond to the comments in this section of
the document. Certain comments are grouped based on common themes; we
grouped similar comments together under the same number and listed them
numerically.
The order of response to the commenters is purely for
organizational purposes and does not signify the comment's value or
importance nor the order in which comments were received. Please note
that in some cases we separated different issues discussed by the same
commenter and designated them as distinct comments for purposes of our
responses.
(Comment 1) FDA received numerous comments in favor of the proposed
reclassification of certain HCV antibody assay devices intended for the
qualitative detection of HCV from class III to class II with special
controls. Commenters stated they believed that special controls, along
with general controls, could provide a reasonable assurance of the
safety and effectiveness of these devices. In addition, they believed
that the decreased regulatory burden resulting from the
reclassification could encourage further development of, and provide
patients more timely access to, these devices. Overall, there was a
general consensus among the commenters that the proposed special
controls are necessary and sufficient to mitigate the risks to health
of patients presented by these devices and to provide reasonable
assurance of the safety and effectiveness of these devices.
(Response 1) Based on the evidence considered, comments received in
response to the proposed order and deliberations of the 2018 Panel, FDA
agrees with the commenters that reclassification of certain HCV
antibody assay devices for the qualitative detection of HCV from class
III into class II and that special controls, in addition to general
controls, can provide a reasonable assurance of the safety and
effectiveness of these devices. In addition, FDA expects that the
reclassification of these devices would enable more manufacturers to
develop them such that patients would benefit from increased access to
safe and effective tests.
(Comment 2) One comment expressed concerns about the proposed
reclassification of these devices from class III into class II. The
commenter suggested that there was not enough justification to
reclassify these devices at this time and asked for clarification on
FDA's justification proposing this reclassification. The commenter also
asked for clarification on whether a high demand of these devices was a
consideration in FDA's proposed reclassification order.
(Response 2) Based on the evidence considered, comments received in
response to the proposed order and deliberations of the 2018 Panel, FDA
disagrees with this comment and continues to believe that
reclassification of these devices is justified for the reasons
identified in the proposed order (85 FR 18490). FDA's justification for
reclassifying these devices is based on the unanimous recommendation of
the 2018 Panel, FDA's accumulated experience with these devices from
review submissions, and from published peer-reviewed literature. In
addition, FDA believes that the special controls identified in this
final order, in addition to the general controls, will provide a
reasonable assurance of the safety and effectiveness of these devices.
FDA relies upon ``valid scientific evidence'' as defined in section
513(a)(3) of the FD&C Act and Sec. 860.7(c)(2) in the classification
process to determine the level of regulation for devices. FDA believes
the standard in section 513(a)(1)(B) of the FD&C Act is met as there is
sufficient information to establish special controls, which, in
addition to general controls, will provide reasonable assurance of the
safety and effectiveness of these devices. While FDA expects that the
reclassification of these devices would enable more manufacturers to
develop HCV antibody tests such that patients would benefit from
increased access to safe and effective tests, this is not a
consideration in the Agency's reclassification determination.
(Comment 3) Several commenters had questions about the scope of the
proposed reclassification order. Several commenters noted that the
proposed reclassification order identified these devices as HCV
antibody tests for prescription use and suggested that the
reclassification order should also include HCV antibody tests intended
for over-the-counter (OTC) use. In addition, one commenter suggested
that FDA's reclassification order should also include HCV antigen
tests, tests for hepatitis A and hepatitis B, and also that the
reclassification should include other specimen types for HCV antibody
tests beyond those identified in the proposed order (e.g., urine or
saliva).
(Response 3) These comments are beyond the scope of FDA's proposed
reclassification order which applies only to HCV antibody tests that
have been previously approved by FDA. FDA has not approved any HCV
antibody tests intended for OTC use and FDA believes that an HCV
antibody tests
[[Page 66175]]
intended for OTC use would be a new type of device not previously
classified based on the criteria at section 513(a)(1) of the FD&C Act
and, as a result, such postamendments devices would be automatically
classified into class III by operation of section 513(f)(1) of the FD&C
Act. FDA believes that an HCV antibody test intended for OTC use may be
a good candidate for the De Novo classification process under section
513(f)(2) of the FD&C Act (Refs. 1 and 2). FDA recommends that device
manufacturers interested in marketing an HCV antibody test for OTC use
submit a Pre-Submission to request FDA feedback on the studies and data
that may be necessary to support a De Novo request (Ref. 3).
Similarly, to date, FDA has only approved HCV antibody tests
intended for use with human serum or plasma and new specimen types are
beyond the scope of this reclassification order.
(Comment 4) Several commenters expressed support of FDA's proposal
to rename these devices from ``hepatitis C virus antibody assay
devices'' to ``hepatitis C virus (HCV) antibody tests.'' These
commenters believed that the new name for these devices made clear that
these are diagnostic tests and is consistent with the naming of similar
diagnostic devices. Alternatively, several commenters provided
suggestions on FDA's proposal to rename these devices to ``hepatitis C
virus (HCV) antibody tests.'' One commenter suggested renaming these
devices ``HCV serological tests.'' Another commenter suggested renaming
these devices ``hepatitis C virus (HCV) antibody test devices.''
(Response 4) FDA believes that the new identification of these
devices as ``hepatitis C virus (HCV) antibody tests'' is both
understandable to consumers and industry and is consistent with the
naming of similar diagnostic devices.
FDA disagrees with those commenters that proposed renaming these
devices ``HCV serological tests'' or ``hepatitis C virus (HCV) antibody
test devices'' as FDA believes that the identification of these devices
as ``hepatitis C virus (HCV) antibody tests'' adequately identifies the
types of devices that would be affected by this reclassification action
and is clear and consistent with the naming of similar diagnostic
devices.
(Comment 5) One commenter suggested that HCV antibody tests could
be classified in part 866 (21 CFR part 866) after ``Hepatitis A virus
(HAV) serological reagents'' which are currently classified under 21
CFR 866.3310.
(Response 5) FDA disagrees with this comment because FDA believes
that the classification of HCV antibody tests under Sec. 866.3169 (21
CFR 866.3169) is appropriate. In addition, FDA has proposed to
reclassify nucleic acid-based HCV ribonucleic acid (RNA) devices
intended for the qualitative or quantitative detection or genotyping of
HCV RNA under Sec. 866.3170 (21 CFR 866.3170) (85 FR 18483). The
classification of HCV antibody tests in Sec. 866.3169 would allow for
these devices to be located next to nucleic acid-based HCV RNA tests in
the Code of Federal Regulations (CFR).
(Comment 6) One commenter requested that FDA state the time that it
generally takes for FDA to review 510(k) submissions and PMA
applications.
(Response 6) Review times for a particular device may vary but the
FD&C Act requires manufacturers to submit a 510(k) to FDA at least 90
days before introducing, or before delivering for introduction, a
device into interstate commerce (see section 510(k) of the FD&C Act).
For comparison, FDA has 180 days to review a PMA starting on the date
an application is accepted for filing (see section 515(d) of the FD&C
Act (21 U.S.C. 360e(d)) and 21 CFR 814.40).
(Comment 7) One comment indicated a patient who was diagnosed with
hepatitis was successfully treated. Another comment requested that FDA
consider reducing the prices of HCV antibody tests as a result of their
reclassification.
(Response 7) Each of these comments are outside the scope of this
reclassification action.
(Comment 8) Several comments expressed general support of the
special controls identified in the proposed order and believed they
would provide a reasonable assurance of safety and effectiveness of
these devices. In addition, several commenters suggested that FDA
revise the special controls to include a requirement that the labeling
identify where and when these devices may be used consistent with
infection control standards and FDA guidance documents for infection
control. Additionally, it was suggested that the labeling specify the
special populations of patients for which test performance may be
affected.
(Response 8) FDA continues to believe that the special controls
identified in the proposed order and finalized in this final order are
sufficient to provide a reasonable assurance of safety and
effectiveness of HCV antibody tests.
FDA disagrees that a further level of specificity is necessary for
inclusion within the special controls to provide a reasonable assurance
of safety and effectiveness for these devices and wants to ensure that
the special controls remain appropriate and applicable to provide a
reasonable assurance of safety and effectiveness for these devices over
time. Further, performance of these devices may evolve over time for
special populations and any special populations for which performance
of these devices may be affected are required to be included in the
labeling for these devices by the special controls (see Sec.
866.3169(b)(1)(ii)(A)).
III. The Final Order
Based on the information discussed in the preamble to the proposed
order (85 FR 18490), the comments received for the proposed order, the
2018 Panel deliberations (Ref. 4), and FDA's experiences over the years
in reviewing these device types, FDA concludes that special controls,
in conjunction with general controls, will provide a reasonable
assurance of the safety and effectiveness of HCV antibody 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. FDA is issuing this
final order to reclassify HCV antibody tests intended for the
qualitative detection of HCV from class III to class II, and
establishing special controls by revising part 866. In this final
order, the Agency has identified the special controls under section
513(a)(1)(B) of the FD&C Act that, together with general controls,
provide a reasonable assurance of the safety and effectiveness of these
devices.
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 HCV antibody tests. Therefore, this device
type is not exempt from premarket notification requirements. Persons
who intend to market a new HCV antibody assay device must submit to FDA
a premarket notification, obtain clearance, and demonstrate compliance
with the special controls included in this final order, prior to
marketing the device.
These devices are assigned the generic name ``HCV antibody tests''
and identified as in vitro diagnostic devices intended for use with
human serum,
[[Page 66176]]
plasma, or other matrices as a prescription device that aids in the
diagnosis of HCV infection in persons with signs and symptoms of
hepatitis and in persons at risk for hepatitis C infection. The test is
not intended for screening blood, plasma, cell, or tissue donors.
Under this final order, HCV antibody tests are identified as
prescription use only devices and as such, HCV antibody tests must
satisfy prescription labeling requirements for in vitro diagnostic
products (see 21 CFR 809.10(a)(4) and (b)(5)(ii)). Under 21 CFR 807.81,
the device continues to be subject to 510(k) requirements.
IV. Codification of Orders
Prior to the amendments in the Food and Drug Administration Safety
and Innovation Act (Pub. L. 112-144) (FDASIA), section 513(e) of the
FD&C Act provided for FDA to issue regulations to reclassify devices.
Although section 513(e), as amended by FDASIA, requires FDA to issue
final orders rather than regulations, it also provides for FDA to
revoke previously issued regulations by order. FDA will continue to
codify classifications and reclassifications in the CFR. Changes
resulting from final orders will appear in the CFR as changes to
codified classification determinations or as newly codified orders.
Therefore, under section 513(e)(1)(A)(i), as amended by FDASIA, in this
final order, we are proposing to codify the classification of hepatitis
c virus antibody tests in the new Sec. 866.3169, under which HCV
antibody tests would be reclassified into 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 establishes special controls that refer to
previously approved FDA collections. These collections of information
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). The
collections of information in part 807, subpart E have been approved
under OMB control number 0910-0120; the collections of information in
21 CFR parts 801 and 809 have been approved under OMB control number
0910-0485; and the collections of information in 21 CFR part 820 have
been approved under OMB control number 0910-0073.
VII. References
The following references are on display at the Dockets Management
Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852, 240-402-7500 and are available for viewing
by interested persons between 9 a.m. and 4 p.m., Monday through Friday;
they also are 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. ``De Novo Classification Process (Evaluation of Automatic Class
III Designation)--Guidance for Industry and Food and Drug
Administration Staff,'' issued October 30, 2017 (available at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/de-novo-classification-process-evaluation-automatic-class-iii-designation).
2. ``Acceptance Review for De Novo Classification Requests--Guidance
for Industry and Food and Drug Administration Staff,'' issued
September 9, 2019 (available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/acceptance-review-de-novo-classification-requests).
3. ``Requests for Feedback and Meetings for Medical Device
Submissions: The Q-Submission Program--Guidance for Industry and
Food and Drug Administration Staff,'' issued May 7, 2019 (available
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program).
4. Transcript of the FDA Microbiology Devices Panel Meeting, March
22, 2018 (available at https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM630139.pdf).
List of Subjects in 21 CFR Part 866
Biologics, Laboratories, Medical devices.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 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. 866.3169 to subpart D to read as follows:
Sec. 866.3169 Hepatitis C virus antibody tests.
(a) Identification. A hepatitis C virus (HCV) antibody test is
identified as an in vitro diagnostic device intended for use with human
serum, plasma, or other matrices as a prescription device that aids in
the diagnosis of HCV infection in persons with signs and symptoms of
hepatitis and in persons at risk for hepatitis C infection. The test is
not intended for screening blood, plasma, cell, or tissue donors.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) The labeling required under Sec. 809.10(b) of this chapter
must include:
(i) A prominent statement that the test is not intended for the
screening of blood, plasma, and cell or tissue donors.
(ii) 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:
(A) When appropriate, the performance characteristics of the test
have not been established in populations of immunocompromised or
immunosuppressed patients or, other special populations where test
performance may be affected.
(B) The detection of HCV antibodies indicates a present or past
infection with hepatitis C virus, but does not differentiate between
acute, chronic, or resolved infection.
(C) The specimen types for which the device has been cleared, and
that use of the test with specimen types other than those specifically
cleared for this device may result in inaccurate test results.
(D) Test results are to be interpreted by qualified licensed
healthcare professionals in conjunction with the individual's clinical
presentation, history, and other laboratory results.
(E) A non-reactive test result may occur early during acute
infection, prior to development of a host antibody response to
infection, or when analyte levels are below the limit of detection of
the test.
(iii) A detailed explanation of the principles of operation and
procedures for performing the test.
(2) Design verification and validation must include the following:
(i) A detailed device description, including all parts that make up
the device, ancillary reagents required but not provided, an
explanation of the device methodology, and design of the antigen(s) and
capture antibody(ies)
[[Page 66177]]
sequences, rationale for the selected epitope(s), degree of amino acid
sequence conservation of the target, and the design and nature of all
primary, secondary, and subsequent standards used for calibration.
(ii) Documentation and characterization (e.g., supplier,
determination of identity, and stability) of all critical reagents
(including description of the antigen(s) and capture antibody(ies)),
and protocols for maintaining product integrity throughout its labeled
shelf life.
(iii) 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.
(iv) 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.
(v) Stability studies for reagents must include documentation of an
assessment of real-time stability for multiple reagent lots using the
indicated specimen types and must use acceptance criteria that ensure
that analytical and clinical performance characteristics are met when
stability is assigned based on the extremes of the acceptance range.
(vi) All stability protocols, including acceptance criteria.
(vii) Final release test results for each lot used in clinical
studies.
(viii) Multisite reproducibility study that includes the testing of
three independent production lots.
(ix) Analytical performance studies and results for determining the
limit of blank (LoB), limit of detection (LoD), cutoff, precision
(reproducibility) including lot-to-lot and/or instrument-to-instrument
precision, interference, cross reactivity, carryover, hook effect,
seroconversion panel testing, matrix equivalency, specimen stability,
reagent stability, and cross-genotype antibody detection sensitivity,
when appropriate.
(x) Analytical sensitivity of the test is the same or better than
that of other cleared or approved tests.
(xi) Detailed documentation of clinical performance testing from a
multisite clinical study. Performance must be analyzed relative to an
FDA cleared or approved HCV antibody test, or a comparator that FDA has
determined is appropriate. This study must be conducted using
appropriate patient samples, with an acceptable number of HCV positive
and negative samples in applicable risk categories. Additional relevant
patient groups must be validated as appropriate. The samples may be a
combination of fresh and repository samples, sourced from
geographically diverse areas. The study designs, including number of
samples tested, must be sufficient to meet the following criteria:
(A) Clinical sensitivity of the test must have a lower bound of the
95 percent confidence interval of greater than or equal to 95 percent.
(B) Clinical specificity of the test must have a lower bound of the
95 percent confidence interval of greater than or equal to 96 percent.
(3) For any HCV antibody test intended for Point of Care (PoC) use,
the following special controls, in addition to those listed in
paragraphs (b)(1) and (2) of this section, apply:
(i) Clinical studies must be conducted at PoC sites.
(ii) Additional labeling must include a brief summary of the
instructions for use that are appropriate for use in a PoC environment.
Dated: November 16, 2021.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2021-25374 Filed 11-19-21; 8:45 am]
BILLING CODE 4164-01-P