[Federal Register Volume 87, Number 213 (Friday, November 4, 2022)]
[Rules and Regulations]
[Pages 66545-66549]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-23868]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2020-N-2297]
Microbiology Devices; Reclassification of Human Immunodeficiency
Virus Viral Load Monitoring Tests
AGENCY: Food and Drug Administration, HHS.
ACTION: Final amendment; final order.
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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
issuing a final order to reclassify human immunodeficiency virus (HIV)
viral load monitoring 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 a
new device classification regulation along with special controls that
are necessary to provide a reasonable assurance of safety and
effectiveness for this device type. The final order reclassifies this
device type from class III (premarket approval) to class II (special
controls) and will reduce the regulatory burdens associated with these
devices because manufacturers will no longer be required to submit a
premarket approval application (PMA) for this device type but can
instead submit a less burdensome premarket notification (510(k)) and
receive clearance before marketing their device.
DATES: This order is effective December 5, 2022.
FOR FURTHER INFORMATION CONTACT: Myrna Hanna, Center for Biologics
Evaluation and Review, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 72, 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), the
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
[[Page 66546]]
safety and effectiveness of the device for its intended use.
In the Federal Register of November 24, 2021 (86 FR 66982), FDA
published a proposed order to reclassify HIV viral load monitoring
tests from class III to class II (special controls), subject to
premarket notification. The comment period on the proposed order closed
on January 24, 2022.
II. Comments on the Proposed Order
In response to the November 24, 2021, proposed order, FDA received
three comments (two comments from public health organizations and one
comment from a device manufacturer) 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 commenters 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) All three commenters expressed general support for the
proposed reclassification and proposed special controls.
(Response 1) We acknowledge and appreciate the supportive comments.
In this final order, we are reclassifying HIV viral load monitoring
tests into class II and establishing the special controls published in
the proposed order (86 FR 66982) without modifications except for minor
editorial changes. See Section III, below, for a summary of the final
order.
(Comment 2) One commenter requested that FDA provide more detail
regarding the application in various analytical studies of the proposed
requirement under Sec. 866.3958(b)(2)(iii) (21 CFR
866.3958(b)(2)(iii)) that ``[s]amples selected for use in analytical
studies or used to prepare samples for use in analytical studies must
be from subjects with clinically relevant genotypes circulating in the
United States.''
(Response 2) FDA does not agree that additional detail is necessary
to describe the requirement under Sec. 866.3958(b)(2)(iii). The
requirement to use or prepare samples from subjects with clinically
relevant genotypes circulating in the United States is intended to
ensure that the device will detect HIV genotypes that are of clinical
concern at the time the device is cleared. How this requirement should
be implemented for a particular analytical study would depend on other
details regarding study design, the specific device at issue, and the
currently circulating genotypes in the United States. Therefore, it is
not practical to describe how this requirement would apply for all
future analytical studies of HIV viral load monitoring tests in this
final order. If the developer of an HIV viral load monitoring test
seeks feedback about the design of an analytical study specific to the
developer's device, such feedback can be provided through the Q-
submission program.\1\
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\1\ FDA has issued guidance for submitters on the Q-submission
program. See ``Requests for Feedback and Meetings for Medical Device
Submissions: The Q-Submission Program; Guidance for Industry and
Food and Drug Administration Staff'' dated January 6, 2021,
available at https://www.fda.gov/media/114034/download.
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(Comment 3) One commenter addressed proposed Sec.
866.3958(b)(2)(v) and agreed with the requirement that ``[s]amples
tested to demonstrate analytical specificity must include appropriate
numbers and types of samples from patients with underlying illness and
infection. . . .'' With respect to the requirement under proposed Sec.
866.3958(b)(2)(v) that samples tested to demonstrate analytical
specificity ``include appropriate numbers and types of samples . . .
from patients with potential interfering substances[,]'' the commenter
suggested that there be an option to test the effect of specific
interfering substances ``in accordance to [sic] CLSI EP07--Interference
Testing in Clinical Chemistry; Ed 3. Approved Guideline.'' The
commenter added that, ``[i]n this case both HIV-1 positive and HIV-1
negative specimens would be spiked with each potentially interfering
substance (endogenous and exogenous) and tested in the investigational
device.''
(Response 3) We agree with the comment that in some circumstances,
a combination of clinical and spiked samples is appropriate based on
the study goals and design, as discussed in EP07. The special control
provision at Sec. 866.3958(b)(2)(v) does not preclude this
possibility. FDA believes that studies conducted to meet the
requirements under Sec. 866.3958(b)(2)(v) should use clinical samples
to the extent possible because spiked samples may not mimic natural
samples from individuals. We encourage device developers to consult the
study designs and recommendations in the FDA recognized voluntary
consensus standard EP07, Interference Testing in Clinical Chemistry,
3rd Ed. (see https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/detail.cfm?standard__identification_no=37749).
(Comment 4) One commenter requested that FDA clarify the meaning of
``production lots'' in Sec. 866.3958(b)(2)(iv), which requires that
device verification and validation include a ``[m]ultisite
reproducibility study that includes the testing of three independent
production lots.'' Specifically, the commenter asked if ``these [could]
be premarket lots, which are equivalent to what would be
commercialized''.
(Response 4) FDA believes the language in Sec. 866.3958(b)(2)(iv)
is sufficiently clear on this issue. The phrase ``three independent
production lots'' means three lots of the finished device, where the
lots are produced independently of each other. While the three
independent lots may be produced in a premarket validation run, the
devices must be manufactured by a process equivalent to that for the
devices that will be commercialized.
(Comment 5) Two commenters recommended harmonizing reclassification
of HIV viral load monitoring tests with the proposed reclassification
of HIV diagnostic and supplemental tests and indicated that doing so
could encourage development of or reduce barriers to marketing devices
intended for use in both monitoring and diagnosis. Another comment
recommended that FDA align the special controls for HIV tests with the
requirements for HCV nucleic acid (NAT) tests in the final
reclassification order ``Microbiology Devices; Reclassification of
Nucleic Acid-Based Hepatitis C Virus Ribonucleic Acid Assay Devices, To
Be Renamed Nucleic Acid-Based Hepatitis C Virus Ribonucleic Acid
Tests'' (Docket No. FDA-2020-N-1088; April 2, 2020; 86 FR 66169).
(Response 5) Where appropriate, the special controls for HIV viral
load monitoring tests in Sec. 866.3958 are aligned with the special
controls for HIV NAT diagnostic and/or supplemental tests in 21 CFR
866.3957, which were established in a final order published May 16,
2022 (Microbiology Devices: Reclassification of Human Immunodeficiency
Virus Serological Diagnostic and Supplemental Tests and Human
Immunodeficiency Virus Nucleic Acid Diagnostic and Supplemental Tests,
87 FR 29661). However, although a test may use the same technology for
two different intended uses, e.g., use of NAT tests as an aid in
diagnosis of HIV infection and for viral load monitoring, the risks of
a false negative result from a diagnostic test are not identical to and
are potentially greater than the risks of a false negative result of a
viral load test. For example, an individual living with HIV whose viral
load is being monitored
[[Page 66547]]
is under the care of a healthcare provider. In this instance, the risk
of an incorrect result may be mitigated by clinical oversight. However,
an individual undergoing diagnostic testing may have no signs or
symptoms of infection, and one risk of an incorrect result is that they
may be lost to care altogether. FDA is committed to working with
manufacturers seeking clearance of a device for both intended uses
using a least-burdensome approach.\2\
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\2\ See ``The Least Burdensome Provisions: Concepts and
Principles; Guidance for Industry and Food and Drug Administration
Staff'' (February 5, 2019), available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/least-burdensome-provisions-concept-and-principles.
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With respect to the comment regarding alignment of special controls
for HIV tests with those finalized for nucleic acid-based HCV
ribonucleic acid (RNA) tests, we note that the special controls
necessary to provide reasonable assurance of safety and effectiveness
of an in vitro diagnostic device are 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 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 versus lab-based)
because the risks associated with each device are different. FDA has
determined that the special controls identified in the proposed order
are, together with general controls, sufficient to provide reasonable
assurance of safety and effectiveness for HIV viral load monitoring
tests. Therefore, FDA is finalizing those special controls in this
order without making changes to align them further with those for
nucleic acid-based HCV RNA tests.
To the extent the comment addresses alignment of special controls
for HIV diagnostic and supplemental tests with those for nucleic acid-
based HCV RNA tests, the comment is outside of the scope of this final
order. For a discussion of comments received on FDA's proposed special
controls for HIV NAT diagnostic and supplemental tests and HIV
serological diagnostic and supplemental tests, please refer to the
final order, ``Microbiology Devices; Reclassification of Human
Immunodeficiency Virus Serological Diagnostic and Supplemental Tests
and Human Immunodeficiency Virus Nucleic Acid Diagnostic and
Supplemental Tests'' (Docket No. FDA-2019-N-5192; May 16, 2022; 87 FR
29661).
III. Final Order
Based on the information discussed in the preamble to the proposed
order (86 FR 66982), the comments received on the proposed order, and
FDA's experience over the years with this device type, FDA concludes
that special controls, in conjunction with general controls, will
provide reasonable assurance of the safety and effectiveness of HIV
viral load monitoring 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 HIV viral load
monitoring tests from class III into class II and to establish special
controls that will be codified at Sec. 866.3958.\3\ 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
viral load monitoring tests. FDA is reclassifying these devices and
establishing special controls as published in the proposed order (86 FR
66982) with minor editorial changes for clarity in Sec. 866.3958(a),
(b)(1)(iii), and (b)(2)(vii).
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\3\ 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.
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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 viral load monitoring tests. Therefore,
this device type is not exempt from premarket notification
requirements. Persons who intend to market HIV viral load monitoring
tests 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 name ``human immunodeficiency virus (HIV) viral
load monitoring tests''. HIV viral load monitoring tests are identified
as in vitro diagnostic prescription devices for the quantitation of the
amount of HIV RNA in human body fluids. HIV viral load monitoring tests
are intended for use in the clinical management of individuals living
with HIV and are for professional use only. These devices are not
intended for use as an aid in diagnosis or for screening donors of
blood or blood products or human cells, tissues, or cellular and
tissue-based products (HCT/Ps).
Under this final order, the HIV viral load monitoring tests are
identified as prescription use only devices. As such, these
prescription devices must satisfy prescription labeling requirements
for in vitro diagnostic products (see 21 CFR 809.10(a)(4) and
(b)(5)(ii)). 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 viral load
monitoring tests in the new Sec. 866.3958, 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
FDA concludes that this final order 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 final order 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
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collections of information in 21 CFR 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.
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. 866.3958 to subpart D to read as follows:
Sec. 866.3958 Human immunodeficiency virus (HIV) viral load
monitoring test.
(a) Identification. A human immunodeficiency virus (HIV) viral load
monitoring test is an in vitro diagnostic prescription device for the
quantitation of the amount of HIV ribonucleic acid (RNA) in human body
fluids. The test is intended for use in the clinical management of
individuals living with HIV and is for professional use only. The test
results are intended to be interpreted in conjunction with other
relevant clinical and laboratory findings. The test is not intended to
be used as an aid in diagnosis or for screening donors of blood or
blood products or human cells, tissues, or cellular and tissue-based
products (HCT/Ps).
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) The labeling must include:
(i) An intended use that states that the device is not intended for
use as an aid in diagnosis or for use in screening donors of blood or
blood products, or HCT/Ps.
(ii) A detailed explanation of the principles of operation and
procedures used for assay performance.
(iii) A detailed explanation of the interpretation of results and
that recommended actions should be based on current clinical
guidelines.
(iv) Limitations, which must be updated to reflect current clinical
practice and patient management. The limitations must include, but are
not limited to, statements that indicate:
(A) The matrices and sample types with which the device has been
cleared and that use of this test with specimen types other than those
specifically cleared for this device may cause inaccurate test results.
(B) Mutations in highly conserved regions may affect binding of
primers and/or probes resulting in the under-quantitation of virus or
failure to detect the presence of virus.
(C) All test results should be interpreted in conjunction with the
individual's clinical presentation, history, and other laboratory
results.
(2) Device verification and validation must include:
(i) Detailed device description, including the device components,
ancillary reagents required but not provided, and an explanation of the
device methodology. Additional information appropriate to the
technology must be included, such as detailed information on the design
of primers and probes.
(ii) 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.
(iii) 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, limit of quantitation, cutoff determination,
precision, linearity, endogenous and exogenous interferences, cross-
reactivity, carry-over, quality control, matrix equivalency, 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 genotypes circulating in the United
States.
(iv) Multisite reproducibility study that includes the testing of
three independent production lots.
(v) Analytical sensitivity of the device must demonstrate
acceptable performance at current clinically relevant medical decision
points. Samples tested to demonstrate analytical sensitivity must
include appropriate numbers and types of samples, including real
clinical samples near the lower limit of quantitation and any
clinically relevant medical decision points. Analytical specificity of
the device must demonstrate acceptable performance. Samples tested to
demonstrate analytical specificity must include appropriate numbers and
types of samples from patients with different underlying illnesses and
infection and from patients with potential interfering substances.
(vi) Detailed documentation of performance from a multisite
clinical study or a multisite analytical method comparison study.
(A) For devices evaluated in a multisite clinical study, the study
must use specimens from individuals living with HIV being monitored for
changes in viral load, and the test results must be compared to the
clinical status of the patients.
(B) For tests evaluated in a multisite analytical method comparison
study, the performance of the test must be compared to an FDA-cleared
or approved comparator. The multisite method comparison study must
include appropriate numbers and types of samples with analyte
concentrations across the measuring range of the assay, representing
clinically relevant genotypes. The multisite method comparison study
design, including number of samples tested, must be sufficient to meet
the following criteria:
(1) Agreement between the two tests across the measuring range of
the assays must have an r2 of greater than or equal to 0.95.
(2) The bias between the test and comparator assay, as determined
by difference plots, must be less than or equal to 0.5 log copies/mL.
(vii) Detailed documentation of a single-site analytical method
comparison study between the device and an FDA-cleared or approved
comparator if a multisite clinical study is performed under
paragraph(b)(2)(vi) of this section. The analytical method comparison
study must use appropriate numbers and types of samples with analyte
concentrations across the measuring range of the assay, representing
clinically relevant genotypes. The results must meet the criteria in
paragraphs (b)(2)(vi)(B)(1) and (2) of this section.
(viii) Strategies for detection of new strains, types, subtypes,
genotypes, and genetic mutations as they emerge.
(ix) 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.
(x) Final release criteria to be used for manufactured device lots
with an appropriate justification that lots released at the extremes of
the specifications will meet the claimed analytical and clinical
performance
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characteristics as well as the stability claims.
(xi) All stability protocols, including acceptance criteria.
(xii) Appropriate and acceptable procedure(s) for addressing
complaints and other device information that determines when to submit
a medical device report.
(xiii) Premarket notification submissions must include the
information contained in paragraphs (b)(2)(i) through (xii) of this
section.
Dated: October 28, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-23868 Filed 11-3-22; 8:45 am]
BILLING CODE 4164-01-P