Proposed Rule2021-25372
Microbiology Devices; Reclassification of Human Immunodeficiency Virus Viral Load Monitoring Tests
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Published
November 24, 2021
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or the Agency) is proposing to reclassify human immunodeficiency virus (HIV) viral load monitoring tests, a postamendments class III device with the product code MZF, into class II (special controls), subject to premarket notification. FDA is also proposing a new device classification regulation along with special controls that the Agency believes are necessary to provide a reasonable assurance of safety and effectiveness for this device type. FDA is proposing this reclassification on its own initiative. If finalized, this order will reclassify this device type from class III (premarket approval) to class II (special controls) and 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.
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[Federal Register Volume 86, Number 224 (Wednesday, November 24, 2021)]
[Proposed Rules]
[Pages 66982-66988]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2021-25372]
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Proposed Rules
Federal Register
________________________________________________________________________
This section of the FEDERAL REGISTER contains notices to the public of
the proposed issuance of rules and regulations. The purpose of these
notices is to give interested persons an opportunity to participate in
the rule making prior to the adoption of the final rules.
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Federal Register / Vol. 86, No. 224 / Wednesday, November 24, 2021 /
Proposed Rules
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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: Proposed amendment; proposed order.
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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
proposing to reclassify human immunodeficiency virus (HIV) viral load
monitoring tests, a postamendments class III device with the product
code MZF, into class II (special controls), subject to premarket
notification. FDA is also proposing a new device classification
regulation along with special controls that the Agency believes are
necessary to provide a reasonable assurance of safety and effectiveness
for this device type. FDA is proposing this reclassification on its own
initiative. If finalized, this order will reclassify this device type
from class III (premarket approval) to class II (special controls) and
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: Submit either electronic or written comments on the proposed
order by January 24, 2022. See section XI of this document for the
proposed effective date of any final order based on this proposed
order.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before January 24, 2022. The <a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of January 24, 2022. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are postmarked or the delivery
service acceptance receipt is on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
<bullet> Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
<bullet> For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2020-N-2297 for ``Microbiology Devices; Reclassification of Human
Immunodeficiency Virus Viral Load Monitoring Tests.'' Received
comments, those filed in a timely manner (see ADDRESSES), will be
placed in the docket and, except for those submitted as ``Confidential
Submissions,'' publicly viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday, 240-402-7500.
<bullet> Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Myrna Hanna, Center for Biologics
Evaluation and Review, Food and Drug Administration, 10903 New
Hampshire
[[Page 66983]]
Ave., Bldg. 66, Rm. 5513, Silver Spring, MD 20993-0002, 301-796-5739.
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 safety and effectiveness of the device
for its intended use.
FDA relies upon ``valid scientific evidence,'' as defined in
section 513(a)(3) and 21 CFR 860.7(c)(2), in the classification process
to determine the level of regulation for devices. To be considered in
the reclassification process, the ``valid scientific evidence'' upon
which the Agency relies must be publicly available (see section 520(c)
of the FD&C Act). Publicly available information excludes trade secret
and/or confidential commercial information, e.g., the contents of a
pending PMA (see section 520(c) of the FD&C Act).
In accordance with section 513(f)(3) of the FD&C Act, the Agency is
proposing to reclassify HIV viral load monitoring tests, a
postamendments class III device, into class II (special controls),
subject to premarket notification because the Agency believes the
standard in 513(a)(1)(B) of the FD&C Act is met because there is
sufficient information to establish special controls, which, in
addition to general controls, will provide reasonable assurance of the
safety and effectiveness of the device.\1\
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\1\ In December 2019, FDA began adding the term ``Proposed
amendment'' to the ``ACTION'' caption for these documents, typically
styled ``Proposed order'', to indicate that they ``propose to
amend'' the Code of Federal Regulations. This editorial change was
made in accordance with the Office of Federal Register's (OFR)
interpretations of the Federal Register Act (44 U.S.C. chapter 15),
its implementing regulations (1 CFR 5.9 and parts 21 and 22), and
the Document Drafting Handbook.
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Section 510(m) of the FD&C Act provides that a class II device may
be exempted from the 510(k) premarket notification requirements under
section 510(k) of the FD&C Act if the Agency determines that premarket
notification is not necessary to reasonably assure the safety and
effectiveness of the device. FDA has determined that premarket
notification is necessary to reasonably assure the safety and
effectiveness of HIV viral load monitoring tests. Therefore, the Agency
does not intend to exempt this proposed class II device from premarket
notification (510(k)) submission under section 510(m) of the FD&C Act.
II. Regulatory History of the Devices
This proposed order addresses HIV viral load monitoring tests.
These are prescription tests that measure HIV RNA as an aid in
monitoring patient status and are assigned product code MZF.\2\ These
postamendments devices are currently regulated as class III devices
under section 513(f)(1) of the FD&C Act. Based on our review experience
and consistent with the FD&C Act and FDA's regulations in 21 CFR
860.134, FDA believes that these devices should be reclassified from
class III into class II with special controls because special controls,
in addition to general controls, are necessary and sufficient to
provide reasonable assurance of the safety and effectiveness of these
devices and there is sufficient
[[Page 66984]]
information to establish special controls to provide such assurance.
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\2\ On February 21, 2020, FDA published a separate proposed
order to reclassify certain HIV serological diagnostic and
supplemental tests and HIV nucleic acid diagnostic and supplemental
tests, which are also currently assigned product code MZF, from
class III into class II (85 FR 10110).
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FDA approved the first in vitro nucleic acid amplification-based
HIV viral load test on June 3, 1996, for the quantitation of HIV-1 RNA
in human plasma. Currently, there are six HIV viral load monitoring
tests on the market, all of which met the performance criteria
specified in the proposed special controls, considered necessary for
the intended use of the test, when they were approved by FDA (Ref. 1).
A review of the FDA's medical device reporting database, MAUDE
(Manufacturer and User Facility Device Experience), indicates a low
number of reported events for HIV viral load monitoring tests. Millions
of devices intended for use as HIV viral load monitoring tests have
been sold since 1996 with fewer than 200 reported adverse events as of
October 2020. Of these events, fewer than 10 are reported to involve
injuries due to incorrect results; the remainder are malfunctions, such
as user errors or incorrect results, that had no reported effect on the
individual being monitored. There has been one class II recall and no
class I (highest risk) recalls specific to HIV viral load monitoring
tests, which, coupled with the low number of reported events, indicates
a good safety record for this device class.
III. Device Description
This proposed order applies to HIV viral load monitoring tests that
are prescription in vitro diagnostic devices for monitoring of HIV
viral load in body fluids. 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)). 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).
HIV viral load monitoring tests are quantitative in vitro
diagnostic tests that measure the amount of HIV RNA in human body
fluids such as plasma and whole blood. The HIV RNA is isolated,
amplified, and detected by labeled probes that produce a quantitative
output that determines the amount of HIV in the sample. The test
results then are used as part of patient management decisions in
conjunction with other relevant clinical and laboratory findings.
Approval of HIV viral load monitoring tests has been based on
studies and established clinical decision points that demonstrate that
changes in viral load correlate with clinically meaningful outcomes,
meaning that HIV RNA measurements could reliably assess the success or
failure of antiretroviral therapy (ART) (Ref. 1).
IV. Proposed Reclassification
FDA is proposing to reclassify HIV viral load monitoring tests. At
a public meeting held on July 19, 2018, the Blood Products Advisory
Committee, convened as a medical device panel (``the Panel''),
unanimously agreed that special controls, in addition to general
controls, are sufficient to mitigate the risk to health from incorrect
results from HIV nucleic acid and serological diagnostic and
supplemental tests. The Panel believed that class II with the special
controls would provide reasonable assurance of the safety and
effectiveness of those devices. In February 2020, FDA issued a proposed
order that, if finalized, would reclassify those devices from class III
into class II (85 FR 10110). As part of the Panel's discussion, the
Panel also recommended that FDA consider reclassification of
quantitative HIV tests indicated for use for monitoring HIV viral load
from class III to class II (Ref. 2).
In accordance with section 513(f)(3) of the FD&C Act and 21 CFR
part 860, subpart C, FDA is proposing to reclassify postamendments HIV
viral load monitoring tests from class III into class II. FDA believes
that there are sufficient data and information available through FDA's
accumulated experience with these devices and from published literature
to demonstrate that the proposed special controls, along with general
controls, would effectively mitigate the risks to health identified in
section V of this document and provide reasonable assurance of safety
and effectiveness of these devices. Absent the special controls
identified in this proposed order, general controls applicable to the
device are insufficient to provide reasonable assurance of the safety
and effectiveness.
FDA is proposing to create a separate classification regulation for
HIV viral load monitoring tests. Under this proposed order, if
finalized, HIV viral load monitoring tests will be reclassified from
class III to class II and identified as prescription devices. In this
proposed order the Agency has proposed the special controls under
section 513(a)(1)(B) of the FD&C Act that, together with general
controls, would provide reasonable assurance of the safety and
effectiveness of HIV viral load monitoring 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 if FDA determines that premarket notification is not
necessary to provide reasonable assurance of the safety and
effectiveness of the device. For these HIV viral load monitoring tests,
FDA has determined that premarket notification is necessary to provide
a reasonable assurance of safety and effectiveness. Therefore, FDA does
not intend to exempt this proposed class II device from the 510(k)
requirements. If this proposed order is finalized, persons who intend
to market this type of device must submit to FDA a 510(k) and receive
clearance prior to marketing the device.
This proposed order, if finalized, will decrease regulatory burden
on industry because manufacturers will no longer have to submit a PMA
for this device type, but can instead submit a 510(k) to the Agency for
review prior to marketing their device. A 510(k) is a less-burdensome
pathway to market a device, which typically results in a shorter
premarket review timeline compared with a PMA, helping to provide more
timely access to this device type to patients. FDA expects that the
reclassification of these devices would enable more manufacturers to
develop HIV viral load monitoring tests such that patients would
benefit from increased access to safe and effective tests.
V. Risks to Health
Viral load is one of the important markers for monitoring the
effectiveness of ART and disease progression. The Department of Health
and Human Services (HHS) in 2014 issued guidelines on the treatment of
HIV in adults and adolescents in United States. The guidelines are
updated periodically based on new data. Regarding viral load
monitoring, the HHS guidelines define optimal viral load suppression as
suppressing viral load levels persistently to <20 to 75 copies per
milliliter (/mL) of HIV RNA, depending on the assay used (Ref. 3).
Virologic failure, at which point changes in treatment are considered,
is defined as the inability to achieve or maintain suppression of viral
replication to an HIV RNA level <200 copies/mL (Ref. 3). The HHS
guidelines recommend that viral load testing should be performed for
all patients with HIV at entry into care, initiation of therapy, and on
a regular basis thereafter (Ref. 3). Therefore, improving access to HIV
viral
[[Page 66985]]
load monitoring tests is a public health priority. After considering
FDA's accumulated experience with these devices from review submissions
and the published literature, FDA has identified the following probable
risks to health associated with HIV viral load monitoring tests:
(1) An inaccurately low viral load test result may influence
patient management decisions, such as continuation of ineffective
treatment, which can lead to serious injury including death.
Inaccurately low viral load test results also may contribute to public
health risk by leading to inadvertent transmission of the virus by an
individual living with HIV. Factors that may cause decreased test
sensitivity and/or increased risk of inaccurately low viral load test
results include, but are not limited to, viral strain variability,
acquisition of de novo mutations in genomic regions of HIV targeted by
the device, and the presence of interfering substances in the sample.
Inaccurately low results also can be caused by improper sample
collection or sample handling, loss of sensitivity of the device,
failure of detection reagents, and failure of instruments.
(2) An inaccurately high viral load test result may contribute to
an unnecessary change in therapy, potentially ending effective
treatment and leading to less effective management of disease, as well
as significant emotional stress. Factors that may cause an increased
rate of inaccurately high viral load test results include, but are not
limited to, cross-reactivity with other substances in the sample,
carryover, viral strain variability, or acquisition of de novo
mutations in genes other than HIV. Inaccurately high results also can
be caused by improper sample collection and sample contamination.
(3) Incorrect interpretation of test results by healthcare
professionals may result in patient management decisions, such as
continuation of ineffective therapy or an unnecessary change in
therapy, that could lead to serious injury, including death, and less
effective management of the disease. Incorrect interpretation of
results may be caused by inadequate labeling, including insufficient
limitations, warnings, and explanations of test procedure.
VI. Summary of the Reasons for Reclassification
FDA believes that HIV viral load monitoring tests should be
reclassified from class III into class II (special controls) because
special controls, in addition to general controls, can be established
to mitigate the risks to health identified in section V and provide
reasonable assurance of the safety and effectiveness of this device
type. The proposed special controls are identified by FDA in section
VII of this proposed order. FDA's reasons for reclassification are as
follows:
(1) There is substantial scientific and medical information
available regarding the nature and complexity of, and risks associated
with, HIV viral load monitoring tests (Refs. 3 to 11). The safety and
effectiveness of this device type has become well-established by the
performance of the approved HIV viral load tests (Ref. 1).
(2) Risks associated with the failure of the device to perform as
indicated (e.g., inaccurately high or low test results) and risks
associated with incorrect interpretation of results can be mitigated
through a combination of special controls, including performance
criteria, certain labeling requirements, and submission of certain
manufacturing information. Performance criteria would consist primarily
of analytical and method comparison study design specifications and
acceptance criteria that are based on public information regarding the
performance and validation of previously approved devices. FDA expects
that a device would demonstrate acceptable performance, e.g.,
analytical sensitivity, at clinically relevant medical decision points
at the time of clearance. This would help ensure that devices meet or
exceed the performance of other cleared or approved HIV viral load
tests at existing clinically relevant medical decision points and, in
the future, demonstrate similar performance if there are changes in
those medical decision points that reflect additional evidence and/or
medical advances. Examples of labeling mitigations include appropriate
limitations, including that results should be interpreted in
conjunction with the individual's clinical presentation, history, and
other laboratory results. These are necessary to ensure that the
devices are used correctly, and the results are interpreted
appropriately, given the diversity of settings in which these devices
are intended to be used. Manufacturing information required to be
submitted would include summaries of strategies to quantitate new HIV
types, subtypes, genotypes, and mutations to ensure the tests continue
to monitor clinically relevant forms of HIV. It also would include a
detailed device description, including information on number and design
of primers and probes, which should be designed according to current
best practices and professional recommendations. It would also include
appropriate and acceptable procedures to determine the severity of
events to ensure appropriate adverse event reporting, protocols for
assessing stability, and evaluation of test performance at the extremes
of specifications to ensure the tests have been validated to function
correctly under diverse conditions.
Taking into account the established health benefits of the use of
the device and the nature of the probable risks of the device (Refs. 1,
3 to 11), FDA, on its own initiative, is proposing to reclassify these
postamendments devices from class III into class II. FDA believes that,
when used as indicated, HIV viral load monitoring tests can provide
significant benefits to clinicians and patients.
VII. Proposed Special Controls
FDA believes that these devices can be classified into class II
with the establishment of special controls. FDA believes that these
special controls, in addition to general controls, will provide a
reasonable assurance of the safety and efficacy of these devices. Table
1 demonstrates how these proposed special controls will mitigate each
of the identified risks to health in section V.
[[Page 66986]]
Table 1--Risks to Health and Mitigation Measures for HIV Viral Load
Monitoring Tests
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Identified risks to health Mitigation measures
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An inaccurately low test result Certain labeling limitations,
may influence patient management warnings, and explanations of the
decisions, including continuation procedures and interpretation
of ineffective antiviral therapy results.
which can lead to serious injury Analytical sensitivity and method
including death. An inaccurately comparison study performance
low test result may contribute to criteria.
public health risk by leading to Acceptable strategies for monitoring
inadvertent transmission of the emergence of and ability of the
virus by a person living with HIV. test to detect new or altered
circulating forms of HIV.
Certain other device verification
and validation information,
including acceptable processes for
risk analysis, testing performance
at extremes of specifications, and
determining severity of adverse
events and malfunctions.
An inaccurately high test result Labeling instructions for
may contribute to unnecessary appropriate confirmation of
change in therapy, potentially elevated results.
disrupting effective treatment Analytical performance criteria.
and leading to less effective Acceptable validation of
management of disease, as well as susceptibility to interference and
significant emotional stress. cross-reactivity.
Acceptable processes for risk
analysis, testing performance at
extremes of specifications, and
determining severity of adverse
events and malfunctions.
Incorrect interpretation of test Certain labeling limitations,
results may result in patient warnings, and explanations of the
management decisions, such as procedures and interpretation
continuation of ineffective results.
therapy or an unnecessary change
in therapy, that could lead to
serious injury, including death,
and less effective management of
the disease.
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If this proposed order is finalized, HIV viral load monitoring
tests will be reclassified into class II (special controls). As
discussed below, the reclassification will be codified in 21 CFR
866.3958. Firms submitting a 510(k) for an HIV viral load monitoring
test will be required to comply with the particular mitigation measures
set forth in the special controls. Adherence to the special controls,
in addition to the general controls, is necessary to provide a
reasonable assurance of the safety and effectiveness of the devices.
VIII. Analysis of Environmental Impact
The Agency has determined under 21 CFR 25.34(b) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
IX. Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed 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 proposed 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 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.
X. Codification of Orders
Under section 513(f)(3) of the FD&C Act, FDA may issue final orders
to reclassify devices. FDA will continue to codify classifications and
reclassifications in the Code of Federal Regulations (CFR). Changes
resulting from final orders will appear in the CFR as newly codified
orders. Therefore, under section 513(f)(3), in the proposed order, we
are proposing to codify HIV viral load monitoring tests in the new 21
CFR 866.3958, under which HIV viral load monitoring tests would be
reclassified from class III to class II.
XI. Proposed Effective Date
FDA proposes that any final order based on this proposed order
become effective 30 days after its date of publication in the Federal
Register.
XII. References
The following references are on display at 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. 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. List of approved HIV viral load monitoring tests with supporting
information can be found at <a href="https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/premarket-approvals-and-humanitarian-device-exemptions-supporting-documents">https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/premarket-approvals-and-humanitarian-device-exemptions-supporting-documents</a>.
2. ``Reclassification of HIV Point of Care and Laboratory-based
serological and NAT diagnostic devices from Class III (PMA) to Class
II 510(k); Issue Summary Prepared for the July 19, 2018, Meeting of
the Blood Products Advisory Committee (BPAC)).'' Available at:
<a href="https://www.fda.gov/advisory-committees/blood-products-advisory-committee/2018-meeting-materials-blood-products-advisory-committee">https://www.fda.gov/advisory-committees/blood-products-advisory-committee/2018-meeting-materials-blood-products-advisory-committee</a>.
3. ``Guidelines for the Use of Antiretroviral Agents in Adults and
Adolescents Living with HIV.'' Department of Health and Human
Services. Accessed November 24, 2020. Available at: <a href="https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/antiretroviral-therapy-prevent-sexual-transmission-hiv">https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/antiretroviral-therapy-prevent-sexual-transmission-hiv</a>.
4. ``Human Immunodeficiency Virus-1 Infection: Developing
Antiretroviral Drugs for Treatment; Guidance for Industry.''
Available at: <a href="https://www.fda.gov/media/86284/download">https://www.fda.gov/media/86284/download</a>.
5. Aberg, J.A., J.E. Gallant, K.H. Ghanem, et al., ``Primary Care
Guidelines for the Management of Persons Infected with HIV: 2013
Update by the HIV Medicine Association of the Infectious Diseases
Society of America,'' Clinical Infectious Disease, 58:e1-34, 2014.
6. Saag, M.S., M. Holodniy, D.R. Kuritzkes, et al., ``HIV Viral Load
Markers in Clinical Practice,'' Nature Medicine, 2:625-629, 1996.
7. Das, M., P.L. Chu, G-M. Santos, et al., ``Decreases in Community
Viral Load are Accompanied by Reductions in New HIV Infections in
San Francisco,'' PLoS ONE, 5:e11068, 2010.
8. Stadhouders, R., S.D. Pas, J. Anber, et al., ``The Effect of
Primer-Template Mismatches on the Detection and Quantification of
Nucleic Acids Using the 5' Nuclease Assay,'' Journal of Molecular
Diagnostics, 12:109-117, 2010.
9. Swenson, L.C., B. Cobb, A.M. Geretti, et al., ``Comparative
Performances of HIV-
[[Page 66987]]
1 RNA Load Assays at Low Viral Load Levels: Results of an
International Collaboration,'' Journal of Clinical Microbiology,
52(2):517-523, 2014.
10. Caniglia, E.C., C. Sabin, J.M. Robins, et al., ``When to Monitor
CD4 Cell Count and HIV RNA to Reduce Mortality and AIDS-Defining
Illness in Virologically Suppressed HIV-Positive Persons on
Antiretroviral Therapy in High-Income Countries: A Prospective
Observational Study,'' Journal of Acquired Immune Deficiency
Syndromes, 72:214-221, 2016.
11. Shoko, C. and D. Chikobvu, ``A Superiority of Viral Load Over
CD4 Cell Count When Predicting Mortality in HIV Patients on
Therapy.'' BioMed Central Infectious Diseases, 19:169, 2019.
List of Subjects in 21 CFR Part 866
Biologics, Laboratories, Medical devices.
Therefore, under the Federal Food, Drug, and Cosmetic Act it is
proposed that 21 CFR part 866 be amended as follows:
PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES
0
1. The authority citation for part 866 continues to read as follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.
0
2. Add Sec. 866.3958 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 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
recommended actions to take 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) If a multisite clinical study is performed under paragraph
(b)(2)(vi) of this section, detailed documentation of a single-site
analytical method comparison study between the device and an FDA-
cleared or approved comparator. 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.
[[Page 66988]]
(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 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: November 16, 2021.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2021-25372 Filed 11-23-21; 8:45 am]
BILLING CODE 4164-01-P
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</html>Indexed from Federal Register on November 24, 2021.
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