Document ID: FDA-2020-N-2297-0001
Agency: fda
Document Type: Proposed Rule
Title: Microbiology Devices; Reclassification of Human Immunodeficiency Virus Viral Load Monitoring Tests
Posted Date: 2021-11-24T05:00Z

[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 [www.gpo.gov]
[FR Doc No: 2021-25372]

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 Proposed Rules
                                                 Federal Register
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 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  

[[Page 66982]]

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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 https://www.regulations.gov 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:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-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 https://www.regulations.gov or at 
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through 
Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 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
------------------------------------------------------------------------
    Identified risks to health               Mitigation measures
------------------------------------------------------------------------
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.
------------------------------------------------------------------------

    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 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. List of approved HIV viral load monitoring tests with supporting 
information can be found at https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/premarket-approvals-and-humanitarian-device-exemptions-supporting-documents.
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: 
https://www.fda.gov/advisory-committees/blood-products-advisory-committee/2018-meeting-materials-blood-products-advisory-committee.
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: https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/antiretroviral-therapy-prevent-sexual-transmission-hiv.
4. ``Human Immunodeficiency Virus-1 Infection: Developing 
Antiretroviral Drugs for Treatment; Guidance for Industry.'' 
Available at: https://www.fda.gov/media/86284/download.
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 
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52(2):517-523, 2014.
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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.
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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