[Federal Register Volume 87, Number 94 (Monday, May 16, 2022)]
[Rules and Regulations]
[Pages 29661-29668]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-10461]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2019-N-5192]


Microbiology Devices; Reclassification of Human Immunodeficiency 
Virus Serological Diagnostic and Supplemental Tests and Human 
Immunodeficiency Virus Nucleic Acid Diagnostic and Supplemental Tests

AGENCY: Food and Drug Administration, HHS.

ACTION: Final amendment; final order.

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SUMMARY: The Food and Drug Administration (FDA, we, or the Agency) is 
issuing a final order to reclassify certain human immunodeficiency 
virus (HIV) serological diagnostic and supplemental tests and HIV 
nucleic acid (NAT) diagnostic and supplemental tests, postamendments 
class III devices with the product code MZF, into class II (special 
controls), subject to premarket notification. Through this final order, 
FDA is also adding two new device classification regulations and 
identifying special controls that the Agency believes are necessary to 
provide a reasonable assurance of safety and effectiveness for these 
device types. This final order will reduce the regulatory burdens 
associated with these device types, as manufacturers will no longer be 
required to submit a premarket approval application (PMA) but can 
instead submit a premarket notification (510(k)) and receive clearance 
before marketing their device.

DATES: This order is effective June 15, 2022.

FOR FURTHER INFORMATION CONTACT: Melissa Segal, Center for Biologics 
Evaluation and Review, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 240-
402-7911.

SUPPLEMENTARY INFORMATION:

I. Background--Regulatory Authorities

    The Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended, 
establishes a comprehensive system for the regulation of medical 
devices intended for human use. Section 513 of the FD&C Act (21 U.S.C. 
360c) established three categories (classes) of devices, reflecting the 
regulatory controls needed to provide reasonable assurance of their 
safety and effectiveness. The three categories of devices are class I 
(general controls), class II (general controls and special controls), 
and class III (general controls and premarket approval).
    Devices that were not in commercial distribution prior to May 28, 
1976 (generally referred to as postamendments devices), are 
automatically classified by section 513(f)(1) of the FD&C Act into 
class III without any FDA rulemaking process. Those devices remain in 
class III and require premarket approval, unless and until, (1) FDA 
reclassifies the device into class I or class II, or (2) FDA issues an 
order finding the device to be substantially equivalent, in accordance 
with section 513(i) of the FD&C Act, to a predicate device that does 
not require premarket approval. FDA determines whether new devices are 
substantially equivalent to predicate devices by means of premarket 
notification procedures in section 510(k) of the FD&C Act and part 807 
(21 CFR part 807), subpart E, of the regulations.
    A postamendments device that has been initially classified in class 
III under section 513(f)(1) of the FD&C Act may be reclassified into 
class I or II under section 513(f)(3) of the FD&C Act. Section 
513(f)(3) of the FD&C Act provides that FDA, acting by administrative 
order, can reclassify the device into class I or class II on its own 
initiative, or in response to a petition from the manufacturer or 
importer of the device. To change the classification of the device, the 
proposed new class must have sufficient regulatory controls to provide 
a reasonable assurance of the safety and effectiveness of the device 
for its intended use.
    On February 21, 2020, FDA published in the Federal Register a 
proposed order (85 FR 10110) to reclassify certain HIV serological 
diagnostic and supplemental tests and HIV NAT diagnostic and 
supplemental tests from class III to class II (special controls), 
subject to premarket notification. The comment period on the proposed 
order closed on April 21, 2020.

II. Comments on the Proposed Order

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

[[Page 29662]]

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

[[Page 29663]]

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

[[Page 29664]]

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

III. Final Order

    Based on the information discussed in the preamble to the proposed 
order (85 FR 10110), the comments received on the proposed order, the 
Panel discussions (Ref. 2), and FDA's experiences over the years with 
these device types, FDA concludes that special controls, in conjunction 
with general controls, will provide reasonable assurance of the safety 
and effectiveness of HIV serological diagnostic and supplemental tests 
and HIV NAT diagnostic and supplemental tests. FDA is adopting its 
findings under section 513(f)(3) of the FD&C Act, as published in the 
preamble to the proposed order (85 FR 10110).
    FDA is issuing this final order to reclassify certain HIV 
serological diagnostic and supplemental tests and HIV NAT diagnostic 
and supplemental tests from class III into class II and to establish 
special controls that will be codified at Sec. Sec.  866.3956 and 
866.3957.\1\ In this final order, the Agency has identified special 
controls under section 513(a)(1)(B) of the FD&C Act which, together 
with general controls, provide a reasonable assurance of the safety and 
effectiveness of HIV serological and NAT diagnostic and supplemental 
tests.
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    \1\ FDA notes that the ``ACTION'' caption for this final order 
is styled as ``Final amendment; final order,'' rather than ``Final 
order.'' Beginning in December 2019, this editorial change was made 
to indicate that the document ``amends'' the Code of Federal 
Regulations. This change was made in accordance with the Office of 
Federal Register's (OFR) interpretations of the Federal Register Act 
(44 U.S.C. chapter 15), its implementing regulations (1 CFR 5.9 and 
parts 21 and 22), and the Document Drafting Handbook.
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    FDA is making a few clarifications and modifications to the special 
controls as published in the proposed order after considering public 
comments, as discussed above, and on its own initiative. These include: 
(1) Correcting a reference to ``prescription use only'' in Sec.  
866.3957(a) to read ``for professional use only'' and moving the 
placement of the text stating the tests are for professional use only 
within both Sec. Sec.  866.3956(a) and 866.3957(a); (2) referring to 
``blood products'' instead of ``plasma'' in Sec.  866.3956(a) and 
(b)(1)(i)(A) and in Sec.  866.3957(a) and (b)(1)(i)(A) for consistency 
with the labeling of more recently approved tests; (3) clarifying in 
Sec. Sec.  866.3956(b)(1)(v)(A) and 866.3957(b)(1)(v)(A) that multisite 
clinical studies required for devices intended for PoC use must be 
conducted at appropriate PoC sites; (4) clarifying that the procedures 
for determining when to submit an MDR described in Sec.  
866.3956(b)(1)(ii)(K) and in Sec.  866.3957(b)(1)(ii)(K) must be 
appropriate and acceptable so that they ensure appropriate adverse 
event reporting; (5) clarifying certain aspects of the special controls 
regarding submission of complaint log; (6) adding references to 
``labeling'' in Sec.  866.3956(b)(2), (b)(3), and (b)(5) and in Sec.  
866.3957(b)(2), (b)(3), and (b)(5) to make clearer that certain 
required statements must be included in the device labeling and making 
other minor wording changes to labeling statements required under 
Sec. Sec.  866.3956(b)(2) and 866.3957(b)(2); (7) changing references 
to the PoC or supplemental ``claim'' to ``PoC use'' or ``supplemental 
use'' for consistency with terminology used elsewhere in the special 
controls; and (8) identifying more clearly that certain information 
must be included in 510(k) submissions for HIV diagnostic and 
supplemental tests.
    Section 510(m) of the FD&C Act provides that FDA may exempt a class 
II device from the premarket notification requirements under section 
510(k) of the FD&C Act if FDA determines that premarket notification is 
not necessary to provide reasonable assurance of the safety and 
effectiveness of the device. FDA has determined that premarket 
notification is necessary to provide a reasonable assurance of the 
safety and effectiveness of HIV serological diagnostic and supplemental 
tests and HIV NAT diagnostic and supplemental tests. Therefore, these 
device types are not exempt from premarket notification requirements. 
Persons who intend to market theses device types must submit and obtain 
clearance of a premarket notification and demonstrate compliance with 
the special controls in this final order, prior to marketing the 
device.
    The devices that are the subject of this reclassification are 
assigned the generic names ``human immunodeficiency virus (HIV) 
serological diagnostic and supplemental tests'' and ``human 
immunodeficiency virus (HIV) nucleic acid (NAT) diagnostic and 
supplemental tests.'' HIV serological diagnostic and supplemental tests 
are identified as prescription devices for the qualitative detection of 
HIV antigen(s) and/or detection of antibodies against HIV in human body 
fluids or tissues. HIV NAT diagnostic and supplemental tests are 
identified as prescription devices for the qualitative detection of HIV 
nucleic acid in human body fluids or tissues. HIV serological 
diagnostic and supplemental tests and the NAT diagnostic and 
supplemental tests are intended for use as an aid in the diagnosis of 
infection with HIV, and their results are intended to be interpreted in 
conjunction with other relevant clinical and laboratory findings. These 
tests are for professional use only and are not intended to be used for 
monitoring patient status or for screening donors of blood or blood 
products, or human cells, tissues, and cellular and tissue-based 
products (HCT/Ps).
    Under this final order, the HIV serological diagnostic and 
supplemental tests and HIV NAT diagnostic and supplemental tests are 
identified as prescription use only devices. Prescription in vitro 
diagnostic devices are exempt from the requirement for adequate 
directions for use under section 502(f)(1) of the FD&C Act (21 U.S.C. 
352(f)(1)) and 21 CFR 801.5, as long as all the conditions of 21 CFR 
801.109 are met. A premarket notification submission for these devices 
will be required in the circumstances described in 21 CFR 807.81.

[[Page 29665]]

IV. Codification of Orders

    Under section 513(f)(3) of the FD&C Act, FDA may issue final orders 
to reclassify devices. FDA will continue to codify classifications and 
reclassifications in the Code of Federal Regulations (CFR). Changes 
resulting from final orders will appear in the CFR as newly codified 
orders. In accordance with section 513(f)(3) of the FD&C Act, we are 
codifying in this final order the classification of HIV serological 
diagnostic and supplemental tests in the new Sec.  866.3956, under 
which these devices are reclassified from class III to class II. In 
addition, we are codifying the classification of HIV NAT diagnostic and 
supplemental tests in the new Sec.  866.3957, under which these devices 
are reclassified from class III to class II.

V. Analysis of Environmental Impact

    The Agency has determined under 21 CFR 25.34(b) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VI. Paperwork Reduction Act of 1995

    This final order contains information collection provisions that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521). 
The information collection provisions in Sec. Sec.  866.3956(b)(1)(iii) 
and 866.3957(b)(1)(iii) have been approved under OMB control number 
0910-0437. This approval expires on March 31, 2025. An Agency may not 
conduct or sponsor, and a person is not required to respond to, a 
collection of information unless it displays a currently valid OMB 
control number.
    This final order also refers to previously approved FDA collections 
of information. These collections of information are subject to review 
by the OMB under the PRA. The collections of information in part 807, 
subpart E, regarding premarket notification submissions have been 
approved under OMB control number 0910-0120; the collections of 
information in 21 CFR part 820 have been approved under OMB control 
number 0910-0073; the collections of information in part 803 have been 
approved under OMB control number 0910-0437; and the collections of 
information in 21 CFR parts 801 and 809 have been approved under OMB 
control number 0910-0485.

VII. References

    The following references are on display in the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at https://www.regulations.gov. FDA has 
verified the website addresses, as of the date this document publishes 
in the Federal Register, but websites are subject to change over time.

1. FDA, ``Requests for Feedback and Meetings for Medical Device 
Submissions: The Q-Submission Program,'' available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program.
2. Transcript of the July 19, 2018, Meeting of the Blood Products 
Advisory Committee (BPAC), available at: https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/ucm597841.htm.

List of Subjects in 21 CFR Part 866

    Biologics, Laboratories, Medical devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
866 is amended as follows:

PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES

0
1. The authority citation for part 866 continues to read as follows:

    Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.


0
2. Add Sec.  866.3956 to subpart D to read as follows:


Sec.  866.3956   Human immunodeficiency virus (HIV) serological 
diagnostic and/or supplemental test.

    (a) Identification. Human immunodeficiency virus (HIV) serological 
diagnostic and supplemental tests are prescription devices for the 
qualitative detection of HIV antigen(s) and/or detection of antibodies 
against HIV in human body fluids or tissues. The tests are intended for 
use as an aid in the diagnosis of infection with HIV and are for 
professional use only. The test results are intended to be interpreted 
in conjunction with other relevant clinical and laboratory findings. 
These tests are not intended to be used for monitoring patient status, 
or for screening donors of blood or blood products, or human cells, 
tissues, and cellular and tissue-based products (HCT/Ps).
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) For all HIV serological diagnostic and supplemental tests
    (i) The labeling must include:
    (A) An intended use that states that the device is not intended for 
use for screening donors of blood or blood products or HCT/Ps.
    (B) A detailed explanation of the principles of operation and 
procedures used for performing the assay.
    (C) A detailed explanation of the interpretation of results and 
recommended actions to take based on results.
    (D) Limitations, which must be updated to reflect current clinical 
practice and disease presentation and management. The limitations must 
include, but are not limited to, statements that indicate:
    (1) The matrices with which the device has been cleared, and that 
use of this test kit with specimen types other than those specifically 
cleared for this device may result in inaccurate test results.
    (2) The test is not intended to be used to monitor individuals who 
are undergoing treatment for HIV infection.
    (3) A specimen with a reactive result should be investigated 
further following current guidelines.
    (4) All test results should be interpreted in conjunction with the 
individual's clinical presentation, history, and other laboratory 
results.
    (5) A test result that is nonreactive does not exclude the 
possibility of exposure to or infection with HIV. Nonreactive results 
in this assay may be due to analyte levels that are below the limit of 
detection of this assay.
    (ii) Device verification and validation must include:
    (A) Detailed device description, including the device components, 
ancillary reagents required but not provided, and an explanation of the 
methodology. Additional information appropriate to the technology must 
be included, such as the amino acid sequence of antigen(s) and design 
of capture antibodies.
    (B) For devices with assay calibrators, the design of all primary, 
secondary, and subsequent quantitation standards used for calibration 
as well as their traceability to a reference material. In addition, 
analytical testing must be performed following the release of a new lot 
of the standard material that was used for device clearance, or when 
there is a transition to a new calibration standard.
    (C) Detailed documentation of analytical performance studies

[[Page 29666]]

conducted as appropriate to the technology, specimen types tested, and 
intended use of the device, including, but not limited to, limit of 
blank, limit of detection, cutoff determination, precision, endogenous 
and exogenous interferences, cross reactivity, carryover, quality 
control, matrix equivalency, and sample and reagent stability. Samples 
selected for use in analytical studies or used to prepare samples for 
use in analytical studies must be from subjects with clinically 
relevant circulating genotypes in the United States.
    (D) Multisite reproducibility study that includes the testing of 
three independent production lots.
    (E) Analytical sensitivity of the test must be the same as or 
better than that of other cleared or approved tests. Samples tested 
must include appropriate numbers and types of samples, including real 
clinical samples near the lower limit of detection. Analytical 
specificity of the test must be the same as or better than that of 
other cleared or approved tests. Samples must include appropriate 
numbers and types of samples from patients with different underlying 
illnesses or infections and from patients with potential endogenous 
interfering substances.
    (F) Detailed documentation of performance from a multisite clinical 
study. Performance must be analyzed relative to an FDA-cleared or 
approved comparator. This study must be conducted using patient 
samples, with an appropriate number of HIV positive and HIV negative 
samples in applicable risk categories. Additional subgroups or types 
must be validated using appropriate numbers and types of samples. The 
samples may be a combination of fresh and repository samples, sourced 
from within and outside the United States, as appropriate. The study 
designs, including number of samples tested, must be sufficient to meet 
the following criteria:
    (1) Clinical sensitivity of the test must have a lower bound of the 
95 percent confidence interval of greater than or equal to 99 percent.
    (2) Clinical specificity of the test must have a lower bound of the 
95 percent confidence interval of greater than or equal to 99 percent.
    (G) Strategies for detection of new strains, types, subtypes, 
genotypes, and genetic mutations as they emerge.
    (H) Risk analysis and management strategies, such as Failure Modes 
Effects Analysis and/or Hazard Analysis and Critical Control Points 
summaries and their impact on test performance.
    (I) Final release criteria to be used for manufactured test lots 
with appropriate evidence that lots released at the extremes of the 
specifications will meet the claimed analytical and clinical 
performance characteristics as well as the stability claims.
    (J) All stability protocols, including acceptance criteria.
    (K) Appropriate and acceptable procedure(s) for evaluating customer 
complaints and other device information that determines when to submit 
a medical device report.
    (L) Premarket notification submissions must include the information 
contained in paragraph (b)(1)(ii)(A) through (K) of this section.
    (iii) Manufacturers must submit a log of all complaints. The log 
must include the following information regarding each complaint if 
available: The type of event (e.g., false negative/false nonreactive or 
false positive/false reactive), lot, date, population, and whether or 
not the complaint was reported under part 803 of this chapter (Medical 
Device Reporting). The log must be submitted annually on the 
anniversary of clearance for 5 years following clearance of a 
traditional premarket notification.
    (2) If the test is intended for Point of Care (PoC) use, the 
following special controls, in addition to those listed in paragraph 
(b)(1) of this section apply:
    (i) The PoC labeling must include a statement that the test is 
intended for PoC use.
    (ii) The PoC labeling must include the following information near 
the statement of the intended use:
    (A) That the test is for distribution to clinical laboratories that 
have an adequate quality assurance program, including planned 
systematic activities that provide adequate confidence that 
requirements for quality will be met and where there is assurance that 
operators will receive and use the instructional materials.
    (B) That the test is for use only by an agent of a clinical 
laboratory.
    (C) Instructions for individuals to receive the ``Subject 
Information Notice'' prior to specimen collection and appropriate 
information when test results are provided.
    (iii) PoC labeling must include instructions to follow current 
guidelines for informing the individual of the test result and its 
interpretation.
    (iv) The instructions in the labeling must state that reactive 
results are considered preliminary and should be confirmed following 
current guidelines.
    (v) Device verification and validation for PoC use must include:
    (A) Detailed documentation of performance from a multisite clinical 
study conducted at appropriate PoC sites. Performance must be analyzed 
relative to an FDA cleared or approved comparator. This study must be 
conducted using patient samples, with appropriate numbers of HIV 
positive and HIV negative samples in applicable risk categories. 
Additional subgroup or type claims must be validated using appropriate 
numbers and types of samples. The samples may be a combination of fresh 
and repository samples, sourced from within and outside the United 
States, as appropriate. If the test is intended solely for PoC use, the 
test must meet only the performance criteria in paragraphs 
(b)(2)(v)(A)(1) and (2) of this section and not the criteria in 
paragraph (b)(1)(ii)(F) of this section:
    (1) Clinical sensitivity of the test must have a lower bound of the 
95 percent confidence interval of greater than or equal to 98 percent.
    (2) Clinical specificity of the test must have a lower bound of the 
95 percent confidence interval of greater than or equal to 98 percent.
    (B) Premarket notification submissions must include the information 
contained in paragraph (b)(2)(v)(A) of this section.
    (3) If the test is intended for supplemental use in addition to use 
as an aid in initial diagnosis, the following special controls, in 
addition to those listed in paragraphs (b)(1) and (2) of this section, 
as appropriate, apply:
    (i) The labeling must include a statement that the test is intended 
for use as an additional test to confirm the presence of HIV antibodies 
or antigens in specimens found to be repeatedly reactive by a 
diagnostic screening test.
    (ii) Device validation and verification for supplemental use must 
include a clinical study, including samples that were initially 
reactive and repeatedly reactive on a diagnostic test but were negative 
or indeterminate on a different confirmatory test. Premarket 
notification submissions must include this information.
    (4) If the test is intended solely as a supplemental test, the 
following special controls, in addition to those listed in paragraphs 
(b)(1) and (2) of this section, except those in paragraphs 
(b)(1)(ii)(F) and (b)(2)(v)(A) of this section, as appropriate, apply:
    (i) The labeling must include a statement that the test is intended 
for use as an additional test to confirm the presence of HIV antibodies 
or antigens in specimens found to be repeatedly reactive by a 
diagnostic screening test.
    (ii) The labeling must clearly state that the test is not for use 
for initial diagnosis or is not intended as a first-line test.

[[Page 29667]]

    (iii) Device validation and verification must include a clinical 
study including samples that were initially reactive and repeatedly 
reactive on a diagnostic test but were negative or indeterminate on a 
confirmatory test. Premarket notification submissions must include this 
information.
    (5) If the test is intended to differentiate different HIV types, 
the following special controls, in addition to those listed in 
paragraphs (b)(1) through (4) of this section, as appropriate, apply:
    (i) The labeling must include the statement that the test is 
intended for the confirmation of initial results from a diagnostic test 
and differentiation of different HIV types.
    (ii) The results interpretation in the labeling must include 
instructions for the user on how to interpret the results, including 
un-typeable and co-infection results.
    (iii) Device validation and verification must include evaluation of 
analytical and clinical sensitivity and specificity for each of the HIV 
types, strains, and subtypes of HIV intended to be differentiated. 
Premarket notification submissions must include this information.

0
3. Add Sec.  866.3957 to subpart D to read as follows:


Sec.  866.3957  Human immunodeficiency virus (HIV) nucleic acid (NAT) 
diagnostic and/or supplemental test.

    (a) Identification. Human immunodeficiency virus (HIV) nucleic acid 
(NAT) diagnostic and supplemental tests are prescription devices for 
the qualitative detection of HIV nucleic acid in human body fluids or 
tissues. The tests are intended for use as an aid in the diagnosis of 
infection with HIV and are for professional use only. The test results 
are intended to be interpreted in conjunction with other relevant 
clinical and laboratory findings. These tests are not intended to be 
used for monitoring patient status, or for screening donors of blood or 
blood products, or human cells, tissues, or cellular or tissue-based 
products (HCT/Ps).
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) For all HIV NAT diagnostic and/or supplemental tests
    (i) The labeling must include:
    (A) An intended use that states that the device is not intended for 
use for screening donors of blood or blood products, or HCT/Ps.
    (B) A detailed explanation of the principles of operation and 
procedures used for performing the assay.
    (C) A detailed explanation of the interpretation of results and 
recommended actions to take based on results.
    (D) Limitations, which must be updated to reflect current clinical 
practice and disease presentation and management. The limitations must 
include, but are not limited to, statements that indicate:
    (1) The matrices with which the device has been cleared, and that 
use of this test kit with specimen types other than those specifically 
cleared for this device may result in inaccurate test results.
    (2) The test is not intended to be used to monitor individuals who 
are undergoing treatment for HIV infection.
    (3) A specimen with a reactive result should be investigated 
further following current guidelines.
    (4) All test results should be interpreted in conjunction with the 
individual's clinical presentation, history, and other laboratory 
results.
    (5) A test result that is nonreactive does not exclude the 
possibility of exposure to or infection with HIV. Nonreactive results 
in this assay may be due to analyte levels that are below the limit of 
detection of this assay.
    (ii) Device verification and validation must include:
    (A) Detailed device description, including the device components, 
ancillary reagents required but not provided, and an explanation of the 
methodology. Additional information appropriate to the technology must 
be included, such as design of primers and probes.
    (B) For devices with assay calibrators, the design and nature of 
all primary, secondary, and subsequent quantitation standards used for 
calibration as well as their traceability to a reference material. In 
addition, analytical testing must be performed following the release of 
a new lot of the standard material that was used for device clearance, 
or when there is a transition to a new calibration standard.
    (C) Detailed documentation of analytical performance studies 
conducted as appropriate to the technology, specimen types tested, and 
intended use of the device, including, but not limited to, limit of 
blank, limit of detection, cutoff determination, precision, endogenous 
and exogenous interferences, cross reactivity, carryover, quality 
control, matrix equivalency, and sample and reagent stability. Samples 
selected for use in analytical studies or used to prepare samples for 
use in analytical studies must be from subjects with clinically 
relevant circulating genotypes in the United States. The effect of each 
claimed nucleic-acid isolation and purification procedure on detection 
must be evaluated.
    (D) Multisite reproducibility study that includes the testing of 
three independent production lots.
    (E) Analytical sensitivity of the test must be the same as or 
better than that of other cleared or approved tests. Samples tested 
must include appropriate numbers and types of samples, including real 
clinical samples near the lower limit of detection. Analytical 
specificity of the test must be as the same as or better than that of 
other cleared or approved tests. Samples must include appropriate 
numbers and types of samples from patients with different underlying 
illnesses or infections and from patients with potential endogenous 
interfering substances.
    (F) Detailed documentation of performance from a multisite clinical 
study. Performance must be analyzed relative to an FDA cleared or 
approved comparator. This study must be conducted using appropriate 
patient samples, with appropriate numbers of HIV positive and negative 
samples in applicable risk categories. Additional subtype, strain, or 
types must be validated using appropriate numbers and types of samples. 
The samples may be a combination of fresh and repository samples, 
sourced from within and outside the United States, as appropriate. The 
study designs, including number of samples tested, must be sufficient 
to meet the following criteria:
    (1) Clinical sensitivity of the test must have a lower bound of the 
95 percent confidence interval of greater than or equal to 99 percent.
    (2) Clinical specificity of the test must have a lower bound of the 
95 percent confidence interval of greater than or equal to 99 percent.
    (G) Strategies for detection of new strains, types, subtypes, 
genotypes, and genetic mutations as they emerge.
    (H) Risk analysis and management strategies, such as Failure Modes 
Effects Analysis and/or Hazard Analysis and Critical Control Points 
summaries and their impact on test performance.
    (I) Final release criteria to be used for manufactured test lots 
with appropriate evidence that lots released at the extremes of the 
specifications will meet the claimed analytical and clinical 
performance characteristics as well as the stability claims.
    (J) All stability protocols, including acceptance criteria.
    (K) Appropriate and acceptable procedure(s) for evaluating customer 
complaints and other device

[[Page 29668]]

information that determine when to submit a medical device report.
    (L) Premarket notification submissions must include the information 
contained in paragraph (b)(1)(ii)(A) through (K) of this section.
    (iii) Manufacturers must submit a log of all complaints. The log 
must include the following information regarding each complaint, if 
available: The type of event (e.g., false negative/false nonreactive or 
false positive/false reactive), lot, date, population, and whether or 
not the complaint was reported under part 803 of this chapter (Medical 
Device Reporting). The log must be submitted annually on the 
anniversary of clearance for 5 years following clearance of a 
traditional premarket notification.
    (2) If the test is intended for Point of Care (PoC) use, the 
following special controls, in addition to those listed in paragraph 
(b)(1) of this section, apply:
    (i) The PoC labeling must include a statement that the test is 
intended for PoC use.
    (ii) The PoC labeling must include the following information near 
the statement of the intended use:
    (A) That the test is for distribution to clinical laboratories that 
have an adequate quality assurance program, including planned 
systematic activities that provide adequate confidence that 
requirements for quality will be met and where there is assurance that 
operators will receive and use the instructional materials.
    (B) That the test is for use only by an agent of a clinical 
laboratory.
    (C) Instructions for individuals to receive the ``Subject 
Information Notice'' prior to specimen collection and appropriate 
information when test results are provided.
    (iii) PoC labeling must include instructions to follow current 
guidelines for informing the individual of the test result and its 
interpretation.
    (iv) The instructions in the labeling must state that reactive 
results are considered preliminary and should be confirmed following 
current guidelines.
    (v) Device verification and validation for PoC use must include:
    (A) Detailed documentation from a well-conducted multisite clinical 
study conducted at appropriate PoC sites. Performance must be analyzed 
relative to an FDA cleared or approved comparator. This study must be 
conducted using patient samples, with appropriate numbers of HIV 
positive and HIV negative samples in applicable risk categories. 
Additional subgroup or type claims must be validated using appropriate 
numbers and types of samples. The samples may be a combination of fresh 
and repository samples, sourced from within and outside the United 
States, as appropriate. If the test is intended solely for PoC use, the 
test must meet only the performance criteria in paragraphs 
(b)(2)(v)(A)(1) and (2) of this section and not the criteria in 
paragraph (b)(1)(ii)(F) of this section:
    (1) Clinical sensitivity of the test must have a lower bound of the 
95 percent confidence interval of greater than or equal to 98 percent.
    (2) Clinical specificity of the test must have a lower bound of the 
95 percent confidence interval of greater than or equal to 98 percent.
    (B) Premarket notification submissions must include the information 
contained in paragraph (b)(2)(v)(A) of this section.
    (3) If the test is intended for supplemental use in addition to use 
as an aid in initial diagnosis, the following special controls, in 
addition to those listed in paragraphs (b)(1) and (2) of this section, 
as appropriate, apply:
    (i) The labeling must include a statement that the test is intended 
for use as an additional test to confirm the presence of HIV viral 
nucleic acid in specimens found to be repeatedly reactive by a 
diagnostic screening test.
    (ii) Device validation and verification for supplemental use must 
include a clinical study, including samples that were initially 
reactive and repeatedly reactive on a diagnostic test but were negative 
or indeterminate on a confirmatory test. Premarket notification 
submissions must include this information.
    (4) If the test is intended solely as a supplemental test, the 
following special controls, in addition to those listed in paragraphs 
(b)(1) and (2) of this section, except those in paragraphs 
(b)(1)(ii)(F) and (b)(2)(v)(A) of this section, as appropriate, apply:
    (i) The labeling must include a statement that the test is intended 
for use as an additional test to confirm the presence of HIV viral 
nucleic acid in specimens found to be repeatedly reactive by a 
diagnostic screening test.
    (ii) The labeling must clearly state that the test is not for use 
for initial diagnosis or is not intended as a first-line test.
    (iii) Device validation and verification must include a clinical 
study including samples that were initially reactive and repeatedly 
reactive on a diagnostic test but were negative or indeterminate on a 
confirmatory test. Premarket notification submissions must include this 
information.
    (5) If the test is intended to differentiate different HIV types, 
the following special controls, in addition to those listed in 
paragraphs (b)(1) through (4) of this section, as appropriate, apply:
    (i) The labeling must include the statement that the test is 
intended for the confirmation of initial results and differentiation of 
different HIV types.
    (ii) The results interpretation in the labeling must include 
instructions for the user on how to interpret the results, including 
un-typeable and co-infection results.
    (iii) Device validation and verification must include evaluation of 
analytical and clinical sensitivity and specificity for each of the 
types, strains, and subtypes of HIV intended to be differentiated. 
Premarket notification submissions must include this information.

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