[Federal Register Volume 89, Number 186 (Wednesday, September 25, 2024)]
[Proposed Rules]
[Pages 78265-78278]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-21932]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2024-N-3533]


Microbiology Devices; Reclassification of Antigen, Antibody, and 
Nucleic Acid-Based Hepatitis B Virus Assay Devices

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed amendment; proposed order; request for comments.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
proposing to reclassify qualitative hepatitis B virus (HBV) antigen 
assays, qualitative HBV antibody assays and quantitative assays that 
detect anti-HBs (antibodies to HBV surface antigen (HBsAg)), and 
quantitative HBV nucleic acid-based assays, all of which are 
postamendments class III devices, into class II (general controls and 
special controls), subject to premarket notification. FDA is also 
proposing three new device classification regulations along with the 
special controls that the Agency believes are necessary to provide a 
reasonable assurance of safety and effectiveness for each device.

DATES: Either electronic or written comments on the proposed order must 
be submitted by November 25, 2024. Please see section X of this 
document for the proposed effective date when the new requirements 
apply and for the proposed effective date of a 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. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of November 25, 2024. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are received on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
    <bullet> Federal Rulemaking 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.
    <bullet> If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:

[[Page 78266]]

    <bullet> Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    <bullet> For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2024-N-3533 for ``Microbiology Devices; Reclassification of 
Antigen, Antibody, and Nucleic Acid-Based Hepatitis B Virus Assay 
Devices.'' 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 Eastern Time, 240-402-7500.
    <bullet> Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on 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, the 
plain language summary of the proposed order of not more than 100 words 
consistent with the ``Providing Accountability Through Transparency 
Act,'' 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: Maria Ines Garcia, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, Rm. 3104, Silver Spring, MD 20993, 301-796-
7017, <a href="/cdn-cgi/l/email-protection#fab79b88939bd4bd9b8899939bba9c9e9bd4929289d49d958c"><span class="__cf_email__" data-cfemail="a1ecc0d3c8c08fe6c0d3c2c8c0e1c7c5c08fc9c9d28fc6ced7">[email protected]</span></a>.

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).
    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 issue 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 before 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 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. The Agency determines whether new devices 
are substantially equivalent to predicate devices by means of the 
premarket notification procedures in section 510(k) of the FD&C Act and 
part 807, subpart E (21 CFR part 807, subpart E) of FDA's 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 class 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 
reasonable assurance of the safety and effectiveness of the device for 
its intended use.
    FDA relies upon ``valid scientific evidence'', as defined in 
section 513(a)(3) of the FD&C Act and 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).

[[Page 78267]]

Publicly available information excludes trade secret and/or 
confidential commercial information, e.g., the contents of a pending 
premarket approval application (PMA) (see section 520(c) of the FD&C 
Act).
    In accordance with section 513(f)(3) of the FD&C Act, FDA is 
issuing this proposed order to reclassify qualitative HBV antigen 
assays intended for qualitative detection of HBV antigens as an aid in 
the diagnosis of acute or chronic HBV infection in specific 
populations, HBV antibody assays (including qualitative and 
quantitative anti-HBs) intended for use in the detection of antibodies 
to HBV, and quantitative HBV nucleic acid-based assays intended for use 
in the detection of HBV nucleic acid in specimens from individuals with 
antibody evidence of HBV infection, all of which are postamendments 
class III devices, into class II (general controls and special 
controls) subject to premarket notification, under three new device 
classification regulations with the names ``Qualitative Hepatitis B 
Virus Antigen Assays,'' ``Hepatitis B Virus Antibody Assays,'' and 
``Hepatitis B Virus Nucleic Acid-Based Assays.'' FDA believes the 
standard in section 513(a)(1)(B) of the FD&C Act is met as there is 
sufficient information to establish special controls, which, in 
addition to general controls, will provide reasonable assurance of the 
safety and effectiveness of these devices.\1\
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    \1\ FDA notes that the ``ACTION'' caption for this proposed 
order is styled as ``Proposed amendment; proposed order,'' rather 
than ``Proposed order.'' Beginning in December 2019, this editorial 
change was made to indicate that the document ``amends'' the Code of 
Federal Regulations. The change was made in accordance with the 
Office of the Federal Register's (OFR) interpretations of the 
Federal Register Act (44 U.S.C. chapter 15), its implementing 
regulations (1 CFR 5.9 and parts 21 and 22), and the Document 
Drafting Handbook.
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    Section 510(m) of the FD&C Act provides that FDA may exempt a class 
II device from the premarket notification requirements under section 
510(k) of the FD&C Act, if FDA determines that premarket notification 
is not necessary to provide reasonable assurance of the safety and 
effectiveness of the device. FDA has determined that premarket 
notification is necessary to provide a reasonable assurance of the 
safety and effectiveness of HBV antigen assays, HBV antibody assays, 
and HBV nucleic acid-based assays for their intended uses, therefore, 
the Agency does not intend to exempt these proposed class II devices 
from the requirement for premarket notification (510(k)) submission as 
provided under section 510(m) of the FD&C Act. If this proposed order 
is finalized, persons who intend to market this type of device must 
submit to FDA a premarket notification under section 510(k) of the FD&C 
Act prior to marketing the device.

II. Regulatory History of the Devices

    Under section 513(f)(1) of the FD&C Act, qualitative HBV antigen 
assays, HBV antibody assays (including qualitative and quantitative 
anti-HBs), and quantitative HBV nucleic acid-based assays are 
automatically classified into class III because they were not 
introduced or delivered for introduction into interstate commerce for 
commercial distribution before May 28, 1976, and have not been found 
substantially equivalent to a device placed in commercial distribution 
after May 28, 1976, which was subsequently classified or reclassified 
into class II or class I. Therefore, they are subject to PMA 
requirements under section 515 of the FD&C Act (21 U.S.C. 360e). 
Qualitative HBV antigen assays and HBV antibody assays (including 
qualitative and quantitative anti-HBs) are prescription devices and 
assigned product code LOM. Quantitative HBV nucleic acid-based assays 
are prescription devices and assigned product code MKT.

A. Qualitative HBV Antigen Assays

    The first proposed device reclassification action applies to 
qualitative HBV antigen assay devices that are prescription in vitro 
diagnostic devices intended for qualitative detection of HBV antigens 
as an aid in the diagnosis of acute or chronic HBV infection in 
specific populations. On February 8, 2001, FDA approved its first HBV 
antigen assay (DiaSorin's ETI-EBK PLUS) for use in the qualitative 
detection of hepatitis Be antigen (HBeAg) in human serum or plasma 
(ethylenediaminetetraacetic acid (EDTA), citrate, or heparin) as 
indicative of a laboratory diagnosis of HBV infection through its PMA 
process under section 515 of the FD&C Act. On June 1, 2001, FDA 
approved its first HBV surface antigen (HBsAg) assay (Roche Elecsys 
HBsAg Immunoassay, Elecsys HBsAg Confirmatory, and Precicontrol HBsAg) 
for the qualitative detection of HBsAg in human serum or plasma 
(heparin, EDTA, sodium citrate) in adult pregnant and non-pregnant 
individuals. In a May 22, 2002, Federal Register notice (67 FR 36009), 
FDA announced the approval order and the availability of the Summary of 
Safety and Effectiveness Data (SSED) for these devices. Since the first 
approval order for an HBV antigen assay issued on February 8, 2001, FDA 
has approved 16 additional original PMAs for qualitative HBV antigen 
assays that are prescription devices intended for the detection of HBV 
antigens. These assays are intended as an aid in the diagnosis of acute 
or chronic HBV infection in conjunction with clinical findings and 
other diagnostic procedures (e.g., HBV serology and antigen testing, 
liver function, etc.). These assays are not intended for use in 
screening of blood, plasma, cells, or tissue donors.
    A review of the medical device reporting (MDR) databases indicates 
that there were 625 reported events for qualitative HBV antigen assays 
as of June 2024. Of these reported events, a significant majority of 
these were determined to be of no known impact or consequence to the 
patient. Events reported included false reactive results, false non-
reactive results, incorrect or inadequate assay results, incorrect/
inadequate/imprecise readings, improper or incorrect procedure or 
method, device operates differently than expected, and adverse event 
without identified device or use problems. Where incorrect results were 
obtained, it was not clear what the correct result should have been. As 
of June 2024, there have been no class III recalls, six class II 
recalls, and no class I recalls \2\ involving qualitative HBV antigen 
assays. The class II recalls occurred since 2006 due to defective caps, 
device design, no marketing application, signal for reactive results, 
and biased results for biotin concentrations that were lower than 
indicated. No patient harm was identified. These facts, coupled with 
the low number of reported events that caused patient harm, indicate a 
good safety record for this device class. These recall events reflect 
the risks to health identified in section V below, and FDA believes the 
special controls proposed herein, in addition to general controls, can 
effectively mitigate the risks identified in these recalls.
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    \2\ Class I, II, and III recalls are defined in 21 CFR 7.3(m).
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B. HBV Antibody Assays (Including Qualitative and Quantitative Anti-
HBs)

    The second type of devices this proposed reclassification order 
applies to are qualitative HBV antibody assays and quantitative anti-
HBs assays that are prescription in vitro diagnostic devices intended 
for use in the detection of antibodies to HBV. These devices are 
intended to aid in the diagnosis of HBV infection in persons with signs 
and symptoms of hepatitis and in persons at risk for HBV infection. On 
September 29, 2000, FDA approved its first qualitative HBV antibody 
assay (Ortho-Clinical Diagnostics, Inc.'s Vitros

[[Page 78268]]

Immunodiagnostic Products: Anti-HBS Reagent Pack/Anti-HBS Calibrators) 
for the qualitative in vitro determination of total antibody to 
hepatitis B surface antigen (anti-HBs) in human serum as an aid in 
determining susceptibility to HBV infection for individuals prior to or 
following HBV vaccination, or where vaccination status is unknown, and 
for use with other HBV serological markers for the laboratory diagnosis 
of HBV disease associated with HBV infection, through its PMA process 
under section 515 of the FD&C Act. In a March 12, 2001, Federal 
Register notice (66 FR 14390), FDA announced the approval order and the 
availability of the SSED for this device. On July 22, 2002, FDA 
approved its first quantitative Anti-HBs (Siemens Healthcare 
Diagnostics Products Ltd.'s Immulite 2000 XPI Anti-HBs) for the 
quantitative measurement of total antibodies to the hepatitis B surface 
antigen (anti-HBs) in human serum and plasma (heparinized or EDTA) as 
an aid in the determination of susceptibility to HBV infection for 
individuals prior to or following HBV vaccination, or where vaccination 
status is unknown, or for use with other HBV serological markers for 
the laboratory diagnosis of HBV disease associated with HBV infection, 
through its PMA process under section 515 of the FD&C Act.
    Since the first approval order of a qualitative HBV antibody assay 
on September 29, 2000, FDA has approved 31 additional original PMAs for 
qualitative HBV antibody assays for the detection of antibodies to HBV. 
FDA has also approved six assays for quantitative anti-HBs detection. 
Qualitative HBV antibody assays and quantitative anti-HBs assays are 
intended to aid in the diagnosis of HBV infection in persons with signs 
and symptoms of hepatitis and in persons at risk for HBV infection in 
conjunction with clinical findings and other diagnostic procedures 
(e.g., HBV serology and antigen testing, liver function, etc.). These 
assays are not intended for use in screening of blood, plasma, cells, 
or tissue donors.
    A review of the MDR databases indicates that there were 1,107 
reported events for HBV antibody assays between years 2001 and June 
2024. Of these reported events, a significant majority of these were of 
no known impact to the patient, and only four resulted in impact to 
patients such as misdiagnosis or viral infection. Events reported 
included adverse events without identified device or use problem, 
disconnection/low assay results, false non-reactive results, false 
reactive results, false high assay results (for example, the first 
assay result had a low signal to cutoff (s/co) value and repeat testing 
produced a higher s/co value), incorrect assay results, inadequate 
assay results, and low assay results (for example, the first assay 
result was in the equivocal zone, repeat testing produced a non-
reactive result, and testing with an alternate device produced a 
reactive result). In numerous cases, it was not possible to determine 
what the correct result should have been (further testing was not 
performed, insufficient sample volume, different assays were used). As 
of June 2024, FDA is aware of 4 class III recalls, 12 class II recalls, 
and no class I recalls for these devices. The class II recalls occurred 
in 2007, 2008, 2009, 2011, 2012, 2013, 2014, 2018, and 2019, and were 
related to issues such as false reactive results, false high assay 
results, defective caps, and errors in labeling, packaging, or 
software. No patient harm has been identified. These facts, coupled 
with the low number of reported events that impacted the patient, 
indicate a good safety record for this device class. These recall 
events reflect the risks to health identified in section V below, and 
FDA believes the special controls proposed herein, in addition to 
general controls, can effectively mitigate the risks identified in 
these recalls.

C. Quantitative HBV Nucleic Acid-Based Assays

    Finally, the third type of device this proposed reclassification 
order applies to are quantitative HBV nucleic acid-based assay devices 
for use as a prescription in vitro diagnostic device intended for use 
in the detection of HBV nucleic acid in specimens from individuals with 
antibody evidence of HBV infection. On September 4, 2008, FDA approved 
its first quantitative HBV nucleic assay (Roche Molecular Systems, 
Inc.'s COBAS TaqMan HBV Test For Use With The High Pure System), an in 
vitro nucleic acid amplification assay for the quantitation of HBV 
deoxyribonucleic acid (DNA) in human serum or plasma (EDTA) intended 
for use as an aid in the management of patients with chronic HBV 
infection undergoing antiviral therapy, through its PMA process under 
section 515 of the FD&C Act.
    Since the first approval order, FDA has approved four additional 
original PMAs for quantitative HBV nucleic acid-based assays for the 
quantitative detection of HBV DNA. The detection of HBV DNA is used for 
management of patients undergoing antiviral therapy for assessing 
response to treatment and not as a diagnostic for HBV infection.
    The following section provides examples of the different 
technologies used. The different technologies begin with specimen lysis 
and HBV DNA through hybridization with magnetic particles. The 
differences in the technologies occur with the method of amplification:
    <bullet> In one technology, the target HBV DNA sequence is 
amplified. The presence of HBV amplification products is detected by 
measuring the fluorescence of the HBV probe that binds to the target. 
Similarly, the presence of the internal control amplification product 
is detected. In the absence of HBV or internal control target 
sequences, probe fluorescence is quenched. In the presence of HBV or 
internal control target, the HBV or internal control probes bind to 
their target.
    <bullet> In another technology, target amplification occurs via 
transcription-based nucleic acid amplification by fluorescent labeled 
probes (torches). More torches hybridize when more amplicon is present 
creating a higher fluorescent signal. The time taken for the 
fluorescent signal to reach a threshold proportional to the starting 
HBV DNA concentration is measured in relation to internal controls.
    A review of the MDR databases indicates that as of June 2024 there 
were 13 reported events for nucleic acid-based HBV DNA assays since the 
first reported event in 2009. MDRs were for the following reasons: (1) 
incorrect, inadequate, or imprecise result or readings; (2) high 
readings; and (3) non-reproducible results. Of these, two had no known 
impact or consequence to the patient and two occurred when the patient 
had no signs, symptoms, or conditions. As of June 2024, FDA is aware of 
one class III recall, five class II recalls, and no class I recalls for 
these devices. The class II recalls occurred between 2005 and 2022 and 
were related to issues such as misquantitation of high results for 
negative samples (carryover from a high positive sample tested adjacent 
to a negative sample may produce an incorrect positive result), liquid 
level detection of reagent cassette, under filled and over filled 
enzyme reagent vials in assay kits, software, and low level of 
recombinant HBV DNA found in one lot of reagent. These facts, coupled 
with the low number of reported events that impacted the patient, 
indicate a good safety record for this device class. These recall 
events reflect the risks to health identified in section V below, and 
FDA believes the special controls proposed herein, in addition to 
general controls, can effectively mitigate the risks identified in 
these recalls.

[[Page 78269]]

III. Device Description

    The HBV assays that are the subject of this proposed order are 
postamendments prescription in vitro diagnostic devices classified into 
class III under section 513(f)(1) of the FD&C Act.

A. Qualitative HBV Antigen Assays

    A qualitative HBV antigen assay is a prescription in vitro 
diagnostic device intended for use in the qualitative detection of HBV 
antigens and for use as an aid in the diagnosis of HBV infection in 
specific populations. HBV antigen assays aid in the diagnosis of acute 
or chronic HBV infection. HBV antigen assays typically detect the 
presence of Hepatitis B surface antigen (HBsAg) or Hepatitis B e 
antigen (HBeAg). HBV antigens (HBsAg and HBeAg), when present in 
samples, bind to anti-HBs or anti-HBe antibodies to form a complex that 
is bound to a solid phase (e.g., microparticles, microtiter plate or 
other technology). Detection of the complexes can be performed using 
different methods which measure the presence/absence of anti-HBs or 
anti-HBe antibodies in the sample.
    Diagnosis of HBV infection should not be established based on a 
single assay result but should be determined in conjunction with 
clinical findings and other diagnostic procedures (e.g., HBV serology 
and antigen testing, liver function, etc.). These assays are not 
intended for use in screening of blood, plasma, cells, or tissue 
donors.

B. HBV Antibody Assays (Including Qualitative and Quantitative Anti-
HBs)

    A qualitative HBV antibody assay is a prescription in vitro 
diagnostic device intended for use in the qualitative detection of 
antibodies to HBV and for use as an aid in the diagnosis of HBV 
infection in specific populations. HBV antibody assays aid in the 
diagnosis of HBV infection in persons with signs and symptoms of 
hepatitis and in persons at risk for HBV infection. Antibody assays 
typically detect the presence of antibodies to HBsAg (anti-HBs), 
Hepatitis B core antigen (anti-HBc), or HBeAg (anti-HBe). Diagnosis of 
HBV infection should not be established based on a single assay result, 
but should be determined in conjunction with clinical findings and 
other diagnostic procedures (e.g., HBV serology and antigen testing, 
liver function, etc.). These assays are not intended for use in 
screening of blood, plasma, cells, or tissue donors.
    A quantitative assay that detects anti-HBs (antibodies to HBV 
surface antigen (HBsAg)) is a prescription in vitro diagnostic device 
that is intended for quantitative use to aid in the diagnosis of HBV 
infection in persons with signs and symptoms of hepatitis and in 
persons at risk for HBV infection. Detection of anti-HBs indicates a 
present or past infection with HBV and can be used in conjunction with 
clinical findings such as other HBV serological markers (detection of 
other HBV antigens and antibodies to HBV) for diagnosis of HBV 
infection. Anti-HBs assay results may be used as an aid in the 
determination of susceptibility to HBV infection in individuals prior 
to vaccination or when vaccination status is unknown.
    In some device designs, HBV antibodies, when present in the sample, 
bind to HBV antigens to form a complex that is bound to a solid phase 
(e.g., microparticles, microtiter plate, or other technology). 
Detection of complexes can be performed using different methods that 
measure the presence/absence of HBV antibodies in the sample.

C. Quantitative HBV Nucleic Acid-Based Assays

    A quantitative HBV nucleic acid-based assay is a prescription in 
vitro diagnostic device intended for use in the detection of HBV 
nucleic acid in specimens from individuals with antibody evidence of 
HBV infection. In these devices, the detection of HBV nucleic acid is 
used for management of patients undergoing antiviral therapy for 
assessing response to treatment and NOT as a diagnostic for HBV 
infection.
    FDA is proposing to reclassify qualitative HBV antigen, HBV 
antibody assays (including qualitative and quantitative anti-HBs), and 
quantitative HBV nucleic acid-based assays from class III (general 
controls and premarket approval) to class II (general controls and 
special controls) and to establish new names for the device types that 
will be within the classification regulations. FDA proposes to revise 
21 CFR part 866 to create three new device classification regulations 
with the names ``Qualitative Hepatitis B Virus Antigen Assays,'' 
``Hepatitis B Virus Antibody Assays,'' and ``Hepatitis B Virus Nucleic 
Acid-Based Assays.'' FDA believes that these names and proposed 
identification language most accurately describe these devices.
    <bullet> A Qualitative Hepatitis B Virus (HBV) Antigen Assay is 
tentatively identified as an in vitro diagnostic device intended for 
prescription use for qualitative use with human serum, plasma, or other 
matrices that aids in the diagnosis of chronic or acute HBV infection. 
HBV surface antigen (HBsAg) is also used for screening of HBV infection 
in pregnant women to identify neonates who are at risk of acquiring 
hepatitis B during perinatal period. The assay is not intended for 
screening of blood, plasma, cells, or tissue donors.
    <bullet> A Hepatitis B Virus (HBV) Antibody Assay is tentatively 
identified as an in vitro diagnostic device intended for prescription 
use in the detection of antibodies to HBV in human serum and plasma, or 
other matrices, and or as an aid in the diagnosis of HBV infection in 
persons with signs and symptoms of hepatitis and in persons at risk for 
hepatitis B infection. In addition, anti-HBc IgM (IgM antibodies to 
core antigen) assay is indicative of recent HBV infection. Anti-HBs 
(antibodies to surface antigen) assay results may be used as an aid in 
the determination of susceptibility to HBV infection in individuals 
prior to or following HBV vaccination or when vaccination status is 
unknown. The assay is not intended for screening of blood, plasma, 
cells, or tissue donors. The assay is intended as an aid in diagnosis 
in conjunction with clinical findings and other diagnostic procedures.
    <bullet> A Hepatitis B Virus (HBV) Nucleic Acid-Based Assay is 
tentatively identified as an in vitro diagnostic device intended for 
prescription use in the detection of HBV nucleic acid in specimens from 
individuals with antibody evidence of HBV infection. In these devices, 
the detection of HBV nucleic acid is used as an aid in the management 
of HBV-infected individuals. The assay is intended for use with human 
serum or plasma (and other matrices as applicable) from individuals 
with HBV. The assay is not intended for use as a donor screening assay 
for the presence of HBV nucleic acids in blood, blood products, plasma, 
cells, or tissue donors.
    Based upon 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 there is sufficient information to establish 
special controls that, along with general controls, can provide 
reasonable assurance of the devices' safety and effectiveness.

IV. Proposed Reclassification and Summary of Reasons for 
Reclassification

    FDA is proposing to reclassify the HBV assays that are the subject 
of this proposed order. On September 7, 2023, the Microbiology Devices 
Panel (Panel) of the Medical Devices Advisory Committee convened to 
discuss and make recommendations regarding the

[[Page 78270]]

reclassification of HBV assays from class III (general controls and 
premarket approval) to class II (general controls and special controls) 
(https://www.fda.gov/media/173609/download). Panel members unanimously 
agreed that special controls, in addition to general controls, are 
necessary and sufficient to mitigate the risks to health of patients 
presented by these devices and to provide reasonable assurance of the 
safety and effectiveness of these devices (Refs. 1 and 2). The Panel 
agreed with FDA-identified risks and identified additional risk(s) and 
benefit(s) to include in the overall risk assessment. The Panel also 
discussed potential mitigation measure(s)/control(s) FDA should 
consider for each of the identified risks and recommended that, as part 
of any reclassification, the expected performance for these devices 
should remain the same. Notably, the performance of approved HBV 
antigen assays has generally been at least 97 percent sensitivity and 
99 percent specificity. For approved anti-HBs, anti-Hbe, and anti-HBc 
total assays the sensitivity has generally been at least 95 percent, 
for approved anti-HBc IgM assays the sensitivity has been at least 86 
percent, and for all HBV approved antibody assays the specificity has 
generally been above 97 percent.
    FDA believes that at this time, sufficient data and information 
exist such that the risks identified in section V below can be 
mitigated by establishing special controls, and that these special 
controls, together with general controls, are necessary to provide a 
reasonable assurance of the safety and effectiveness of these HBV 
assays and therefore proposes these devices to be reclassified from 
class III (general controls and premarket approval) to class II 
(general controls and special controls). In accordance with section 
513(f)(3) of the FD&C Act and 21 CFR part 860, subpart C, FDA is 
proposing to reclassify qualitative HBV antigen assays, HBV antibody 
assays (including qualitative and quantitative anti-HBs), and 
quantitative HBV nucleic acid-based assays from class III into class 
II, subject to premarket notification (510(k)) requirements. FDA 
believes that there is sufficient information available to FDA through 
FDA's accumulated experience with these devices from reviewing the PMAs 
for these HBV assays, and the Panel considerations and recommendations 
regarding the proposed special controls that FDA believes would 
effectively mitigate the risks to health identified in section V. 
Absent the special controls identified in this proposed order, general 
controls applicable to the devices are insufficient to provide 
reasonable assurance of the safety and effectiveness of the devices. 
FDA expects that the reclassification of these devices would enable 
more manufacturers to develop these assays such that patients would 
benefit from increased access to safe and effective tests.
    FDA is proposing to create three separate classification 
regulations for HBV assays that will be reclassified from class III to 
class II. HBV assays are prescription in vitro diagnostic devices, and 
under this proposed order, if finalized, these devices will be 
identified as prescription in vitro diagnostic devices. As such, the 
devices must satisfy prescription labeling requirements for in vitro 
diagnostic products (see 21 CFR 809.10(a)(4) and (b)(5)(ii)). In this 
proposed order, if finalized, FDA has identified the special controls 
under section 513(a)(1)(B) of the FD&C Act that, together with general 
controls, will provide a reasonable assurance of the safety and 
effectiveness of these assays.
    FDA is also proposing to create a new product code for HBV antibody 
assays (including qualitative and quantitative anti-HBs) that will be 
assigned upon any finalization of this proposed order. Qualitative HBV 
antigen assays will continue to be assigned the product code LOM upon 
any finalization of this proposed order.
    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. For these HBV assays, FDA has determined 
that premarket notification is necessary to provide a reasonable 
assurance of the safety and effectiveness of these devices. Therefore, 
the Agency does not intend to exempt these proposed class II devices 
from 510(k) requirements. If this proposed order is finalized, persons 
who intend to market a new HBV assay will no longer need to have a PMA 
for these devices but can instead submit to FDA a 510(k) and receive 
clearance prior to marketing the device. A 510(k) typically results in 
a shorter premarket review timeline compared to a PMA, which ultimately 
provides more timely access of these types of devices to patients.

V. Public Health Benefits and Risks to Health

    FDA is providing a substantive summary of the valid scientific 
evidence concerning the public health benefits of the use of HBV assays 
(see also https://www.fda.gov/media/171770/download), and the nature 
(and if known, the incidence) of the risks of the devices (see further 
discussion of the special controls being proposed to mitigate these 
risks in section VII of this proposed order).
    HBV infection represents a significant global public health burden. 
According to the World Health Organization (WHO), in 2019 there were 
approximately 296 million people chronically infected people worldwide, 
with 1.5 million new HBV infections each year.\3\ It is estimated by 
the Centers for Disease Control and Prevention (CDC) that chronic HBV 
infection in the United States affects at least between 580,000 to 1.17 
million people with HBV infection in the United States; two-thirds of 
whom may be unaware of their infection.\4\ HBV infection can be 
asymptomatic, and accordingly, many HBV-infected individuals are 
unaware of their HBV infection. Approximately 95 percent of adult 
patients with acute infection, defined as the first 6 months after 
infection, recover completely, and 5 percent of adults develop chronic 
HBV.\5\ Infants born to women who are HbsAg-positive are at high risk 
of HBV infection. In absence of treatment, infants infected with HBV 
have a 90 percent risk of progression to chronic HBV and up to 25 
percent of infants who acquire chronic HBV infection will die 
prematurely from HBV-related hepatocellular carcinoma or cirrhosis.\6\ 
Patients who are tested and become aware that they are HBV infected may 
modify risk behaviors to prevent transmission to others and can be 
referred for treatment. Patients with chronic HBV infection have a risk 
of developing liver damage, liver cancer, or liver failure. They can 
also spread their infection to others. HBV can be reactivated in 
patients receiving immunosuppressive therapies, resulting in serious 
risk of liver failure or liver-associated death (Ref. 3). HBV is a 
vaccine-preventable liver infection.
---------------------------------------------------------------------------

    \3\ https://www.who.int/news-room/fact-sheets/detail/hepatitis-b. Accessed on July 12, 2024.
    \4\ Centers for Disease Control and Prevention--Clinical 
Overview of Hepatitis B (Available at https://www.cdc.gov/hepatitis-b/hcp/clinical-overview/index.html). Accessed on July 12, 2024.
    \5\ Ibid.
    \6\ Ibid.
---------------------------------------------------------------------------

    With the initiation of the WHO Viral Hepatitis Elimination Plan \7\ 
and the Department of Health and Human Services (HHS) Viral Hepatitis 
National

[[Page 78271]]

Strategic Plan for the United States,\8\ it is important for 
individuals to know their HBV infected status, to link HBV infected 
individuals to care, and to eliminate virus transmission. Therefore, 
diagnosis of patients with HBV infection through devices such as HBV 
antibody and antigen assays is essential to ensure that patients are 
linked to the appropriate care. Current CDC HBV Screening and Testing 
Recommendations include testing of the following groups: all adults 18 
and older at least once in their lifetime using a triple panel test, 
pregnant women during pregnancy, people who are at ongoing risk for 
exposure, and anyone who requests HBV testing.\9\
---------------------------------------------------------------------------

    \7\ https://www.who.int/health-topics/hepatitis/elimination-of-hepatitis-by-2030#tab=tab_1. Accessed on July 12, 2024.
    \8\ https://www.hhs.gov/sites/default/files/Viral-Hepatitis-National-Strategic-Plan-2021-2025.pdf. Accessed on July 12, 2024.
    \9\ https://www.cdc.gov/hepatitis/hbv/index.htm. Accessed on 
July 12, 2024.
---------------------------------------------------------------------------

    FDA considered our accumulated experience with the regulation of 
these HBV assays, input from the Panel meeting, and postmarket 
information regarding these HBV assays, i.e., information from FDA's 
publicly available MDR, Manufacturer and User Facility Device 
Experience (MAUDE), and Medical Device Recall databases.
    These HBV assays provide a benefit to the public health by 
informing individuals of their HBV infected status, linking HBV 
infected individuals to appropriate care, and aiding in eliminating 
virus transmission. Once an individual is tested and diagnosed as HBV 
infected, HBV nucleic acid testing is performed to inform treatment 
decisions. While HBV infection is treatable, it is not curable, which 
means that most people who start HBV antiviral treatment must continue 
it for life. The goal of current treatment is to suppress the virus and 
reduce the likelihood of long-term complications and transmission 
(Refs. 3 and 4). Thus, identifying individuals who are HBV infected, 
linking them to care, and managing their HBV infection to alleviate 
development of liver damage, liver cancer, liver failure, and potential 
HBV transmission would not only greatly impact public health but also 
go a long way towards helping the United States achieve HBV 
elimination.
    Probable risks to health associated with the use of HBV assays 
include risks related to the risk of false results (false positives, 
false negatives, inaccurate low assay results, inaccurate high assay 
results, false reactive results, or false non-reactive results), 
failure to correctly interpret assay results, and failure to correctly 
operate the device. For HBV antigen and antibody assays, false positive 
results are generally referred to as false reactive results and false 
negative results are generally referred to as false non-reactive 
results. False results can lead to uninfected individuals receiving 
unnecessary further testing and treatment or infected individuals 
remaining undiagnosed and untreated. Undiagnosed and untreated 
individuals are likely to experience increases in morbidity and 
mortality and can spread the infection to others. FDA has identified 
the following additional specific risks to health associated with each 
of the HBV assays listed below.

A. Qualitative HBV Antigen Assays

    Factors that may cause decreased assay sensitivity and/or an 
increased rate of false non-reactive results include, but are not 
limited to, the presence of interfering substances in the sample, acute 
infection at a stage that is too early for a device to detect the 
infection, and antigen concentrations that are too low to be detected 
by the device. Factors that may lead to false reactive results include 
device contamination from reactive samples, cross-reactivity with other 
antigens, or misinterpretation of invalid results as reactive.
    <bullet> A false reactive assay result for HbeAg. Incorrectly 
interpreting the assay results as a reactive assay result or failing to 
correctly operate the assay causing a false reactive assay result may 
lead to continued treatment for hepatitis B with antiviral medication 
when it otherwise would not be indicated. Antiviral medication has 
risks including toxicity and more rarely allergic reactions. Over time, 
viral resistance in patients who are co-infected but undiagnosed with 
other viruses that are treated with the same antiviral medication, such 
as HIV, can lead to viral resistance.
    <bullet> A false reactive assay result for HbsAg. Incorrectly 
interpreting the assay results as a reactive assay result or failing to 
correctly operate the assay causing a false reactive assay result may 
contribute to unnecessary additional testing, potentially delaying 
diagnosis of alternative causes of liver disease when present and may 
impact the psychological well-being of the patient. Factors that may 
increase the rate of false reactive assay reporting include cross-
reactivity with antigens from other microorganisms or other disease 
conditions.
    <bullet> A false non-reactive result for HbeAg. Incorrectly 
interpreting the assay results as a non-reactive assay result or 
failing to correctly operate the assay causing a false non-reactive 
assay result may lead to missing the opportunity for treatment of an 
HBV infected individual with antiviral medication or premature 
discontinuation of antiviral treatment when continuation of treatment 
is otherwise indicated should a clinician be falsely led to determine a 
patient has seroconverted HbeAg to anti-Hbe. Premature discontinuation 
of antiviral medication could result in adverse effects on patient 
health, such as cirrhosis, liver cancer, and liver damage, all of which 
are known to contribute to patient morbidity and mortality, or may 
contribute to public health risk by leading to virus transmission.
    <bullet> A false non-reactive assay result for HbsAg. Incorrectly 
interpreting the assay results as a non-reactive assay result or 
failing to correctly operate the assay causing a false non-reactive 
assay result may delay or prevent a patient with HBV infection from 
being identified and linked to care. Missed identification of patients 
with chronic HBV infection could lead to adverse effects on patient 
health such as cirrhosis, liver cancer, and liver damage, all of which 
are known to contribute to patient morbidity and mortality. A false 
non-reactive HbsAg assay incorrectly interpreted as non-reactive also 
may contribute to public health risk by leading to virus transmission.

B. HBV Antibody Assays (Including Qualitative and Quantitative Anti-
HBs)

    Factors that may cause decreased assay sensitivity and/or an 
increased rate of false non-reactive results include, but are not 
limited to, the presence of interfering substances in the sample, acute 
infection at a stage that is too early for a device to detect the 
infection, and antibody concentrations that are too low to be detected 
by the device. They also can be caused by misinterpretation of invalid 
results as non-reactive. Factors that may lead to false reactive 
results include device contamination from reactive samples, cross-
reactivity with other antibodies, or misinterpretation of invalid 
results as reactive.
    <bullet> A false reactive assay result for anti-HBs and anti-HBc. 
Incorrectly interpreting the assay results as a reactive assay result 
or failing to correctly operate the assay causing a false reactive 
assay result may lead to improper patient management. A false reactive 
antibody assay result could result in the unnecessary continuation of 
antiviral treatment. Antiviral medication has risks including toxicity 
and more rarely allergic reactions. Over time, viral resistance in 
patients who are co-infected but undiagnosed with other viruses that 
are treated with the same antiviral medication, such as HIV, can

[[Page 78272]]

lead to viral resistance. Consequently, repeatedly false reactive 
results have the potential to lead to inappropriate patient management 
decisions.
    <bullet> A false reactive assay result for anti-HBs. Incorrectly 
interpreting the assay results as a reactive assay result or failing to 
correctly operate the assay causing a false reactive assay result when 
the device is used as an aid in the determination of susceptibility to 
HBV infection in individuals prior to or following HBV vaccination or 
where vaccination status is unknown may cause a patient to be 
considered previously exposed and therefore immune to HBV or that the 
patient was successfully vaccinated. A false reactive result may cause 
the patient to not receive a vaccine, vaccine booster, hyperimmune 
globulin, and would be at higher risk of infection if exposed to HBV.
    <bullet> A false reactive assay result for anti-Hbe. Incorrectly 
interpreting the assay results as a reactive assay result, or failing 
to correctly operate the assay causing a false reactive assay result 
may lead to missing the opportunity for treatment of HBV infection with 
antiviral medications in a subset of individuals for whom treatment 
would otherwise be indicated, or premature discontinuation of antiviral 
treatment when continuation of treatment is otherwise indicated should 
a clinician be falsely led to determine a patient has seroconverted 
HbeAg to anti-Hbe. Premature discontinuation of antiviral medication 
could result in adverse effects on patient health such as cirrhosis, 
liver cancer, and liver damage, all of which are known to contribute to 
patient morbidity and mortality, or may contribute to public health 
risk by leading to inadvertent transmission of virus by an infected 
individual.
    <bullet> A false non-reactive assay result for anti-HBc. When the 
device is used as an aid in the diagnosis of HBV infection in patients 
with symptoms of hepatitis or who may be at risk for HBV infection, 
incorrectly interpreting the assay results as non-reactive assay 
result, or failing to correctly operate the assay causing a false non-
reactive assay result may lead to non-diagnosis or a delay in diagnosis 
of HBV infection with an associated delay in therapy and potentially 
increased risk of HBV-related morbidity or mortality. Patients with 
active infection may unknowingly continue to infect others. False non-
reactive results can also lead to unnecessary diagnostic evaluation if 
alternative etiologies of hepatitis are pursued. False non-reactive 
assay results may occur if the level of antibody in a specimen is below 
the limit of detection of the assay.
    <bullet> A false non-reactive assay result for anti-HBs. When the 
device is used as an aid in the determination of susceptibility to HBV 
infection in individuals prior to or following HBV vaccination or where 
vaccination status is unknown, incorrectly interpreting the assay 
results as a non-reactive assay result or failing to correctly operate 
the assay causing a false non-reactive assay result may lead to 
unnecessary repeated vaccination for HBV.
    <bullet> A false non-reactive assay result for anti-Hbe. 
Incorrectly interpreting the assay results as non-reactive assay result 
or failing to correctly operate the assay causing a false non-reactive 
assay result may lead to improper patient management, including 
continued treatment for HBV with antiviral medication. Antiviral 
medication has risks including toxicity and more rarely allergic 
reactions. Over time, viral resistance in patients who are co-infected 
but undiagnosed with other viruses using the same antiviral medication, 
such as HIV, can lead to viral resistance.

C. Quantitative HBV Nucleic Acid-Based Assays

    Decreased assay sensitivity and/or an increased rate of false 
negative assay reporting may occur with patient samples that contain 
different genotypes or rare de novo mutations in HBV genomic regions 
targeted by the device. In these situations, HBV viral load can 
transiently decrease and/or become undetectable in samples before the 
virus enters chronic replication.
    <bullet> A false positive or falsely elevated quantitative HBV 
nucleic acid assay result. Incorrectly interpreting the assay results 
as a positive assay result or failing to correctly operate the assay 
causing a false positive assay result may negatively influence patient 
management decisions. Such decisions may include the administration or 
continuation of unnecessary antiviral treatment in patients with 
chronic HBV infection with its known toxicities and more rarely 
allergic reactions. Certain patients with falsely elevated HBV nucleic 
acid assay results may not undergo liver biopsy to investigate other 
causes of liver disease when the biopsy would otherwise be indicated 
for certain patients.
    <bullet> A false negative or falsely decreased quantitative HBV 
nucleic acid assay result. Incorrectly interpreting the assay results 
as a negative assay result, or failing to correctly operate the assay 
causing a false negative assay result may negatively influence patient 
management decisions for patients with chronic HBV infection, including 
the withholding of treatment, failure to treat, or premature 
discontinuation of treating HBV infection when antiviral treatment is 
otherwise indicated or the choice of an inappropriate treatment. This 
could lead to adverse effects on patient health such as progressive 
liver disease, cirrhosis and/or hepatocellular carcinoma, and other 
cancers. Patients with active HBV replication also risk spreading the 
virus to others. Certain patients with falsely low HBV nucleic acid 
assay results may undergo liver biopsy to investigate other causes of 
liver disease.

VI. Summary of Data Upon Which the Reclassification Is Based

    The safety and effectiveness of these device types has become well 
established since the initial approval of the first qualitative HBV 
antibody assay in 2000, the first HBV antigen assay in 2001, and the 
first quantitative HBV nucleic acid-based assay in 2008. FDA has 
considered and analyzed the following information: (1) accumulated 
experience regulating these HBV assays, (2) input from the Panel 
meeting, and (3) postmarket information regarding HBV assays, i.e., 
information from FDA's publicly available MDR, MAUDE, and Medical 
Device Recall databases. The available evidence demonstrates that there 
are public health benefits derived from the use of HBV assays indicated 
for use to aid in diagnosis of HBV infection and/or for use to aid in 
the management of HBV infected patients, or as an aid in the 
determination of susceptibility to HBV infection (anti-HBs). In 
addition, the nature of the associated risks to health are known, and 
special controls can be established to sufficiently mitigate these 
risks.
    Based on our review of the information described above, FDA has 
determined that special controls, in addition to general controls, are 
necessary to provide a reasonable assurance of safety and effectiveness 
for HBV assays, and that sufficient information exists to establish 
such special controls. Therefore, FDA, on its own initiative, is 
proposing to reclassify these postamendments devices from class III 
(general controls and premarket approval) into class II (general 
controls and special controls), subject to premarket notification 
(510(k)) requirements.

VII. Proposed Special Controls

    FDA believes that these devices can be classified into class II 
with the establishment of special controls. FDA believes that the 
following proposed special controls would mitigate each of

[[Page 78273]]

the risks to health described in section V and that these special 
controls, in addition to general controls, would provide a reasonable 
assurance of safety and effectiveness for HBV assays. Tables 1 through 
3 below demonstrate how FDA believes each risk to health described in 
section V would be mitigated by the proposed special controls for each 
device type.

A. Qualitative HBV Antigen Assays

    The risk of inaccurate interpretation of assay results can be 
mitigated by special controls requiring certain labeling, including 
providing clearly stated warnings and limitations and information on 
principles of operation and procedures in performing the assay.
    Risks associated with false results (e.g., false non-reactive and 
false reactive assay results) and with the failure to correctly operate 
the device can be mitigated through a combination of special controls, 
including certain labeling requirements, certain design verification 
and validation information, and performance studies. Examples of 
verification and validation information to be included in the design of 
the device include documentation of performance specifications 
including analytical and clinical performance criteria. In addition, 
design verification and validation activities must include 
documentation of a complete device description, critical reagents, risk 
analysis strategies, lot release criteria, stability studies, and 
protocols. Required statements in labeling can aid in mitigating the 
failure of the device to perform as indicated, for example including a 
statement that use of the assay with specimen types other than those 
specifically identified for use with this device may cause inaccurate 
assay results. Special controls requiring additional labeling to 
provide a brief summary of the instructions for use can also mitigate 
these risks.

  Table 1--Risks to Health and Mitigation Measures for Qualitative HBV
                             Antigen Assays
------------------------------------------------------------------------
      Identified risks to health              Mitigation measures
------------------------------------------------------------------------
False reactive/non-reactive assay      Certain labeling information,
 result.                                including limitations,
                                        explanation of procedures, and
                                        results interpretation
                                        information.
                                       Certain design verification and
                                        validation information,
                                        including certain device
                                        description information, risk
                                        analysis strategies, lot release
                                        criteria, stability studies and
                                        protocols, and performance
                                        criteria including analytical
                                        studies and clinical studies.
Failure to correctly interpret the     Certain labeling information,
 assay results.                         including warnings, limitations,
                                        results interpretation
                                        information, and explanation of
                                        procedures.
                                       Certain design verification and
                                        validation information,
                                        including certain device
                                        description information,
                                        critical reagent information,
                                        risk analysis strategies, lot
                                        release criteria, and stability
                                        studies and protocols.
Failure to correctly operate the       Certain labeling information,
 device.                                including warnings, limitations,
                                        results interpretation
                                        information, and explanation of
                                        procedures.
                                       Certain design verification and
                                        validation information,
                                        including certain device
                                        description, critical reagent
                                        information, risk analysis
                                        strategies, lot release
                                        criteria, and stability studies
                                        and protocols.
------------------------------------------------------------------------

B. HBV Antibody Assays (Including Qualitative and Quantitative Anti-
HBs)

    The risk of falsely reactive, non-reactive, elevated, or lowered 
assay results can be mitigated by special controls requiring certain 
labeling, including providing clearly stated warnings and limitations 
and information on principles of operation and procedures in performing 
the assay.
    Risks associated with the failure of the device to perform as 
indicated (e.g., false non-reactive and false reactive assay results) 
can be mitigated through a combination of special controls, including 
certain labeling requirements, certain design verification and 
validation information, and performance studies. Examples of 
verification and validation information to be included in the design of 
the device include documentation of performance specifications 
including analytical and clinical performance criteria. In addition, 
design verification and validation activities must include 
documentation of a complete device description, critical reagents, risk 
analysis strategies, lot release criteria, stability studies, and 
protocols. Required statements in labeling can aid in mitigating the 
failure of the device to perform as indicated; for example, including a 
statement that use of the assay with specimen types other than those 
specifically identified for use with this device may cause inaccurate 
assay results.

Table 2--Risks to Health and Mitigation Measures for HBV Antibody Assays
            (Including Qualitative and Quantitative Anti-HBs)
------------------------------------------------------------------------
      Identified risks to health              Mitigation measures
------------------------------------------------------------------------
False reactive/false non-reactive      Certain labeling information,
 assay result. In addition, for         including limitations,
 quantitative assays: Falsely           explanation of procedures, and
 elevated/falsely lowered assay         results interpretation
 result.                                information.
                                       Certain design verification and
                                        validation information including
                                        certain device description
                                        information, risk analysis
                                        strategies, lot release
                                        criteria, stability studies and
                                        protocols, and performance
                                        criteria including analytical
                                        studies and clinical studies.
Failure to correctly interpret the     Certain labeling information,
 assay results.                         including warnings, limitations,
                                        results interpretation
                                        information, and explanation of
                                        procedures.
                                       Certain design verification and
                                        validation information including
                                        certain device description,
                                        critical reagent information,
                                        risk analysis strategies, lot
                                        release criteria, and stability
                                        studies and protocols.

[[Page 78274]]

 
Failure to correctly operate the       Certain labeling information,
 devices.                               warnings, limitations, results
                                        interpretation information, and
                                        explanation of procedures.
                                       Certain design verification and
                                        validation information including
                                        certain device description,
                                        critical reagent information,
                                        risk analysis strategies, lot
                                        release criteria, and stability
                                        studies and protocols.
------------------------------------------------------------------------

C. Quantitative HBV Nucleic Acid-Based Assays

    The risk of falsely positive, negative, elevated, or lowered assay 
results can be mitigated by special controls requiring certain 
labeling, including providing clearly stated warnings and limitations, 
device description information, and detailed instructions in the device 
labeling regarding the interpretation of assay results and principles 
of operation and procedures in performing the assay.
    Risks associated with the failure of the device to perform as 
indicated (e.g., inaccurately low or high results, false negative 
results, and false positive assay results) can be mitigated through a 
combination of special controls related to certain labeling 
requirements, design verification and validation activities, and 
performance studies. Examples of verification and validation 
information to be included in the design of the device include 
documentation of a complete device description, calibrators, critical 
reagents, traceability, and lot release criteria. In addition, design 
verification and validation must include documentation of performance 
specifications, including analytical and clinical performance criteria. 
Required statements in labeling can aid in mitigating the occurrence of 
inaccurate results. The risks of false positive/false negative/falsely 
elevated/falsely lowered results due to decreased assay sensitivity can 
be mitigated by special controls related to certain labeling, design 
verification and validation activities, risk analysis strategies, and 
performance studies.

  Table 3--Risks to Health and Mitigation Measures for Quantitative HBV
                        Nucleic Acid-Based Assays
------------------------------------------------------------------------
      Identified risks to health              Mitigation measures
------------------------------------------------------------------------
False positive/false negative/falsely  Certain labeling information,
 elevated/falsely lowered result.       including limitations,
                                        explanation of procedures, and
                                        results interpretation
                                        information.
                                       Certain design verification and
                                        validation information,
                                        including certain device
                                        description information, risk
                                        analysis strategies, lot release
                                        criteria, stability studies and
                                        protocols, and performance
                                        criteria including analytical
                                        studies and clinical studies.
Failure to correctly interpret the     Certain labeling information,
 assay results.                         including warnings, limitations,
                                        results interpretation
                                        information, and explanation of
                                        procedures.
                                       Certain design verification and
                                        validation information,
                                        including certain device
                                        description, critical reagent
                                        information, risk analysis
                                        strategies, lot release
                                        criteria, and stability studies
                                        and protocols.
Failure to correctly operate the       Certain labeling warnings,
 device.                                limitations, results
                                        interpretation information, and
                                        explanation of procedures.
                                       Certain design verification and
                                        validation information including
                                        certain device description,
                                        critical reagent information,
                                        risk analysis strategies, lot
                                        release criteria, and stability
                                        studies and protocols.
------------------------------------------------------------------------

    If this proposed order is finalized, qualitative HBV antigen 
assays, HBV antibody assays (including qualitative and quantitative 
anti-HBs), and quantitative HBV nucleic acid-based assays will be 
reclassified into class II (general controls and special controls) and 
would be subject to premarket notification requirements under section 
510(k) of the FD&C Act. Firms submitting a 510(k) of the FD&C Act for 
such devices will be required to comply with the particular mitigation 
measures set forth in the special controls. FDA believes that adherence 
to the special controls, in addition to the general controls, is 
necessary to provide a reasonable assurance of safety and effectiveness 
of HBV assays.

VIII. Analysis of Environmental Impact

    We have 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

    While this proposed order contains no new collections of 
information, it does refer to previously approved FDA collections of 
information. The previously approved FDA collections of information 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 
collections of information in 21 CFR part 820 have been approved under 
OMB control number 0910-0073; the collections of information in part 
807, subpart E, have been approved under OMB control number 0910-0120; 
and the collections of information in 21 CFR parts 801 and 809 have 
been approved under OMB control number 0910-0485.

X. Proposed Effective Date

    FDA proposes that any final order based on this proposed order 
become effective 30 days after the date of its publication in the 
Federal Register.

XI. 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

[[Page 78275]]

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) of the FD&C Act, in the 
proposed order, we are proposing to codify qualitative hepatitis B 
virus antigen assays in the new Sec.  866.3178, hepatitis B virus 
antibody assays (including qualitative and quantitative anti-HBs) in 
the new Sec.  866.3179, and quantitative hepatitis B virus nucleic 
acid-based assays in the new Sec.  866.3180, under which these HBV 
assays would be reclassified from class III into class II.

XII. References

    The following references marked with an asterisk (*) 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 also are available electronically at https://www.regulations.gov. References without asterisks are not on public 
display at https://www.regulations.gov because they have copyright 
restriction. Some may be available at the website address, if listed. 
References without asterisks are available for viewing only at the 
Dockets Management Staff. Although FDA verified the website addresses 
in this document, please note that websites are subject to change over 
time.

*1. Summary Minutes Prepared for the September 7, 2023, Meeting of 
the Microbiology Devices Panel (available at https://www.fda.gov/media/173610/download).
*2. Meeting Transcript Prepared for the September 7, 2023, Meeting 
of the Microbiology Devices Panel (available at https://www.fda.gov/media/173609/download).
3. Terrault, N.A., A.S.F. Lok, B.J. McMahon, et al., ``Update on 
Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 
2018 Hepatitis B Guidance.'' Hepatology, 67(4): 1560-1599, 2018.
4. CDC, ``Clinical Testing and Diagnosis for Hepatitis B,'' https://www.cdc.gov/hepatitis-b/hcp/diagnosis-testing/index.html. Accessed 
July 11, 2024.

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, 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.  866.3178 to subpart D to read as follows:


Sec.  866.3178  Qualitative hepatitis B virus antigen assays.

    (a) Identification. A qualitative hepatitis B virus (HBV) antigen 
assay is identified as an in vitro diagnostic device intended for 
prescription use for qualitative use with human serum, plasma, or other 
matrices that aids in the diagnosis of chronic or acute HBV infection. 
HBV surface antigen (HbsAg) is also used for screening of HBV infection 
in pregnant women to identify neonates who are at risk of acquiring 
hepatitis B during perinatal period. The assay is not intended for 
screening of blood, plasma, cells, or tissue donors.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) The labeling required under Sec.  809.10(b) of this chapter 
must include:
    (i) A prominent statement that the assay is not intended for the 
screening of blood, plasma, cells, or tissue donors.
    (ii) A detailed explanation of the principles of operation and 
procedures for performing the assay.
    (iii) A detailed explanation of the interpretation of results.
    (iv) Limitations, which must be updated to reflect current clinical 
practice and disease presentation and management. The limitations must 
include statements that indicate:
    (A) The specimen types for which the device has been cleared, and 
that use of this assay with specimen types other than those 
specifically cleared for this device may result in inaccurate assay 
results.
    (B) When appropriate, performance characteristics of the assay have 
not been established in populations of immunocompromised or 
immunosuppressed patients or other populations where assay performance 
may be affected.
    (C) Diagnosis of hepatitis B infection should not be established on 
the basis of a single assay result but should be determined by a 
licensed healthcare professional in conjunction with the clinical 
presentation, history, and other diagnostic procedures.
    (D) Detection of HBV antigens indicates a current infection with 
hepatitis B virus but does not differentiate between acute or chronic 
infection. False reactive HbsAg result may occur for up to 2 weeks 
after vaccination with HbsAg containing vaccine.
    (E) Current methods for the detection of hepatitis B antigens may 
not detect all potentially infected individuals. A non-reactive assay 
result does not exclude the possibility of exposure to or infection 
with hepatitis B virus. A non-reactive assay result in individuals with 
prior exposure to hepatitis B may be due to but not limited to antigen 
levels below the detection limit of this assay or lack of antigen 
reactivity to the antibodies in this assay. HBV mutants lacking the 
ability to produce antigens have been reported. These may occur as 
``escape'' mutants in the presence of anti-HBV antibodies and such 
patients may be infectious.
    (F) Results obtained with this assay may not be used 
interchangeably with results obtained with a different manufacturer's 
assay.
    (2) Design verification and validation must include the following:
    (i) A detailed device description, including all parts that make up 
the device, ancillary reagents required but not provided, an 
explanation of the device methodology, design of the capture 
antibody(ies), external controls, and computational path from collected 
raw data to reported result (e.g., how collected raw signals are 
converted into a reported signal and result), as applicable to the 
detection method and device design.
    (ii) For devices with assay calibrators, the design and composition 
of all primary, secondary, and subsequent quantitation standards used 
for calibration as well as their traceability to a standardized 
reference material that FDA has determined is appropriate (e.g., a 
recognized consensus standard). 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 approval, or when there is a 
transition to a new calibration standard.
    (iii) Documentation and characterization (e.g., supplier, 
determination of identity, purity, and stability) of all critical 
reagents (including description of the capture antibody(ies)), and 
protocols for maintaining product integrity throughout its labeled 
shelf life.
    (iv) Risk analysis and management strategies, such as Failure Modes 
Effects Analysis and/or Hazard Analysis and Critical Control Points 
summaries and their impact on assay performance.
    (v) Final release criteria to be used for manufactured assay lots 
with appropriate evidence that lots released

[[Page 78276]]

at the extremes of the specifications will meet the identified 
analytical and clinical performance characteristics as well as 
stability.
    (vi) Stability studies for reagents must include documentation of 
an assessment of real-time stability for multiple reagent lots using 
the indicated specimen types and must use acceptance criteria that 
ensure that analytical and clinical performance characteristics are met 
when stability is assigned based on the extremes of the acceptance 
range.
    (vii) All stability protocols, including acceptance criteria.
    (viii) Final release assay results for each lot used in clinical 
studies.
    (ix) Reproducibility study data that includes the testing of three 
independent production lots.
    (x) Detailed documentation of analytical performance studies 
conducted, as appropriate to the technology, specimen types tested, and 
intended use of the device, including, the limit of blank (LoB), limit 
of detection (LoD), cutoff, precision (reproducibility) including lot-
to-lot and/or instrument-to-instrument precision, interference, cross 
reactivity, carryover, hook effect, seroconversion panel testing, 
matrix equivalency, prominent mutants/variants detection (e.g., for 
HbsAg), specimen stability, reagent stability, and cross-genotype 
antigen detection sensitivity, when appropriate.
    (xi) Analytical sensitivity of the assay is the same or better than 
that of other cleared or approved assays.
    (xii) For devices with associated software or instrumentation, 
documentation must include a detailed description of device software, 
including software applications and hardware-based devices that 
incorporate software. The detailed description must include 
documentation of verification, validation, and hazard analysis and risk 
assessment activities, including an assessment of the impact of threats 
and vulnerabilities on device functionality and end users/patients as 
part of cybersecurity review.
    (xiii) Detailed documentation and results from a clinical study. 
Performance must be analyzed relative to an FDA cleared or approved HBV 
antigen assay or a comparator that FDA has determined is appropriate. 
This study must be conducted using appropriate patient samples, with an 
appropriate number of HBV reactive and non-reactive samples in 
applicable risk and disease categories, and any applicable confirmatory 
testing. Additional relevant patient groups must be validated as 
appropriate. The samples must include prospective (sequential) samples 
for each identified specimen type and, as appropriate, additional 
characterized clinical samples. Samples must be sourced from 
geographically diverse areas. This study must be conducted in the 
appropriate settings by the intended users to demonstrate clinical 
performance.
0
3. Add Sec.  866.3179 to subpart D to read as follows:


Sec.  866.3179  Hepatitis B virus antibody assays (including 
qualitative and quantitative anti-HBs).

    (a) Identification. A hepatitis B virus (HBV) antibody assay is 
identified as an in vitro diagnostic device intended for prescription 
use in the detection of antibodies to HBV in human serum, plasma, or 
other matrices, and as a device that aids in the diagnosis of HBV 
infection in persons with signs and symptoms of hepatitis and in 
persons at risk for hepatitis B infection. In addition, results from an 
anti-HBc IgM (IgM antibodies to core antigen) assay indicating the 
presence of anti-HBc IgM are indicative of recent HBV infection. Anti-
HBs (antibodies to surface antigen) assay results may be used as an aid 
in the determination of susceptibility to HBV infection in individuals 
prior to or following HBV vaccination or when vaccination status is 
unknown. The assay is not intended for screening of blood, plasma, 
cells, or tissue donors. The assay is intended as an aid in diagnosis 
in conjunction with clinical findings and other diagnostic procedures.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) The labeling required under Sec.  809.10(b) of this chapter 
must include:
    (i) A prominent statement that the assay is not intended for the 
screening of blood, plasma, cells, or tissue donors.
    (ii) A detailed explanation of the principles of operation and 
procedures for performing the assay.
    (iii) A detailed explanation of the interpretation of results.
    (iv) Limitations, which must be updated to reflect current clinical 
practice and disease presentation and management. The limitations must 
include statements that indicate:
    (A) When appropriate, performance characteristics of the assay have 
not been established in populations of immunocompromised or 
immunosuppressed patients or other special populations where assay 
performance may be affected.
    (B) Detection of HBV antibodies to a single viral antigen indicates 
a present or past infection with hepatitis B virus, but does not 
differentiate between acute, chronic, or resolved infection.
    (C) The specimen types for which the device has been cleared, and 
that use of the assay with specimen types other than those specifically 
cleared for this device may result in inaccurate assay results.
    (D) Diagnosis of hepatitis B infection should not be established on 
the basis of a single assay result but should be determined by a 
licensed healthcare professional in conjunction with the clinical 
presentation, history, and other diagnostic procedures.
    (E) A non-reactive assay result may occur early during acute 
infection, prior to development of a host antibody response to 
infection, or when analyte levels are below the limit of detection of 
the assay.
    (F) Results obtained with this assay may not be used 
interchangeably with results obtained with a different manufacturer's 
assay.
    (v) For devices intended for the quantitative detection of HBV 
antibodies (anti-HBs), in addition to the special controls listed in 
paragraphs (b)(1) and (2) of this section, labeling required under 
Sec.  809.10(b) of this chapter must include:
    (A) The assay calibrators' traceability to a standardized reference 
material that FDA has determined is appropriate (e.g., a recognized 
consensus standard) and the limit of blank (LoB), limit of detection 
(LoD), limit of quantitation (LoQ), linearity, and precision to define 
the analytical measuring interval.
    (B) Performance results of the analytical sensitivity study testing 
a standardized reference material that FDA has determined is 
appropriate (e.g., a recognized consensus standard).
    (2) Design verification and validation must include the following:
    (i) Detailed device description, including all parts that make up 
the device, ancillary reagents required but not provided, an 
explanation of the device methodology, and design of the antigen(s) and 
capture antibody(ies) sequences, rationale for the selected epitope(s), 
degree of amino acid sequence conservation of the target, and the 
design and composition of all primary, secondary and subsequent 
standards used for calibration.
    (ii) Documentation and characterization (e.g., supplier, 
determination of identity, and stability) of all critical reagents 
(including description of the antigen(s) and capture antibody(ies)), 
and protocols for maintaining product integrity throughout its labeled 
shelf life.
    (iii) Risk analysis and management strategies, such as Failure 
Modes Effects

[[Page 78277]]

Analysis and/or Hazard Analysis and Critical Control Points summaries 
and their impact on assay performance.
    (iv) Final release criteria to be used for manufactured assay lots 
with appropriate evidence that lots released at the extremes of the 
specifications will meet the identified analytical and clinical 
performance characteristics as well as stability.
    (v) Stability studies for reagents must include documentation of an 
assessment of real-time stability for multiple reagent lots using the 
indicated specimen types and must use acceptance criteria that ensure 
that analytical and clinical performance characteristics are met when 
stability is assigned based on the extremes of the acceptance range.
    (vi) All stability protocols, including acceptance criteria.
    (vii) When applicable, analytical sensitivity of the assay is the 
same or better than that of other cleared or approved assays.
    (viii) Analytical performance studies and results for determining 
the limit of blank (LoB), limit of detection (LoD), cutoff, precision 
(reproducibility), including lot-to-lot and/or instrument-to-instrument 
precision, interference, cross reactivity, carryover, hook effect, 
seroconversion panel testing, matrix equivalency, specimen stability, 
reagent stability, and cross-genotype antibody detection sensitivity, 
when appropriate.
    (ix) For devices intended for the detection of antibodies for which 
a standardized reference material (that FDA has determined is 
appropriate) is available, the analytical sensitivity study and results 
testing the standardized reference material. Detailed documentation of 
that study and its results must be provided, including the study 
protocol, study report, testing results, and all statistical analyses.
    (x) For devices with associated software or instrumentation, 
documentation must include a detailed description of device software, 
including software applications and hardware-based devices that 
incorporate software. The detailed description must include 
documentation of verification, validation, and hazard analysis and risk 
assessment activities, including an assessment of the impact of threats 
and vulnerabilities on device functionality and end users/patients as 
part of cybersecurity review.
    (xi) Detailed documentation of clinical performance testing from a 
clinical study with an appropriate number of HBV reactive and non-
reactive samples in applicable risk categories and conducted in the 
appropriate settings by the intended users. Performance must be 
analyzed relative to an FDA cleared or approved HBV antibody assay or a 
comparator that FDA has determined is appropriate. Additional relevant 
patient groups must be validated as appropriate. The samples must 
include prospective (sequential) samples for each identified specimen 
type and, as appropriate, additional characterized clinical samples. 
Samples must be sourced from geographically diverse areas.
    (3) For any HBV antibody assay intended for quantitative detection 
of anti-HBV antibodies, the following special controls, in addition to 
those special controls listed in paragraphs (b)(1) and (2) of this 
section, also apply:
    (i) Detailed documentation of the metrological calibration 
traceability hierarchy to a standardized reference material that FDA 
has determined is appropriate.
    (ii) Detailed documentation of the following analytical performance 
studies conducted, as appropriate to the technology, specimen types 
tested, and intended use of the device, including upper and lower 
limits of quantitation (UloQ and LloQ, respectively), linearity using 
clinical samples, and an accuracy study using the recognized 
international standard material.
    4. Add Sec.  866.3180 to subpart D to read as follows:


Sec.  866.3180  Hepatitis B virus nucleic acid-based assays.

    (a) Identification. A nucleic acid-based hepatitis B virus (HBV) 
assay is identified as an in vitro diagnostic device intended for 
prescription use in the detection of HBV nucleic acid in specimens from 
individuals with antibody evidence of HBV infection. In these devices, 
the detection of HBV nucleic acid is used as an aid in the management 
of HBV-infected individuals. The assay is intended for use with human 
serum or plasma (and other matrices as applicable) from individuals 
with HBV. The assay is not intended for use as a donor screening assay 
for the presence of HBV nucleic acids in blood, blood products, plasma, 
cells, or tissue donors, or as a diagnostic assay to confirm the 
presence of HBV infection.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) Labeling required under Sec.  809.10(b) of this chapter must 
include:
    (i) A prominent statement that the assay is not intended for use as 
a screening assay for the presence of HBV DNA in blood or blood 
products, plasma, cells, or tissue donors, or as a diagnostic assay to 
confirm the presence of HBV infection.
    (ii) A detailed explanation of the principles of operation and 
procedures for performing the assay.
    (iii) A detailed explanation of the interpretation of results.
    (iv) Limitations, which must be updated to reflect current clinical 
practice and disease presentation and/or management. These limitations 
must include statements that indicate:
    (A) Management of patients undergoing hepatitis B virus treatment 
should not be established on the basis of a single assay result but 
should be determined by a licensed healthcare professional in 
conjunction with the clinical presentation, history, and other 
diagnostic procedures, e.g., HBV serologic testing, liver function 
assays, liver elastography, etc.
    (B) The specimen types for which the device has been cleared, and 
that use of this assay with specimen types other than those 
specifically cleared for this device may result in inaccurate assay 
results.
    (C) The results obtained with this assay may not be used 
interchangeably with results obtained with a different manufacturer's 
assay.
    (2) Design verification and validation must include the following:
    (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 design of primers and probes, 
rationale for the selected gene targets, specifications for amplicon 
size, and degree of nucleic acid sequence conservation.
    (ii) For devices with assay calibrators, the design and composition 
of all primary, secondary, and subsequent quantitation standards used 
for calibration as well as their traceability to a standardized 
reference material that FDA has determined is appropriate (e.g., a 
recognized consensus standard). 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 approval, or when there is a 
transition to a new calibration standard.
    (iii) Documentation and characterization (e.g., determination of 
the identity, supplier, purity, and stability) of all critical reagents 
(including nucleic acid sequences for primers and probes) and protocols 
for maintaining product integrity.
    (iv) Risk analysis and management strategies demonstrating how risk

[[Page 78278]]

control measures are implemented to address device system hazards, such 
as Failure Modes Effects Analysis and/or Hazard Analysis and Critical 
Control Points summaries and their impact on assay performance.
    (v) Final release criteria to be used for manufactured assay lots 
with appropriate evidence that lots released at the extremes of the 
specification will meet the identified analytical and clinical 
performance characteristics as well as stability.
    (vi) Stability studies for reagents must include documentation of 
an assessment of real-time stability for multiple reagent lots using 
the indicated specimen types and must use acceptance criteria that 
ensure that analytical and clinical performance characteristics are met 
when stability is assigned based on the extremes of the acceptance 
range.
    (vii) All stability protocols, including acceptance criteria.
    (viii) Detailed documentation of analytical performance studies 
conducted as appropriate to the technology, specimen types tested, and 
intended use of the device, including limit of detection (LoD), 
linearity, precision, endogenous and exogenous interferences, cross-
reactivity, carryover, matrix equivalency, sample and reagents 
stability, and as applicable, upper and lower limits of quantitation 
(ULoQ and LLoQ, respectively). Samples selected for use must be from 
subjects with clinically relevant circulating genotypes in the United 
States. Cross-reactivity studies must include samples from HBV nucleic 
acid negative subjects with other viral or non-viral causes of liver 
disease, including autoimmune hepatitis, alcoholic liver disease, 
chronic hepatitis C virus (HCV), primary biliary cirrhosis, and 
nonalcoholic steatohepatitis, when applicable. The effect of each 
identified nucleic-acid isolation and purification procedure on 
detection must be evaluated.
    (ix) For devices with associated software or instrumentation, 
documentation must include a detailed description of device software, 
including software applications and hardware-based devices that 
incorporate software. The detailed description must include 
documentation of verification, validation, and hazard analysis and risk 
assessment activities, including an assessment of the impact of threats 
and vulnerabilities on device functionality and end users/patients as 
part of cybersecurity review.
    (x) Detailed documentation of performance from a clinical study 
with a design and number of clinical samples (appropriately 
statistically powered) that is appropriate for the intended use of the 
device as well as conducted in the appropriate settings by the intended 
users. The samples must include prospective (sequential) samples for 
each claimed specimen type and, as appropriate, additional 
characterized clinical samples. Samples must be sourced from 
geographically diverse areas.

    Dated: September 20, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-21932 Filed 9-24-24; 8:45 am]
BILLING CODE 4164-01-P


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