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Proposed Rule2024-21932

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

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Published

September 25, 2024

Issuing agencies

Health and Human Services DepartmentFood and Drug Administration

Abstract

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.

Full Text

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<title>Federal Register, Volume 89 Issue 186 (Wednesday, September 25, 2024)</title>
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<body><pre>
[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 [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of 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: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

Submit written/paper submissions as follows:

[[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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents, 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
<a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the docket number, found in
brackets in the heading of this document, into the ``Search'' box and
follow the prompts and/or go to the Dockets Management Staff, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: 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&#160;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)
(<a href="https://www.fda.gov/media/173609/download">https://www.fda.gov/media/173609/download</a>). 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 <a href="https://www.fda.gov/media/171770/download">https://www.fda.gov/media/171770/download</a>), 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\ <a href="https://www.who.int/news-room/fact-sheets/detail/hepatitis-b">https://www.who.int/news-room/fact-sheets/detail/hepatitis-b</a>. Accessed on July 12, 2024.
\4\ Centers for Disease Control and Prevention--Clinical
Overview of Hepatitis B (Available at <a href="https://www.cdc.gov/hepatitis-b/hcp/clinical-overview/index.html">https://www.cdc.gov/hepatitis-b/hcp/clinical-overview/index.html</a>). 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\ <a href="https://www.who.int/health-topics/hepatitis/elimination-of-hepatitis-by-2030#tab=tab_1">https://www.who.int/health-topics/hepatitis/elimination-of-hepatitis-by-2030#tab=tab_1</a>. Accessed on July 12, 2024.
\8\ <a href="https://www.hhs.gov/sites/default/files/Viral-Hepatitis-National-Strategic-Plan-2021-2025.pdf">https://www.hhs.gov/sites/default/files/Viral-Hepatitis-National-Strategic-Plan-2021-2025.pdf</a>. Accessed on July 12, 2024.
\9\ <a href="https://www.cdc.gov/hepatitis/hbv/index.htm">https://www.cdc.gov/hepatitis/hbv/index.htm</a>. 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)

[[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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. References without asterisks are not on public
display at <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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 <a href="https://www.fda.gov/media/173610/download">https://www.fda.gov/media/173610/download</a>).
*2. Meeting Transcript Prepared for the September 7, 2023, Meeting
of the Microbiology Devices Panel (available at <a href="https://www.fda.gov/media/173609/download">https://www.fda.gov/media/173609/download</a>).
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,'' <a href="https://www.cdc.gov/hepatitis-b/hcp/diagnosis-testing/index.html">https://www.cdc.gov/hepatitis-b/hcp/diagnosis-testing/index.html</a>. 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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