[Federal Register Volume 90, Number 179 (Thursday, September 18, 2025)]
[Rules and Regulations]
[Pages 44969-44978]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2025-18082]
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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, Department of Health and Human
Services (HHS).
ACTION: Final amendment; final order.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final
order reclassifying qualitative hepatitis B virus (HBV) antigen assays
(product code LOM), HBV antibody assays (product code LOM), and
quantitative HBV nucleic acid-based assays (product code MKT), all of
which are postamendments class III devices, into class II (special
controls), subject to premarket notification. FDA is also establishing
the special controls that are necessary to provide a reasonable
assurance of safety and effectiveness of these device types.
DATES: This order is effective October 20, 2025. See further discussion
in Section IV, ``Implementation Strategy.''
FOR FURTHER INFORMATION CONTACT: Bhawna Poonia, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 3226, Silver Spring, MD 20993, 240-402-6830,
[email protected].
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 classes of devices, reflecting the regulatory
controls needed to provide reasonable assurance of their safety and
effectiveness. The three classes of devices are class I (general
controls), class II (special controls), and class III (premarket
approval).
Devices that were not in commercial distribution prior to May 28,
1976 (generally referred to as postamendments devices) are
automatically classified by section 513(f)(1) of the FD&C Act into
class III without any action taken by FDA (or the Agency). Those
devices remain in class III and require premarket approval,
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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
previously marketed devices by means of the procedures in section
510(k) of the FD&C Act (21 U.S.C. 360(k)) and our implementing
regulations (part 807, subpart E (21 CFR part 807, subpart E)).
A postamendments device that has been initially classified into
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) 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
new class must have sufficient regulatory controls to provide
reasonable assurance of the safety and effectiveness of the device for
its intended use.\1\
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\1\ See section 513 of the FD&C Act.
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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.\2\ In general, to be considered in the reclassification
process, the ``valid scientific evidence'' upon which the Agency relies
must be publicly available. Publicly available information excludes
trade secret and/or confidential commercial information, e.g., the
contents of a pending PMA (see section 520(c) of the FD&C Act (21
U.S.C. 360j(c))).
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\2\ Id.
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Section 510(m) of the FD&C Act provides that FDA may exempt a class
II device from the requirements under section 510(k) of the FD&C Act if
FDA determines that a premarket notification (510(k)) is not necessary
to provide reasonable assurance of the safety and effectiveness of the
device type.
On September 25, 2024, FDA published a proposed order \3\ in the
Federal Register to reclassify qualitative HBV antigen assays (product
code LOM),\4\ qualitative HBV antibody assays and quantitative assays
that detect anti-HBs (antibodies to HBV surface antigen (HBsAg))
(product code LOM),\5\ and quantitative HBV nucleic acid-based assays
(product code MKT) from class III to class II (89 FR 78265, the
``proposed order'').\6\ FDA has considered the information available to
the Agency, including the deliberations of the Microbiology Devices
Panel (the ``Panel'') convened on September 7, 2023, to discuss the
proposed reclassification of these devices, and considered comments for
that meeting as well as comments received from the public docket on the
proposed order (as discussed in Section II of this document), to
determine that there is sufficient information to establish special
controls to effectively mitigate the risks to health. FDA has also
determined that based on this information that the special controls,
together with general controls, provide a reasonable assurance of
safety and effectiveness when applied to these devices.
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\3\ The ``ACTION'' caption for this proposed order was styled as
``Proposed amendment; proposed order; request for comments'' 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.
\4\ FDA's Center for Devices and Radiological Health (CDRH) uses
product codes to help categorize and ensure consistent regulation of
medical devices. A product code consists of three characters that
are assigned at the time a product code is generated and is unique
to a product type. The three characters carry no other significance
and are not an abbreviation. See FDA guidance entitled, ``Medical
Device Classification Product Codes'' available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/medical-device-classification-product-codes-guidance-industry-and-food-and-drug-administration-staff.
\5\ These devices are currently regulated under product code
LOM, but upon the finalization of this action they will fall within
the newly created product code SEI.
\6\ In the proposed order, FDA proposed to reclassify
``Hepatitis B virus antibody assays (including qualitative and
quantitative anti-HBs)'' under the classification regulation 21 CFR
866.3179. In this final order, FDA is simplifying the identification
of the classification regulation name to ``Hepatitis B virus
antibody assays'' and adding further description to the
identification language to better describe the devices that fit
within this generic device type and are subject to this
reclassification order. In addition, in the proposed order, FDA
proposed to reclassify qualitative hepatitis B virus antigen assays
under new classification regulation 21 CFR 866.3178 and quantitative
hepatitis B virus nucleic acid-based assays under new classification
regulation 21 CFR 866.3180. However, at the time of publication of
this final order, a different regulation has been codified at Sec.
866.3180. Therefore, in this final order, FDA is reclassifying these
device types under different sections of the Code of Federal
Regulations than was proposed in the proposed order. Specifically,
FDA is reclassifying qualitative hepatitis B virus antigen assays
under new classification regulation 21 CFR 866.3172, hepatitis B
virus antibody assays under new classification regulation 21 CFR
866.3173, and hepatitis B virus nucleic acid-based assays under new
classification regulation 21 CFR 866.3174.
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Therefore, in accordance with section 513(f)(3) of the FD&C Act,
FDA, on its own initiative, is issuing this final order \7\ to
reclassify qualitative HBV antigen assays, HBV antibody assays, and
quantitative HBV nucleic acid-based assays \8\ from class III
(premarket approval) to class II (special controls). Absent the special
controls identified in this final order, general controls applicable to
these device types are insufficient to provide reasonable assurance of
the safety and effectiveness of these devices. FDA expects that the
reclassification of these devices will enable more manufacturers to
develop these types of devices such that patients will benefit from
increased access to safe and effective diagnostics.
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\7\ FDA notes that the ``ACTION'' caption for this final order
is styled as ``Final amendment; final order,'' rather than ``Final
order.'' Beginning in December 2019, this editorial change was made
to indicate that the document ``amends'' the Code of Federal
Regulations. The change was made in accordance with the Office of
Federal Register's (OFR) interpretations of the Federal Register Act
(44 U.S.C. chapter 15), its implementing regulations (1 CFR 5.9 and
parts 21 and 22), and the Document Drafting Handbook.
\8\ We use the phrase ``quantitative HBV nucleic acid-based
assays'' to refer to the devices being reclassified in 21 CFR
866.3174 Hepatitis B virus nucleic acid-based assays.
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For these class II devices, instead of a PMA, manufacturers may
submit a premarket notification and obtain FDA clearance of the devices
before marketing them. This action will decrease regulatory burden on
industry, as manufacturers will no longer have to submit a PMA for
these types of devices but can instead submit a 510(k) to the Agency
for review prior to marketing their device. A 510(k) typically results
in a shorter premarket review timeline compared to a PMA, which
ultimately provides patients with more timely access to these types of
devices.
This final order is expected to result in decreased regulatory
burdens for affected devices moved from class III to class II and is
considered deregulatory under Executive Order 14192.
II. Comments on the Proposed Order and FDA Responses
A. Introduction
FDA received more than 25 comments on the proposed order. The
comment period on the proposed order closed on November 25, 2024. The
majority of the comments received by the close of the comment period
came from research, disease and patient advocacy groups, individual
medical professionals and an association of health care organizations,
patients, and members of the medical device industry. Many commenters
provided multiple comments on one or more issues. Comments provided
support for the proposed reclassification
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as well as included recommendations for clarity.
We describe and respond to the comments in Section II.B of this
document. The order of the comments and our response to them is purely
for organizational purposes and does not signify the comment's value or
importance of the comment nor the order in which comments were
received. Certain comments are grouped together under a single number
because the subject matter is similar. Please note that in some cases
we separate different issues discussed by the same commenter and
designate them as distinct comments for purposes of our responses.
B. Description of Comments and FDA Response
(Comment 1) FDA received numerous comments in favor of the proposed
reclassification of 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 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, from class III to class II with
special controls. Commenters stated they believe that special controls,
along with general controls, could provide reasonable assurance of the
safety and effectiveness of these devices. In addition, they believed
that the decreased regulatory burden resulting from the
reclassification could encourage further development of, and provide
patients more timely access to, these devices.
(Response 1) Based on the evidence considered, comments received in
response to the proposed order, and the 2023 Panel deliberations (Refs.
1 and 2), FDA agrees with the commenters that reclassification of
qualitative HBV antigen assays, HBV antibody assays, and quantitative
HBV nucleic acid-based assays from class III into class II and that
special controls, in addition to general controls, can provide
reasonable assurance of the safety and effectiveness of these devices.
In addition, FDA expects that the reclassification of these devices
would enable more manufacturers to develop them such that patients
would benefit from increased access to safe and effective tests.
(Comment 2) Many commenters emphasized the importance of Point of
Care (PoC) tests, particularly for settings that do not have access to
blood serum testing whether because of cost or patient hesitancy, for
testing and treating patients at the same visit and reducing the risk
of patients not returning for follow-up, and for increased mobility and
portability. Several commenters suggested that FDA should consider a
Clinical Laboratory Improvements Amendments of 1988 (CLIA)--waiver
designation for hepatitis B testing to make PoC tests available.
(Response 2) These comments are beyond the scope of FDA's
reclassification order, which applies only to qualitative HBV antigen
assays, HBV antibody assays, and quantitative HBV nucleic acid-based
assays that have been previously approved by FDA. FDA has not approved
any such assays as PoC tests or categorized them as CLIA waived. FDA
agrees that PoC tests should increase access to testing and encourages
the development of such tests in the future.
(Comment 3) Several comments suggested that FDA set reasonable
cutoff values for test sensitivity and specificity, and asserted this
would make it feasible for a PoC test to be available in the United
States, while limiting false positives and false negatives. Several
comments also recommended information be provided, such as sensitivity
and specificity benchmark values or a statement to guide clinicians on
whether or not reflex testing is warranted, due to the potential for
misleading results.
One commenter stated that screening tests should have high
sensitivity to reduce the incidence of false negative results. In
situations where a hepatitis B PoC test may have lower sensitivity, the
commenter further recommended inclusion of a statement that individuals
should have lab-based triple panel confirmatory testing that includes
testing for HBsAg, hepatitis B surface antibody (anti-HBs), and total
antibody to hepatitis B core antigen (total anti-HBc) to definitively
determine a person's hepatitis B status.
(Response 3) As discussed in response to comment 2, PoC tests are
outside the scope of this reclassification. Moreover, the Panel
recommendations from the September 7, 2023, meeting were unanimous that
performance expectations should not be compromised or lowered compared
with approved tests (Refs. 1 and 2). The proposed special controls for
qualitative HBV antigen assays and, when applicable, HBV antibody
assays state that analytical sensitivity of the assay is the same or
better than that of other cleared or approved assays. FDA has added
this special control in Sec. 866.3174(b)(2)(ix) for HBV nucleic acid-
based assays because it was inadvertently omitted from the proposed
order. FDA continues to believe that the special controls finalized in
this administrative order are necessary and sufficient to provide
reasonable assurance of safety and effectiveness for the HBV assays
that are within the scope of this final order.
The comments regarding providing sensitivity and specificity
benchmark values to guide reflex testing and triple panel confirmatory
testing are beyond the scope of this reclassification order as they
relate to the practice of medicine and current Centers for Disease
Control and Prevention (CDC) guidelines (Ref. 3). However, we note that
such guidelines are useful to practitioners as they administer these
tests and we acknowledged such guidelines in our proposed order.\9\
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\9\ See 89 FR 78265 at 78271.
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FDA also notes that the scope of the order is diagnostic devices
reviewed by CDRH. Screening tests are not within the scope of the
reclassification order as indicated by the identification of the
respective classification regulations.
(Comment 4) Several comments encouraged FDA to allow reliable data
obtained from approved hepatitis B PoC tests used globally with success
for many years when determining the required sample size within the
United States.
(Response 4) As discussed in response to comment 2, PoC tests are
outside the scope of this reclassification because FDA has not approved
qualitative HBV antigen assays, HBV antibody assays, and quantitative
HBV nucleic acid-based assays as PoC tests. FDA has not specified a
sample size requirement as a necessary risk mitigation in the proposed
special controls or final special controls included within this final
order. Regarding the utilization of data sourced from outside the
United States, FDA has regulations on the acceptance of data from
clinical investigations conducted outside the United States (OUS) to
support marketing applications for devices and recommends that sponsors
that include OUS data in their marketing application explain how the
OUS data are applicable to the US population and US medical
practice.\10\
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\10\ See ``Human Subject Protection; Acceptance of Data from
Clinical Investigations for Medical Devices'' (83 FR 7366) and FDA
guidance entitled ``Acceptance of Clinical Data to Support Medical
Device Applications and Submissions Frequently Asked Questions'',
available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/acceptance-clinical-data-support-medical-device-applications-and-submissions-frequently-asked.
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(Comment 5) Some commenters asked for clarification on whether the
proposed reclassification is referring to all anti-HBV immunoassays,
which would include the rapid serum assays commonly used in the
inpatient setting. Commenters stated that it was unclear whether
hepatitis B core antibody (HBcAb) Immunoglobulin M (IgM) and
Immunoglobulin G (IgG), hepatitis B core antibody total (HBcAb total),
and HBe antibody are included in the proposed reclassification.
(Response 5) The identification language in the classification
regulation for HBV antibody assays as stated in the proposed order and
new Sec. 866.3173 states that an HBV antibody assay is ``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'' (see Sec. 866.3173(a)).
This classification regulation covers HBV antibody assay types approved
to date and assigned to product code LOM,\11\ including serology
devices that detect anti-HBc IgM, anti-HBc IgG, anti-HBc total, anti-
HBs and anti-HBe. To further clarify which devices are included within
the classification, we are simplifying the classification regulation
name to ``Hepatitis B virus antibody assays'' and explaining in the
identification language that ``results from assays may be qualitative
or quantitative, such as quantitative anti-HBs.'' The quantitative HBV
antibody assays approved to date are quantitative anti-HBs. A
quantitative HBV antibody assay other than for anti-HBs could also
potentially fall within this classification regulation, if the device
has the same intended use and does not raise different questions of
safety and effectiveness.\12\
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\11\ As noted elsewhere in this document, upon the finalization
of this action these devices will fall within the newly created
product code SEI.
\12\ The statutory standard for establishing substantial
equivalence is defined in section 513(i) of the FD&C Act and further
described in FDA guidance entitled ``The 510(k) Program: Evaluating
Substantial Equivalence in Premarket Notifications [510(k)],
available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/510k-program-evaluating-substantial-equivalence-premarket-notifications-510k.
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(Comment 6) One commenter encouraged FDA to continue post approval
safety surveillance and consider implementing mandatory reviews by
third parties at certain time intervals to ensure the specificity and
sensitivity of these assays remain as initially reported.
(Response 6) FDA notes there are various mechanisms in place to
monitor the post market safety of devices. FDA maintains the MDR
database, MAUDE database, and Medical Device Recall database, which
allows for additional post-market surveillance of these devices and
helps to ensure continued safety for marketed devices. For example,
manufacturers are required to report to FDA information that reasonably
suggests that their device may have caused or contributed to a death or
serious injury, or has malfunctioned and the device or a similar device
that the manufacturer markets would be likely to cause or contribute to
a death or serious injury if the malfunction were to recur under
section 519(a) of the FD&C Act (21 U.S.C. 360i(a)). Manufacturers also
must report to FDA any correction or removal of a device undertaken to
reduce a risk to health posed by the device, or to remedy a violation
of the FD&C Act caused by the device which may present a risk to health
under section 519(g) of the FD&C Act. Additionally, if a device's
quality falls below that which it purports or is represented to
possess, then it may be deemed to be adulterated under section 501(c)
of the FD&C Act (21 U.S.C. 351(c)). In addition, routine or for-cause
inspections, which may consider compliance with quality system
requirements \13\ applicable to the device, allow for appropriate post-
market oversight of these devices with respect to inspections. Hence,
FDA does not believe that additional postmarket special controls are
necessary to provide reasonable assurance of safety and effectiveness
for the HBV assays that are within the scope of this final order. The
suggestion of mandatory reviews by third parties is outside the scope
of this reclassification order.
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\13\ On February 2, 2024, FDA issued a final rule amending the
device Quality System Regulation, 21 CFR part 820, to align more
closely with internal consensus standards for devices (89 FR 7496).
This final rule will take effect on February 2, 2026. Once in
effect, this rule will withdraw the majority of the current
requirements in part 820 and instead incorporate by reference the
2016 edition of the International Organization for Standardization
(ISO) 13485, Medical devices--Quality management systems--
Requirements for regulatory purposes, in part 820. As stated in the
final rule, the requirements in ISO 13485 are, when taken in
totality, substantially similar to the requirements of the current
part 820, providing a similar level of assurance in a firm's quality
management system and ability to consistently manufacture devices
that are safe and effective and otherwise in compliance with the
FD&C Act.
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(Comment 7) One comment stated that there should be clear
instructions to inform individuals that hepatitis B testing performed
during early infection may not accurately detect hepatitis B and it is
critical for these individuals to be retested at the appropriate
interval to reduce the likelihood of false negative results and missed
diagnoses.
(Response 7) FDA agrees with this comment. The special controls for
the HBV antibody assays include labeling limitations that 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'' (see Sec.
866.3173(b)(1)(iv)(E)). Additionally, the special controls for the HBV
antigen assays include labeling limitations that state that a ``non-
reactive assay result does not exclude the possibility of exposure to
or infection with hepatitis B virus'' (see Sec.
866.3172(b)(1)(iv)(E)). Finally, the special controls include labeling
limitations that indicate that ``[d]iagnosis 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'' (see Sec. 866.3172(b)(1)(iv)(C); Sec.
866.3173(b)(1)(iv)(D)).
(Comment 8) One comment stated there is significant confusion among
clinicians regarding when it is appropriate to order total antibody to
hepatitis B core antigen (total anti-HBc, which is a measure of both
anti-HBc IgG and anti-HBc IgM) testing and when to order hepatitis B
core antibody IgM (anti-HBc IgM) testing and how to interpret the
results. The commenter recommended the inclusion of clear instructions
that clarify anti-HBc IgM testing align with CDC guidelines. Another
comment also recommended clear instructions on when to test for and how
to interpret the different types of hepatitis B core antibody tests.
(Response 8) These comments regarding when to conduct total anti-
HBc testing or anti-HBc IgM testing based on CDC guidelines and
recommendations for clear instructions on testing and interpretation of
hepatitis B core antibody tests relate to medical practice guidelines
and recommendations provided by professional organizations and are
beyond the scope of this reclassification order. However, the special
controls for HBV antibody assays include labeling to provide detailed
explanation of the interpretation of results and limitations, which
must be updated to reflect current clinical practice and disease
presentation and management, that address result interpretation (see
Sec. 866.3173(b)(1)(iii) and (iv)).
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(Comment 9) Another comment stated that for all positive PoC test
results, there should be clear instructions on the type of testing
necessary to confirm an individual's hepatitis B status. The commenter
also stated that for negative PoC test results, the individual should
be informed of the need for hepatitis B vaccination to prevent
infection.
(Response 9) These comments regarding confirmatory testing and
medical practice and recommendations provided by professional
organizations are beyond the scope of this reclassification order.
(Comment 10) One comment requested that FDA consider expanding the
regulation for quantitative HBV nucleic acid-based assays to include
diagnostic use (independent of antibody status) for HBV infection in
addition to monitoring. The comment stated that detectable HBV DNA is
indicative of infection and can be used as a diagnostic marker. In
addition, HBV DNA may be detectable sooner after infection than viral
antigens and/or antibodies and therefore may enable earlier detection
of infection or reactivation of infection.
(Response 10) This comment is beyond the scope of this
reclassification order, which applies only to nucleic acid-based HBV
DNA tests for patient management that have been previously approved by
FDA. FDA has not approved nucleic acid-based HBV DNA tests intended for
diagnosis of HBV infection. Thus, this additional intended use is
beyond the scope of FDA's reclassification order.
(Comment 11) One commenter noted the special controls for HBV
nucleic acid-based assays state that: ``Samples selected for use must
be from subjects with clinically relevant circulating genotypes in the
United States'' (see Sec. 866.3174(b)(2)(viii)). The commenter
requested FDA clarify whether clinical specimens must be used for the
analytical studies and whether samples contrived using pre-screened HBV
negative clinical specimens containing clinically relevant circulating
HBV genotypes in the United States could be used in analytical studies.
The commenter suggested that FDA revise the statement to ``Samples
selected for use in analytical studies or used to prepare samples for
use in analytical studies must be from subjects with clinically
relevant circulating genotypes in the United States.''
(Response 11) FDA disagrees that such a clarification is needed. In
the past, FDA has generally preferred native clinical samples to
provide a reasonable assurance of safety and effectiveness for HBV
assays. However, FDA has considered alternative approaches that used
contrived samples in specific analytical studies with adequate
justification, for example, see the Summary of Safety and Effectiveness
Data for P190034 (Ref. 4).
(Comment 12) One commenter supported FDA's proposal to reclassify
certain hepatitis B assays from class III to class II and, citing human
immunodeficiency virus (HIV), hepatitis and sexually transmitted
infections, stated that FDA should continue to partner with the CDC,
National Institutes of Health (NIH) and others to support additional
research and interdisciplinary collaboration on these issues. The
commenter also recommended that FDA and its partners evaluate the
impact of this and other reclassifications in the context of other
proposed or recently implemented changes, including those changes per
FDA's January 31, 2024, announcement \14\ that it intended to initiate
the reclassification process for most high risk IVDs, the majority of
which are infectious disease and companion diagnostic in vitro
diagnostic devices.
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\14\ CDRH Announces Intent to Initiate the Reclassification
Process for Most High Risk IVDs [verbar] FDA available at https://www.fda.gov/medical-devices/medical-devices-news-and-events/cdrh-announces-intent-initiate-reclassification-process-most-high-risk-ivds.
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(Response 12) FDA appreciates these comments. FDA is undertaking
this reclassification of certain HBV assays on its own initiative as
reflected in the Agency's January 31, 2024, announcement. As warranted,
FDA collaborates with other organizations such as CDC and NIH to
support cross-cutting issues.
(Comment 13) One commenter recommended that FDA introduce an app
that would connect administrators, vaccine manufacturers, public and
private vaccine facilities, vaccine recipients, etc. The commenter
envisioned that the app would allow individuals to book and schedule
online appointments for vaccination and obtain a vaccine certificate
and track adverse events following immunization.
(Response 13) This comment is beyond the scope of this
reclassification order.
(Comment 14) Several commenters also asked FDA to reclassify
quantitative HBsAg assays and asserted these assays will be necessary
to predict response and monitor efficacy of new therapies that are now
in clinical testing if such therapies are approved. One commenter asked
FDA to provide device classification if a rapid device is used in
combination with other analytes such as HIV Ab, hepatitis C virus (HCV)
Ab, or syphilis testing.
(Response 14) FDA has not approved any quantitative HBsAg test, nor
any HBV assay in combination with other analytes such as HIV Ab, HCV
Ab, or syphilis testing, thus the comments requesting the
reclassification of such devices are beyond the scope of this
reclassification order.
III. The Final Order
FDA is adopting its findings under section 513(f)(3) of the FD&C
Act, as published in the preamble to the September 25, 2024 proposed
order (89 FR 78265). FDA has made some minor revisions in this final
order in response to comments received (see Section II). FDA is issuing
this final order to reclassify qualitative HBV antigen assays, HBV
antibody assays, and quantitative HBV nucleic acid-based assays from
class III into class II under three new device classification
regulations, and to establish special controls by revising 21 CFR part
866 (adding 21 CFR 866.3172, 866.3173, and 866.3174, respectively).
The qualitative HBV antigen assay is assigned the classification
regulation name ``Qualitative hepatitis B virus antigen assays'' and it
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.
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.
The HBV antibody assay is assigned the classification regulation
name ``Hepatitis B virus antibody assays'' and it 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. Results from assays may be qualitative or
quantitative, such as quantitative anti-HBs. 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
[[Page 44974]]
blood, plasma, cells, or tissue donors. The assay is intended as an aid
in diagnosis in conjunction with clinical findings and other diagnostic
procedures. The identification for Sec. 866.3173(a)(1) has been
revised to provide a more accurate description of the devices in this
classification regulation.
The quantitative HBV nucleic acid-based assay is assigned the
classification regulation name ``Hepatitis B virus nucleic acid-based
assays'' and it 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.
Based on the information discussed in the preamble to the proposed
order, the comments received for the proposed order and the Panel
meeting, and the 2023 Panel deliberations (Ref. 1 and 2), FDA concludes
that special controls, in addition to general controls, provide a
reasonable assurance of the safety and effectiveness of qualitative HBV
antigen assays, HBV antibody assays, and quantitative HBV nucleic acid-
based assays. In this final order, the Agency has identified the
special controls under section 513(a)(1)(B) of the FD&C Act that, along
with general controls, provide a reasonable assurance of the safety and
effectiveness of these devices. In this final order, FDA has added the
special control at Sec. 866.3174(b)(2)(ix) to require that design
verification and validation include analytical sensitivity of the assay
that is the same or better than that of other cleared or approved
assays because this special control was inadvertently omitted from the
proposed order. In addition, FDA has simplified the classification
regulation name in Sec. 866.3173 to ``Hepatitis B virus antibody
assays'' and also clarified in the identification language which assays
fall within the classification regulation. Finally, in this final
order, to provide additional clarification and to efficiently implement
this order, the Agency has added an implementation strategy in Section
IV.
FDA has also created a new product code SEI for HBV antibody
assays. Qualitative HBV antigen assays will continue to be assigned the
product code LOM. Quantitative HBV nucleic acid-based assays will
continue to be assigned the product code MKT.
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.\15\ FDA has determined that premarket
notification is necessary to provide a reasonable assurance of the
safety and effectiveness of qualitative HBV antigen assays, HBV
antibody assays, and quantitative HBV nucleic acid-based assays.
Therefore, these devices are not exempt from premarket notification
requirements. Thus, under sections 510(k) and 513(f) of the FD&C Act,
persons who intend to market a device in any of these device types must
submit to FDA a premarket notification, obtain clearance, and
demonstrate compliance with the special controls included in this final
order, prior to marketing the device.
---------------------------------------------------------------------------
\15\ In considering whether to exempt class II devices from
premarket notification, FDA considers whether premarket notification
for the type of device is necessary to provide reasonable assurance
of safety and effectiveness of the device. FDA generally considers
the factors initially identified in 63 FR 3142 (January 21, 1998)
and further explained in FDA guidance ``Procedures for Class II
Device Exemptions from Premarket Notification, Guidance for
Industry, and CDRH Staff'' to determine whether premarket
notification is necessary for class II devices. FDA also considers
that even when exempting devices from the 510(k) requirements, these
devices would still be subject to certain limitations on exemptions,
for example, the general limitations set forth in 21 CFR 866.9.
---------------------------------------------------------------------------
Manufacturers may wish to use predetermined change control plans
(PCCPs) as a way to implement future modifications to their devices
without needing to submit a new 510(k) for each significant change or
modification \16\ while continuing to provide a reasonable assurance of
device safety and effectiveness.\17\ FDA reviews a PCCP as part of a
marketing submission for a device to ensure the continued safety and
effectiveness of the device without necessitating additional marketing
submissions for implementing each modification described in the PCCP.
When used appropriately, PCCPs authorized by FDA are expected to be
least burdensome for manufacturers and FDA.\18\
---------------------------------------------------------------------------
\16\ For the purpose of this final order reference to
``modification'' means a significant change or modification that
would generally require a new premarket notification under 21 CFR
807.81(a)(3).
\17\ Section 3308 of the Food and Drug Omnibus Reform Act of
2022, Title III of Division FF of the Consolidated Appropriations
Act, 2023, Public Law 117-328 (``FDORA''), enacted on December 29,
2022, added section 515C ``Predetermined Change Control Plans for
Devices'' to the FD&C Act. Section 515C has provisions regarding
predetermined change control plans (PCCPs) for devices requiring
premarket approval or premarket notification. Under section 515C,
supplemental applications (section 515C(a)) and new premarket
notifications (section 515C(b)) are not required for a change to a
device that would otherwise require a premarket approval supplement
or new premarket notification if the change is consistent with a
PCCP approved or cleared by FDA.
\18\ Sections 513 and 515 of the FD&C Act. See also, FDA's
guidance ``The Least Burdensome Provisions: Concept and Principles
[verbar] FDA''.
---------------------------------------------------------------------------
Under this final order, these qualitative HBV antigen assays, HBV
antibody assays, and quantitative HBV nucleic acid-based assays are
prescription use IVD devices and as such, these assays must satisfy
prescription labeling requirements for in vitro diagnostic products
(see 21 CFR 809.10(a)(4) and (b)(5)(ii)). These device types would
continue to be subject to the submission and device clearance
requirements of sections 510(k) and 513 of the FD&C Act and of part
807, subpart E.
IV. Implementation Strategy
This final order is effective 30 days after the date of its
publication in the Federal Register.
For qualitative HBV antigen assays, HBV antibody assays, and
quantitative HBV nucleic acid-based assays that have not been offered
for sale prior to the effective date of the final order, or for devices
that have been legally marketed via PMA before the effective date of
this final order but the device is about to be significantly changed or
modified per 21 CFR 807.81(a)(3) after the effective date,
manufacturers must obtain 510(k) clearance, among other relevant
requirements, and demonstrate compliance with the special controls
included in this final order, before marketing the new or changed
device.
For qualitative HBV antigen assays, HBV antibody assays, and
quantitative HBV nucleic acid-based assays that have been offered for
sale prior to the effective date of the final order and have prior PMA
approval, such devices may continue to be marketed per the previously
approved PMA and do not require an additional marketing application.
Any future changes to the device would be subject to 510(k)
requirements and governed by 21 CFR 807.81(a)(3).
V. 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
[[Page 44975]]
environment. Therefore, neither an environmental assessment nor an
environmental impact statement is required.
VI. Paperwork Reduction Act of 1995
This final administrative order establishes special controls that
refer to previously approved collections of information found in FDA
regulations. These previously approved collections of information are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). The
collections of information in 21 CFR part 820 (Quality System
Regulation) have been approved under OMB control number 0910-0073; the
collections of information in part 807, subpart E (Premarket
Notification Procedures), have been approved under OMB control number
0910-0120; and the collections of information in 21 CFR parts 801 and
809 (Device Labeling) have been approved under OMB control number 0910-
0485.
VII. Codification of Orders
Under section 513(f)(3) of the FD&C Act, FDA may issue final orders
to reclassify devices. FDA will continue to codify classifications and
reclassifications in the Code of Federal Regulations (CFR). Changes
resulting from final orders will appear in the CFR as newly codified
orders. Therefore, under section 513(f)(3) of the FD&C Act, we are
codifying in this final order the classification of (i) qualitative
hepatitis B virus antigen assays in the new 21 CFR 866.3172; (ii)
hepatitis B virus antibody assays in the new 21 CFR 866.3173; and (iii)
hepatitis B virus nucleic acid-based assays in the new 21 CFR 866.3174,
under which each of these device types are reclassified from class III
into class II.
VIII. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-
402-7500, and are available for viewing by interested persons between 9
a.m. and 4 p.m., Monday through Friday; they also are available
electronically at https://www.regulations.gov. References without
asterisks are not on public display at https://www.regulations.gov
because they have copyright restriction. Some may be available at the
website address, if listed. References without asterisks are available
for viewing only at the Dockets Management Staff. Although FDA verified
the website addresses in this document, please note that websites are
subject to change over time.
*1. Meeting Transcript Prepared for the September 7, 2023, Meeting
of the Microbiology Devices Panel (available at https://www.fda.gov/media/173609/download).
*2. Summary Minutes Prepared for the September 7, 2023, Meeting of
the Microbiology Devices Panel (available at https://www.fda.gov/media/173610/download).
3. CDC, ``Clinical Testing and Diagnosis for Hepatitis B,'' https://www.cdc.gov/hepatitis-b/hcp/diagnosis-testing/index.html. Accessed
March 18, 2025.
*4. P190034 Summary of Safety and Effectiveness, available at:
https://www.accessdata.fda.gov/cdrh_docs/pdf19/P190034B.pdf.
List of Subjects in 21 CFR Part 866
Biologics, Laboratories, Medical devices.
Therefore, under the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 321 et seq., as amended), and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR part 866 is amended as follows:
PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES
0
1. The authority citation for part 866 continues to read as follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.
0
2. Add Sec. 866.3172 to subpart D to read as follows:
Sec. 866.3172 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.
[[Page 44976]]
(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 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 that 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. 866.3173 to subpart D to read as follows:
Sec. 866.3173 Hepatitis B virus antibody assays.
(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. Results from assays may be
qualitative or quantitative, such as quantitative anti-HBs. 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
[[Page 44977]]
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 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 that 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.
0
4. Add Sec. 866.3174 to subpart D to read as follows:
Sec. 866.3174 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 HBV 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
[[Page 44978]]
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
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, 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) Analytical sensitivity of the assay that is the same or better
than that of other cleared or approved assays.
(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 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.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-18082 Filed 9-17-25; 8:45 am]
BILLING CODE 4164-01-P