Proposed Rule2026-06064
Microbiology Devices; Reclassification of Mycobacterium Tuberculosis Cell-Mediated Immunity Tests and Immune Response Enzyme-Linked Immunospot Tests
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Published
March 30, 2026
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA) is proposing to reclassify Mycobacterium tuberculosis cell-mediated immunity tests and Mycobacterium tuberculosis cell-mediated immune response enzyme-linked immunospot tests intended for use as an aid in the diagnosis of Mycobacterium tuberculosis infection (product codes NCD and OJN, respectively), both of which are postamendments class III devices (premarket approval), into class II (special controls), subject to premarket notification. FDA is also proposing a new device classification regulation along with the special controls that FDA believes are necessary to provide a reasonable assurance of safety and effectiveness for these devices.
Full Text
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<title>Federal Register, Volume 91 Issue 60 (Monday, March 30, 2026)</title>
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[Federal Register Volume 91, Number 60 (Monday, March 30, 2026)]
[Proposed Rules]
[Pages 15572-15582]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2026-06064]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2026-N-2590]
Microbiology Devices; Reclassification of Mycobacterium
Tuberculosis Cell-Mediated Immunity Tests and Immune Response Enzyme-
Linked Immunospot Tests
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) is proposing to
reclassify Mycobacterium tuberculosis cell-mediated immunity tests and
Mycobacterium tuberculosis cell-mediated immune response enzyme-linked
immunospot tests intended for use as an aid in the diagnosis of
Mycobacterium tuberculosis infection (product codes NCD and OJN,
respectively), both of which are postamendments class III devices
(premarket approval), into class II (special controls), subject to
premarket notification. FDA is also proposing a new device
classification regulation along with the special controls that FDA
believes are necessary to provide a reasonable assurance of safety and
effectiveness for these devices.
DATES: Submit electronic or written comments on the proposed order by
May 29, 2026. Please see section X of this document for the proposed
effective date when the new requirements would 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 May 29, 2026. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are received on or before that date.
[[Page 15573]]
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:
<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-2026-N-2590 for ``Microbiology Devices; Reclassification of
Mycobacterium tuberculosis Cell-Mediated Immunity Tests and Immune
Response Enzyme-Linked Immunospot Tests.'' Received comments, those
filed in a timely manner (see ADDRESSES), will be placed in the docket
and, except for those submitted as ``Confidential Submissions,''
publicly viewable at <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.'' FDA 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: Noel Gerald, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 3114, Silver Spring, MD 20993, 301-796-4695,
<a href="/cdn-cgi/l/email-protection#89c7e6ece5a7ceecfbe8e5edc9efede8a7e1e1faa7eee6ff"><span class="__cf_email__" data-cfemail="95dbfaf0f9bbd2f0e7f4f9f1d5f3f1f4bbfdfde6bbf2fae3">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background--Regulatory Authorities
The Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended,
establishes a comprehensive system for the regulation of medical
devices intended for human use. Section 513 of the FD&C Act (21 U.S.C.
360c) establishes 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).
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 of the device;
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
issuance of performance standards, postmarket surveillance, patient
registries, development and dissemination of guidelines,
recommendations, and other appropriate actions FDA (the Agency or we)
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 introduced or delivered for introduction into
interstate commerce for 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 action. Those devices remain in class III and require approval
of a premarket approval application (PMA), unless, and until: (1) FDA
reclassifies the device into class I or II,
[[Page 15574]]
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 (21 U.S.C. 360(k)) and part 807, subpart
E, of FDA's regulations (21 CFR part 807, subpart E).
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.\1\
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\1\ See generally section 513 of the FD&C Act.
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FDA relies upon ``valid scientific evidence'', as stated in section
513(a)(3) of the FD&C Act and defined in 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). Section
520(h)(4) of the FD&C Act provides that FDA may use, for
reclassification of a device, certain information in a PMA 6 years
after the application has been approved. This includes information from
clinical and preclinical tests or studies that demonstrate the safety
and effectiveness of the device, but it does not include the
descriptions of methods of manufacture and product composition and
other trade secrets.
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\2\ See generally id.
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In accordance with section 513(f)(3) of the FD&C Act, FDA is
issuing this proposed order to reclassify Mycobacterium tuberculosis
cell-mediated immunity tests (product code NCD) \3\ and Mycobacterium
tuberculosis cell-mediated immune response enzyme-linked immunospot
tests (product code OJN), both qualitative assays intended for use as
an aid in the diagnosis of Mycobacterium tuberculosis (TB) infection,
hereafter collectively referred to as ``qualitative TB immune response
assays,'' which are postamendments class III devices, into class II
(special controls), subject to premarket notification, under a new
device classification regulation with the name ``Qualitative
Mycobacterium tuberculosis cell-mediated immune response assay.''
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\3\ FDA's Center for Devices and Radiological Health (CDRH) uses
product codes to assist in accurate identification and tracking of
current medical devices and to allow for tracking of and easy
reference to predicate device types. CDRH and a subset of Center for
Biologics Evaluation and Research regulated medical device product
codes consist of a three-letter combination which associates a
device's type with a product classification designated for the
application. There is no definitive meaning for the three-digit
classification product codes in CDRH's Product Classification
Database. See FDA guidance titled, ``Medical Device Classification
Product Codes'' available at <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/medical-device-classification-product-codes-guidance-industry-and-food-and-drug-administration-staff">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/medical-device-classification-product-codes-guidance-industry-and-food-and-drug-administration-staff</a>.
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Based upon the PMA data available to FDA in accordance with section
520(h)(4) of the FD&C Act,<SUP>4 5</SUP> clinical practice guidelines,
deliberations and recommendations from the Microbiology Devices Panel
of the Medical Devices Advisory Committee discussions held in 2001,
2011, and 2023, and data available to the Agency demonstrating a lack
of significant postmarket safety signals with these assays, FDA
believes there is sufficient information to reclassify these devices
from class III (premarket approval) into class II (special controls).
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, would provide reasonable
assurance of the safety and effectiveness of these devices.\6\
Therefore, FDA is proposing to establish a new device classification
regulation, ``Qualitative Mycobacterium tuberculosis cell-mediated
immune response assay,'' and classify these devices into class II with
the special controls that the Agency believes are necessary to provide
a reasonable assurance of the safety and effectiveness for these
devices.
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\4\ In proposing to reclassify, on its own initiative,
qualitative TB immune response assays from class III to class II,
FDA is relying on data from PMAs with product codes of NCD or OJN
that are available to FDA in accordance with the six-year rule (see
section 520(h)(4) of the FD&C Act (21 U.S.C. 360j(h)(4))) (see also,
FDA guidance titled ``Guidance on Section 216 of the Food and Drug
Administration Modernization Act of 1997--Guidance for Industry and
for FDA Reviewers,'' available at <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-section-216-food-and-drug-administration-modernization-act-1997-guidance-industry-and-fda">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-section-216-food-and-drug-administration-modernization-act-1997-guidance-industry-and-fda</a>). This data was from PMAs approved after November 28, 1990
and before December 1, 2019, for this specific proposed
reclassification as noted in section II of this proposed order. See
also FDA's premarket approval database, available at <a href="https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm">https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm</a>.
\5\ For the purpose of this proposed order, PMA data considered
in accordance with section 520(h)(4) includes only that data which
was submitted to and therefore considered by FDA at the time the PMA
was reviewed and approval was issued.
\6\ FDA notes that the ``ACTION'' caption for this proposed
order is 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,
if finalized, will amend 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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Under the FD&C Act, premarket notification (510(k)) submissions are
required to reasonably assure the safety and effectiveness of class II
devices unless FDA determines that the device type should be exempt
from 510(k) requirements under section 510(m) of the FD&C Act.\7\ FDA
has not made this determination for qualitative Mycobacterium
tuberculosis cell-mediated immune response assays and therefore, FDA is
not proposing that this class II device type be exempt from the 510(k)
requirements. If this proposed order is finalized, persons who intend
to market this type of device will have to submit to FDA a premarket
notification under section 510(k) of the FD&C Act prior to marketing
the device.
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\7\ 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 the January 21, 1998, Federal
Register notice (63 FR 3142) and further explained in FDA's guidance
issued on February 19, 1998, titled ``Procedures for Class II Device
Exemptions from Premarket Notification, Guidance for Industry and
CDRH Staff'', available at <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/procedures-class-ii-device-exemptions-premarket-notification-guidance-industry-and-cdrh-staff">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/procedures-class-ii-device-exemptions-premarket-notification-guidance-industry-and-cdrh-staff</a>, in determining 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.
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II. Regulatory History of the Devices
In accordance with section 513(f)(1) of the FD&C Act, qualitative
TB immune response 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,
have not been reclassified into
[[Page 15575]]
class I or II, 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, these devices are subject to the PMA requirements under
section 515 of the FD&C Act (21 U.S.C. 360e).
On June 1, 2001, FDA filed an original PMA (P010033) for the
QuantiFERON[supreg]-TB (Ref. 1). At a meeting on October 12, 2001, the
Microbiology Devices Panel (2001 Panel) of the Medical Devices Advisory
Committee deliberated and made recommendations on the QuantiFERON-TB
PMA (Ref. 2). The 2001 Panel unanimously recommended the PMA be
considered Approvable with Conditions, which conditions included, among
other items, stratification of the data by risk groups, labeling
warnings or limitations, and interpretation of results and
recommendations for use of the test provided in the labeling. On
November 28, 2001, FDA approved the original PMA for the Cellestis
Limited's (now QIAGEN) QuantiFERON-TB, (P010033, product code NCD) for
the qualitative measurement of interferon-gamma (IFN-[gamma]) generated
by human lymphocytes in whole blood in response to stimulation antigens
for use as an aid in the detection of infection with Mycobacterium
tuberculosis, through its PMA process under section 515 of the FD&C Act
(21 U.S.C. 360e) (Ref. 3).
Since the first approval order for a qualitative TB immune response
assay issued on November 28, 2001, FDA has approved an additional
original PMA, on November 26, 2019, for a qualitative TB immune
response assay (product code NCD, DiaSorin, Inc.'s LIAISON
QuantiFERON--TB Gold Plus, LIAISON Control QuantiFERON--TB Gold Plus
and LIAISON QuantiFERON Software, P180047, collectively ``LIAISON
QuantiFERON--TB Gold Plus'') for the detection of IFN-[gamma] generated
by human lymphocytes in whole blood in response to stimulation antigens
for use as a qualitative indirect test for Mycobacterium tuberculosis
infection (including disease) (Ref. 4). The QuantiFERON-TB and LIAISON
QuantiFERON--TB Gold Plus are prescription devices intended for use as
an aid in the detection of infection with Mycobacterium tuberculosis
and are intended for use in conjunction with risk assessment,
radiography, and other medical and diagnostic evaluations to assist the
clinician in making individual patient management decisions.
On July 30, 2008, FDA approved a qualitative TB immune response
enzyme-linked immunospot assay (product code OJN, Oxford Immunotec,
Inc.'s T-SPOT[supreg]-TB, P070006) for the detection of effector T
cells that respond to stimulation by Mycobacterium tuberculosis
antigens by capturing IFN-[gamma] in the vicinity of T cells in human
whole blood for use as an aid in the diagnosis of Mycobacterium
tuberculosis infection, through its PMA process under section 515 of
the FD&C Act (21 U.S.C. 360e) (Ref. 5).
As of the date of issuance of this proposed order, fewer than 6
years have passed since FDA's approval of certain PMA supplements for
these three PMAs. Therefore, in accordance with the ``six-year rule''
described in section 520(h)(4) of the FD&C Act (21 U.S.C. 360j(h)(4)),
no information from those PMA supplements has been used in support of
this proposed order to reclassify qualitative TB immune response assays
into class II (see section 520(h)(4) of the FD&C Act (21 U.S.C.
360j(h)(4))).
Since the 2001 Panel discussed the first PMA for this device type,
there have been two other panel meetings that have considered
reclassification of qualitative TB immune response assays. At a meeting
on June 29, 2011, the Microbiology Devices Panel of the Medical Devices
Advisory Committee (2011 Panel) discussed the possible reclassification
of immunologically-based tests such as interferon gamma release assays
(IGRAs) that are intended for the detection of tuberculosis infection
by indirect means, and specifically considered appropriate validation,
the risks of inaccurate results, and labeling limitations to mitigate
risks (Ref. 6). While the overall 2011 Panel agreed that
reclassification could be considered, multiple concerns were expressed
with down classification, and several members were not in favor. It was
noted that then-ongoing studies of existing IGRAs may provide
additional information important for identifying appropriate special
controls. At the time of the 2011 Panel, FDA had approved the
QuantiFERON-TB (P010033) (product code NCD) and the T-SPOT-TB (P070006)
(product code OJN). However, it was several years after the 2011 Panel
that FDA approved the LIAISON QuantiFERON--TB Gold Plus (P180047), the
second PMA assigned product code NCD.
On September 7, 2023, the Microbiology Devices Panel of the Medical
Devices Advisory Committee (2023 Panel) convened to discuss and make
recommendations regarding the reclassification of qualitative
Mycobacterium tuberculosis (TB) cell mediated immune reactivity/
Interferon Gamma Release Assays from class III (premarket approval) to
class II (special controls) (Ref. 7). The 2023 Panel members
unanimously agreed with down classification from class III to class II
for these assays, and that there was sufficient data to proceed with
the reclassification (see ``MDP Sept. 7, 2023 Transcript'' and ``MDP
Sept. 7, 2023 Summary Minutes'' of the 2023 Panel materials, Ref. 7).
The 2023 Panel agreed with the FDA-identified risks (false negative or
false positive results, including from incorrectly operating the device
and incorrectly interpreting the results) and identified additional
risk(s) to include in the overall risk assessment. These additional
risks included the higher risks posed by false results for specific
populations, such as immunocompromised individuals; risk of an
indeterminate result where the clinical interpretation is not clear;
risk of inappropriate use of the test for a particular patient; and
risk of an incorrect result that leads to treatment delays for other
diseases (see ``MDP Sept. 7, 2023 Summary Minutes'' of the 2023 Panel
materials, Ref. 7). The 2023 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, new
devices should be held to the same level of clinical and analytical
validation with the same performance criteria as currently approved
tests, including adequate validation of the pre-analytical stages of
specimen preparation that have the potential to impact the performance
of these tests and that labeling should clarify how risks differ
depending on the population being tested and the pre-test probability
of disease.
A review of data from FDA's Manufacturer and User Facility Device
Experience (MAUDE) database, which contains the medical device reports
(MDRs) of adverse events using product codes NCD and OJN, indicates
that as of October 23, 2025, there were 27 MDRs for qualitative TB
immune response assays (all 27 are for product code NCD and there are
none identified for OJN). Of these MDRs, approximately half were
determined by FDA to be of no known impact or consequence to the
patient. Of the events that were reported to have resulted in patient
misdiagnosis or inappropriate treatment, a majority were reported due
to adverse effects of antibiotic treatment, with a small number of
cases reporting worsening of other medical conditions. As of October
23, 2025, there have been two class III recalls, six class II recalls,
and no class
[[Page 15576]]
I recalls \8\ involving qualitative TB immune response assays. The
class II recalls occurred in 2013, 2016, and 2022, due to the potential
presence of endotoxin or other contamination in assay components, and
products being stored at temperatures outside the validated storage
conditions. The class III recalls occurred in 2020, due to incorrect
expiration dating included in the kit labeling. No patient harm was
identified related to the recalls. The issues leading to these recall
events were considered and incorporated into the risks to health
identified in section V. These facts, coupled with the low number of
MDRs that could have caused patient harm, indicate a lack of
significant postmarket safety signals for this device class. FDA
believes the special controls proposed herein, in addition to general
controls, can effectively mitigate the risks to health identified to
provide a reasonable assurance of the safety and effectiveness of
qualitative TB immune response assays.
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\8\ Class I, II, and III recalls are defined in 21 CFR 7.3(m).
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Following the meeting of the 2011 Panel, but prior to the meeting
of the 2023 Panel, FDA received a petition requesting that the FDA
reclassify Mycobacterium tuberculosis cell-mediated immunity tests
(product code NCD) from class III to class II (FDA-2019-P-1800). As
discussed in this proposed order, FDA has considered the information
available to the Agency and believes that there is sufficient
information available to establish special controls, and that the
special controls proposed in section VII, together with general
controls, would provide a reasonable assurance of the safety and
effectiveness of qualitative TB immune response assays, including
qualitative Mycobacterium tuberculosis cell-mediated immunity tests
(product code NCD). Accordingly, FDA is proposing, on its own
initiative, that qualitative Mycobacterium tuberculosis cell-mediated
immunity tests (product code NCD) and Mycobacterium tuberculosis cell-
mediated immune response enzyme-linked immunospot tests (product code
OJN) be reclassified from class III to class II.
III. Device Description
The qualitative TB immune response assays intended for use as an
aid in the diagnosis of Mycobacterium tuberculosis infection 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.
The immune response to infection with Mycobacterium tuberculosis is
predominantly a cell-mediated immune response that results in
sensitization of T-cell lymphocytes specific to Mycobacterium
tuberculosis antigens. A TB immune response assay for the qualitative
measurement of IFN-[gamma] generated by human lymphocytes in response
to stimulation antigens is a prescription in vitro diagnostic device
intended for use as an aid in the diagnosis of Mycobacterium
tuberculosis infection. A TB immune response enzyme-linked immunospot
assay is a prescription in vitro diagnostic device intended for use for
the qualitative detection of effector T cells that respond to
stimulation by Mycobacterium tuberculosis antigens by capturing IFN-
[gamma] in the vicinity of the T cell in human whole blood and as an
aid in the diagnosis of Mycobacterium tuberculosis infection.
Qualitative TB immune response assays are intended for use in
conjunction with risk assessment, radiography, and other medical and
diagnostic evaluations. Diagnosis of TB infection should not be
established based on a single test result from a qualitative TB immune
response assay.
Currently, qualitative TB immune response assays are used as an aid
in the diagnosis of tuberculosis infection, including disease.
Qualitative TB immune response assays can be used to assess for latent
and active tuberculosis infection, however, such assays cannot
differentiate between latent and active tuberculosis. Additional
diagnostic testing is necessary to determine if there is active
tuberculosis before selecting a treatment regimen. Qualitative TB
immune response assays are preferred over the Mantoux tuberculin skin
test method when evaluating patients with a history of bacille
Calmette-Gu[eacute]rin (BCG) vaccine and in clinical scenarios where a
single patient visit is advantageous (Ref. 8). Epidemiological,
demographic, and clinical factors should be considered when determining
the appropriate patients for testing with a qualitative TB immune
response assay and should inform any additional diagnostic workup that
may be necessary to guide therapeutic decisions (Ref. 8).
Healthcare professionals may refer to clinical practice guidelines
from the American Thoracic Society (Ref. 8), Infectious Disease Society
of America (Ref. 8), or Centers for Disease Control and Prevention
(Ref. 8) when determining how to use qualitative TB immune response
assays to manage patients suspected of latent or active tuberculosis,
or patients with risk factors for tuberculosis infection. Since the
original FDA approval of the QuantiFERON-TB Mycobacterium tuberculosis
cell-mediated immune response assay in 2001, qualitative TB immune
response assays have become an important part of the management of
tuberculosis infection and are one component of a larger diagnostic
approach for the evaluation of patients with potential tuberculosis
infections (Ref. 8). However, management of tuberculosis should be
determined in conjunction with patient-specific clinical and
epidemiological risk factors and other diagnostic information, such as
supportive radiographic imaging and other laboratory testing (Ref. 9).
FDA is proposing to reclassify qualitative TB immune response
assays from class III (premarket approval) to class II (special
controls) and to establish a new name for the device type within the
classification regulations. FDA proposes to revise 21 CFR part 866 to
create a new device classification regulation with the name
``Qualitative Mycobacterium tuberculosis cell-mediated immune response
assay.'' FDA believes that this name and the proposed identification
language most accurately describes this device type.
A qualitative Mycobacterium tuberculosis cell-mediated immune
response assay is tentatively identified as a prescription in vitro
diagnostic device intended to aid in the diagnosis of Mycobacterium
tuberculosis infection. Qualitative Mycobacterium tuberculosis cell-
mediated immune response assays measure the production of IFN-[gamma]
or other cytokines by human lymphocytes in response to stimulation
antigens. The assay is intended for use by a licensed healthcare
professional as an aid in the diagnosis of Mycobacterium tuberculosis
infection in conjunction with risk assessment, radiographic imaging,
and other medical and diagnostic evaluations.
IV. Proposed Reclassification and Summary of Reasons for
Reclassification
In accordance with section 513(f)(3) of the FD&C Act and 21 CFR
part 860, subpart C, FDA is proposing to reclassify the qualitative TB
immune response assays that are the subject of this proposed order from
class III to class II, subject to premarket notification (510(k))
requirements.
FDA believes that at this time, sufficient data and information
exist such that the risks to health identified in section V can be
mitigated by establishing special controls, and that
[[Page 15577]]
these special controls, together with general controls, are necessary
to provide a reasonable assurance of the safety and effectiveness of
these qualitative TB immune response assays and therefore proposes
these devices be reclassified from class III (premarket approval) to
class II (special controls). FDA believes that the information
available to FDA through the QuantiFERON-TB (P010033), LIAISON
QuantiFERON--TB Gold Plus (P180047), and T-SPOT-TB (P070006) PMAs \9\
(Refs. 3-5) that may be considered under section 520(h)(4) of the FD&C
Act, deliberations and recommendations from associated panel
discussions held during the 2001 Panel, 2011 Panel, and 2023 Panel,
published clinical practice guidelines (Refs. 8-9), and FDA's publicly
available MAUDE and the Medical Device Recall databases is sufficient
to establish special controls that, together with general controls,
effectively mitigate the risks to health identified in section 0. FDA
does not believe that the general controls applicable to the devices
are sufficient to effectively mitigate the risks to health identified
for these devices, and therefore does not believe that the general
controls applicable to the devices are sufficient to provide reasonable
assurance of the safety and effectiveness of these devices.
---------------------------------------------------------------------------
\9\ In accordance with section 520(h)(4) of the FD&C Act, FDA
has not relied on information in PMAs and PMA supplements approved
within the last 6 years to develop the proposed special controls or
to otherwise inform this proposed reclassification action.
---------------------------------------------------------------------------
FDA is proposing to revise 21 CFR part 866 to create a new device
classification regulation with the name ``Qualitative Mycobacterium
tuberculosis cell-mediated immune response assay.'' If the proposed
order is finalized, qualitative Mycobacterium tuberculosis cell-
mediated immune response assays will be identified as prescription in
vitro diagnostic devices. Such devices are subject to the prescription
labeling requirements for in vitro diagnostic products (see 21 CFR
809.10(a)(4) and (b)(5)(ii)). In this proposed order, FDA has
identified the special controls under section 513(a)(1)(B) of the FD&C
Act that it believes, together with general controls, will provide a
reasonable assurance of the safety and effectiveness of these assays.
Under the FD&C Act, 510(k) submissions are required to reasonably
assure the safety and effectiveness of class II devices unless FDA
determines that the device type should be exempt from 510(k)
requirements under section 510(m) of the FD&C Act.\10\ FDA has not made
this determination for these qualitative TB immune response assays, and
therefore, FDA is not proposing that this class II device type be
exempt from 510(k) requirements. If this proposed order is finalized,
persons who intend to market qualitative TB immune response assays will
need to submit to FDA a 510(k) and receive clearance prior to marketing
the device.
---------------------------------------------------------------------------
\10\ See supra note 7.
---------------------------------------------------------------------------
This proposed order, if finalized, will decrease regulatory burden
on industry, as manufacturers will no longer have to submit a PMA for
this type of device but can instead submit a 510(k) to the Agency for
review prior to marketing their device. The 510(k) pathway is less
burdensome and generally more cost-effective for industry and FDA than
the PMA pathway, the most stringent type of device marketing pathway. A
510(k) typically results in a shorter premarket review timeline
compared to a PMA, which ultimately may provide more timely patient
access to this type of device. FDA expects that the reclassification of
these devices would enable more manufacturers to develop this type of
device such that patients would benefit from increased access to
appropriately safe and effective tests.
Additionally, 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 \11\ while continuing to provide a
reasonable assurance of device safety and effectiveness.\12\ 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.\13\
---------------------------------------------------------------------------
\11\ For the purpose of this proposed 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).
\12\ 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.
\13\ Sections 513 and 515 of the FD&C Act. See also, FDA's
guidance ``The Least Burdensome Provisions: Concept and
Principles'', available at <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/least-burdensome-provisions-concept-and-principles">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/least-burdensome-provisions-concept-and-principles</a>.
---------------------------------------------------------------------------
V. Risks to Health
FDA is providing a substantive summary of the valid scientific
evidence concerning the public health benefits of the use of
qualitative TB immune response assays (see also ``MDP Sept. 7, 2023 FDA
Executive Summary'' of the 2023 Panel materials, Ref. 7), and the
nature (and if known, the incidence) of the risks to health of the
devices (see further discussion of the special controls being proposed
to mitigate these risks in section VII of this proposed order). FDA
considered data from three PMAs available to FDA under section
520(h)(4) of the FD&C Act, deliberations and recommendations from
associated panel discussions held during the 2001 Panel, 2011 Panel,
and 2023 Panel (Refs. 2, 6-7), published clinical practice guidelines
(Refs. 8-9), and postmarket information regarding qualitative TB immune
response assays.
Qualitative TB immune response assays provide a benefit to the
public health by aiding in the diagnosis of Mycobacterium tuberculosis
infection. The incidence of tuberculosis infection varies considerably
with epidemiological risk factors such as immigration from a country
with high tuberculosis prevalence or close contacts with known active
tuberculosis cases (Ref. 8). Certain patients who may be at increased
risk of progression from latent to active tuberculosis include young
children, individuals with human immunodeficiency virus (HIV) or those
receiving immunosuppressive medications (Ref. 8). Individuals
considered to be at higher risk for progression to active tuberculosis
infection may benefit from testing with a qualitative TB immune
response assay. Treatment of latent tuberculosis in high-risk
individuals can decrease the risk of developing active tuberculosis and
clinicians may assess tuberculosis status using a qualitative TB immune
response assay in patients prior to starting immunosuppressive
medications, or in patients with other known risk factors for
tuberculosis. Distinguishing between latent and active tuberculosis
requires additional diagnostic evaluation; however, qualitative TB
immune response assays are considered an important part of the
diagnostic workup for tuberculosis. Additionally, qualitative TB immune
[[Page 15578]]
response assays are preferred in patients with prior BCG vaccination
and in patients where a single clinical visit is advantageous (Ref. 8).
Qualitative TB immune response assays provide a further benefit to the
public health by linking TB infected individuals to appropriate care
and potentially reducing the risk of TB transmission. Antibiotic
regimens to treat latent TB infection and active TB disease are
available.
The probable risks associated with qualitative TB immune response
assays, when used as intended, are those related to risks of inaccurate
results, including failure to correctly interpret the test results, the
risk of false test results, and failure to correctly operate the device
causing false results. Factors that may cause an increased rate of
inaccurate results include, but are not limited to, incorrect blood
sample collection or improper handling of the specimen affecting
lymphocyte function, inaccurate lymphocyte quantification, and co-
morbid conditions that affect immune functions. Based on FDA's review
of data in the PMAs for QuantiFERON-TB (P010033), LIAISON QuantiFERON--
TB Gold Plus (P180047), and T-SPOT-TB (P070006) available to FDA under
section 520(h)(4) of the FD&C Act, deliberations and recommendations
from associated panel discussions held during the 2001 Panel, 2011
Panel, and 2023 Panel for the reclassification of these devices (see
``MDP Sept. 7, 2023 Summary Minutes'' and ``MDP Sept. 7, 2023
Transcript'' of the 2023 Panel materials, Ref. 7), postmarket
information, and the clinical practice guidelines (Refs. 8-9), FDA has
identified the following probable risks to health associated with
qualitative TB immune response assays. These risks to health (and the
proposed special controls in section VII) incorporate feedback from the
2023 Panel, including the higher risks posed by false results for
specific populations, such as immunocompromised individuals; risk of an
indeterminate result where the clinical interpretation is not clear;
risk of inappropriate use of the test for a particular patient; and
risk of an incorrect result that leads to treatment delays for other
diseases.
<bullet> Failure to correctly interpret the test results. Failure
to correctly interpret the test results, such as incorrectly
interpreting the qualitative TB immune response assay result by a
clinician as either a negative or positive result may negatively
influence patient management decisions. A positive test result
misinterpreted as negative may lead to a non-diagnosis or delay in
diagnosis of active or latent TB infection with an associated delay in
therapy and potential for progression of active infection or
reactivation of latent TB disease, which can contribute to an increased
risk of TB-related morbidity or mortality. Additionally, incorrectly
interpreting a positive test result as a negative result may facilitate
the spread of Mycobacterium tuberculosis to other individuals in the
community. Incorrectly interpreting the test result as a negative
result may represent a missed opportunity for evaluation and subsequent
treatment of underlying immunocompromising conditions such as HIV, as
well as a missed opportunity to provide antimicrobial therapy for
latent tuberculosis infection. Incorrectly interpreting the test result
as positive may contribute to improper patient management including
unnecessary additional testing and radiologic imaging, patient
isolation, public health contact tracing leading to wasted healthcare
resources, as well as unnecessary antimicrobial treatment for TB
infection with associated drug toxicities, and the risk of delayed
treatment for the true cause of disease.
<bullet> False negative/positive result. A false negative
qualitative TB immune response assay result may lead to a non-diagnosis
or delay in diagnosis of active or latent TB infection with an
associated delay in therapy and potential for progression of active
infection or reactivation of latent TB disease, which can contribute to
an increased risk of TB-related morbidity or mortality. Additionally, a
false negative result may facilitate the spread of Mycobacterium
tuberculosis to other individuals in the community. A false negative
result may represent a missed opportunity for evaluation and subsequent
treatment of underlying immunocompromising conditions such as HIV, as
well as a missed opportunity to provide antimicrobial therapy for
latent tuberculosis infection. A false positive qualitative TB immune
response assay result may contribute to improper patient management
including unnecessary additional testing and radiologic imaging,
patient isolation, public health contact tracing leading to wasted
healthcare resources, as well as unnecessary antimicrobial treatment
for TB infection with associated drug toxicities, and the risk of
delayed treatment for the true cause of disease.
<bullet> Failure to correctly operate the assay. Failure to
correctly operate the qualitative TB immune response assay may cause a
false negative or false positive result, which may lead to the risks to
health discussed in the preceding bullet.
VI. Summary of Data Upon Which the Reclassification Is Based
The safety and effectiveness of these devices have become well
established since the initial approval of the first qualitative TB
immune response assay in 2001. FDA believes that qualitative TB immune
response assays should be reclassified from class III (premarket
approval) into class II (special controls) on the basis that special
controls, in addition to general controls, can be established to
mitigate the risks to health identified in section V and there is
sufficient information to establish special controls, which, in
addition to general controls, would provide a reasonable assurance of
the safety and effectiveness of these devices. The proposed special
controls are identified by FDA in section VII of this proposed order.
Taking into account the available evidence, including the health
benefits of the use of these devices and the nature and known incidence
of the risks to health of the devices, FDA, on its own initiative, is
proposing to reclassify these postamendments class III devices into
class II. FDA has considered and analyzed the following information to
support this proposed reclassification: (1) clinical practice
guidelines from professional organizations and government
organizations, such as the Centers for Disease Control and Prevention,
the American Thoracic Society, and the Infectious Diseases Society of
America (see Refs. 8 and 9), that discuss the appropriate use and
interpretation of qualitative TB immune response assays, (2) data from
three PMAs for qualitative TB immune response assays available to FDA
in accordance with section 520(h)(4) of the FD&C Act, (3) input from
the 2001, 2011 and 2023 Panel meetings, and (4) postmarket information
regarding qualitative TB immune response assays, including information
from FDA's publicly available MAUDE and Medical Device Recall
databases. The available evidence demonstrates that there are public
health benefits derived from the use of qualitative TB immune response
assays indicated for use as an aid in the diagnosis of TB infection. In
addition, the nature of the associated risks to health are known, and
special controls can be established to sufficiently mitigate these
risks.
FDA considered the safety and effectiveness of qualitative TB
immune response assays through review of PMA data from the following
three original PMAs, in accordance with section 520(h)(4) of the FD&C
Act: QIAGEN's QuantiFERON-TB (P010033), DiaSorin,
[[Page 15579]]
Inc.'s LIAISON QuantiFERON--TB Gold Plus (P180047), and Oxford
Immunotec, Inc.'s T-SPOT-TB (P070006) (Refs. 3-5).
As part of the Agency's analysis in proposing to reclassify
qualitative TB immune response assays, FDA reviewed and considered
information provided within each of these applications, including
information available in the Summary of Safety and Effectiveness Data
and device labeling for each application, which helped to demonstrate
reasonable assurance of safety and effectiveness for the devices. The
Agency considered the analytical and clinical studies performed and
device performance data demonstrating appropriate performance of the
device, which supported each approval, when developing the proposed
special controls which FDA believes can effectively mitigate the risks
to health identified in section V and, along with general controls, can
provide a reasonable assurance of the safety and effectiveness for
qualitative TB immune response assays. Additionally, FDA identified the
probable adverse effects or risks to health of the devices, consistent
with information provided within the applications, to be failure to
correctly interpret the test results, false positive/negative results,
and failure to correctly operate the device. Consistent with data
collected in the corresponding clinical studies submitted in support of
the approvals, the adverse event profile for these devices was
generally deemed acceptable.
On November 28, 2001, FDA approved the original PMA for the
QuantiFERON-TB, the first TB immune response assay approved for the
qualitative measurement of IFN-[gamma] generated by human lymphocytes
in whole blood in response to stimulation antigens for use as an aid in
the detection of infection with Mycobacterium tuberculosis (product
code NCD) (P010033) (Ref. 3). The Agency considered the submitted
studies and data in the original PMA, which demonstrated that the
QuantiFERON-TB has acceptable performance in detecting immune responses
associated with Mycobacterium tuberculosis infection. Such studies
included analytical performance studies in addition to clinical studies
demonstrating that the QuantiFERON-TB has acceptable performance,
including clinical sensitivity and clinical specificity from a number
of study subjects including individuals with confirmed active
tuberculosis, individuals with no known risk factors for tuberculosis,
and individuals with at least one known risk factor for tuberculosis
and/or latent tuberculosis. Potential adverse effects of the device
included the identified risks of false positive or false negative test
results, failure to correctly interpret the test results, and failure
to correctly operate the device. FDA's review of the PMA determined
that the data generated from these studies was sufficient to
demonstrate a reasonable assurance of the safety and effectiveness of
this device when used as intended and these studies demonstrated
appropriate performance of the device.
Additionally, on July 30, 2008, FDA approved the original PMA for
the T-SPOT-TB, the second qualitative TB immune response assay and
first enzyme-linked immunospot assay approved for the detection of
effector T cells that respond to stimulation by Mycobacterium
tuberculosis antigens by capturing IFN-[gamma] in the vicinity of T
cells in human whole blood for use as an aid in the diagnosis of
Mycobacterium tuberculosis infection (product code OJN) (P070006) (Ref.
5). Analytical and clinical data provided in this PMA supported that
there is reasonable assurance of safety and effectiveness of this
device for its intended use, including appropriate clinical study data
from individuals with nontuberculous mycobacterial infection,
individuals who had received the BCG vaccine, and specific populations
at high risk of disease, such as immunocompromised individuals.
Potential adverse effects of the T-SPOT-TB include false positive test
results or false negative test results. Conclusions drawn from non-
clinical and clinical studies indicated overall acceptable performance
including specificity and reproducibility demonstrating that the device
is reasonably safe and effective for its intended use and supported PMA
approval.
On November 26, 2019, FDA approved through an original PMA, a third
TB immune response assay, LIAISON QuantiFERON--TB Gold Plus, which is a
qualitative indirect test for Mycobacterium tuberculosis infection
(including disease) and is intended for use in conjunction with risk
assessment, radiography, and other medical and diagnostic evaluations
to assist the clinician in making individual patient management
decisions (product code NCD) (P180047) (Ref. 4). The Agency considered
the submitted studies and data in the original PMA, which demonstrated
that the LIAISON QuantiFERON--TB Gold Plus has acceptable performance
in detecting immune responses associated with Mycobacterium
tuberculosis infection. Such studies included analytical performance
studies in addition to clinical studies demonstrating that the LIAISON
QuantiFERON--TB Gold Plus has acceptable performance, including
clinical sensitivity and clinical specificity from a number of study
subjects including individuals with confirmed active tuberculosis,
individuals with no known risk factors for tuberculosis, and
individuals with at least one known risk factor for tuberculosis and/or
latent tuberculosis. Potential adverse effects of the device included
the identified risks of false positive or false negative test results,
failure to correctly interpret the test results, and failure to
correctly operate the device. FDA's review of the PMA determined that
the data generated from these studies was sufficient to demonstrate a
reasonable assurance of the safety and effectiveness of this device
when used as intended and these studies demonstrated appropriate
performance of the device.
Finally, a search of FDA's publicly available MAUDE database
revealed that as of October 23, 2025, there were 27 reported events for
qualitative TB immune response assays under the product codes NCD and
OJN, and approximately half were determined by FDA to be of no known
impact or consequence to the patient. A search of FDA's publicly
available Medical Device Recall database revealed that as of October
23, 2025, there have been two class III recalls, six class II recalls,
and no class I recalls involving qualitative TB immune response assays;
however, none of the recalls were determined to have caused or led to
patient harm. This postmarket data demonstrating a low number of
reported events indicate a lack of significant postmarket safety
signals for these devices (see further discussion of the MDR and recall
data in section II of this proposed order).
Based on our review of the information described in this proposed
order, FDA has determined that special controls, in addition to general
controls, are necessary to provide a reasonable assurance of safety and
effectiveness for qualitative TB immune response assays, and that
sufficient information exists to establish such special controls.
Therefore, FDA, on its own initiative, is proposing to reclassify these
postamendment devices from class III (premarket approval) into class II
(special controls), subject to premarket notification (510(k))
requirements.
VII. Proposed Special Controls
FDA believes that qualitative TB immune response assays can be
[[Page 15580]]
reclassified into class II with the establishment of special controls.
FDA believes that the following proposed special controls would
mitigate each of 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 qualitative TB
immune response assays. Table 1 demonstrates how FDA believes each risk
to health described in section V would be mitigated by the proposed
special controls.
The risk of inaccurate interpretation of test results can be
mitigated by special controls requiring certain labeling, including
providing clearly stated warnings and limitations such as directing
licensed healthcare professionals to consult appropriate public health
authority resources that assist in diagnosing tuberculosis infection,
information on principles of operation and procedures in performing the
test, a detailed explanation of the interpretation of results including
indeterminate results, and a statement that diagnosis of tuberculosis
disease and assessment of the probability of latent tuberculosis
infection is based on a combination of epidemiological, clinical and
diagnostic findings (including historical and medical); certain design
verification and validation information including information related
to performance studies. Design verification and validation
documentation would be required to include a detailed description of
the device, all critical reagents, risk analysis demonstrating how risk
control measures are implemented to address device hazards, lot release
criteria, and stability studies.
Risks associated with false results (e.g., false negative and false
positive test results) can be mitigated through a combination of
special controls including certain labeling requirements, certain
design verification and validation information, including information
related to performance studies. Examples of information to be included
in the design verification and validation documentation for the device
include documentation of analytical studies and device performance data
from clinical studies. In addition, design verification and validation
documentation would be required to include a detailed description of
the device, all critical reagents, a risk analysis demonstrating how
risk control measures are implemented to address device hazards, lot
release criteria, and stability studies. Required statements in the
labeling can aid in mitigating false results, for example by providing
a detailed explanation of the interpretation of results including
indeterminate results and clearly stated warnings and limitations such
as directing licensed healthcare professionals to consult appropriate
public health authority resources that assist in diagnosing
tuberculosis infection.
Risks associated with the failure to correctly operate the device
can be mitigated through labeling information and design verification
and validation information, including a detailed description of the
device, all critical reagents, a risk analysis demonstrating how risk
control measures are implemented to address device hazards, lot release
criteria, and stability studies. Required statements in labeling can
aid in mitigating the failure to operate the device or interpret the
results correctly. For example, a statement that results must be
interpreted by licensed healthcare professionals in conjunction with
risk assessment, radiographic imaging, and other medical and diagnostic
evaluations, clearly stated warnings and limitations such as directing
licensed healthcare professionals to consult appropriate public health
authority resources that assist in diagnosing tuberculosis infection,
and providing a detailed explanation of the interpretation of results
including indeterminate results.
Table 1--Risks to Health and Mitigation Measures for Qualitative
Mycobacterium tuberculosis Cell-Mediated Immune Response Assays
------------------------------------------------------------------------
Identified risks to health Mitigation measures
------------------------------------------------------------------------
Failure to correctly interpret the Certain labeling information,
test 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.
False negative/positive result.... Certain labeling information,
including warnings, limitations,
results interpretation information,
and explanation of procedures.
Certain design verification and
validation information, including
certain device description
information, risk analysis
strategies, lot release criteria,
stability studies, and performance
studies, including analytical
studies and clinical studies.
Failure to correctly operate the Certain labeling information,
assay. 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.
------------------------------------------------------------------------
If this proposed order is finalized, qualitative TB immune response
assays will be identified as prescription in vitro diagnostic (IVD)
devices. Therefore, these devices would be subject to the prescription
labeling requirements for IVD products (see 21 CFR 809.10(a)(4) and
(b)(5)(ii)).
If this proposed order is finalized, qualitative TB immune response
assays will be reclassified into class II (special controls) and will
be subject to premarket notification requirements under section 510(k)
of the FD&C Act. As discussed in this proposed order, the intent is for
the reclassification to be codified in 21 CFR 866.3371. If finalized,
firms 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 qualitative TB immune response 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
[[Page 15581]]
refer to previously approved FDA collections of information. The
previously approved 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 (Quality Management System Regulation) have been
approved under OMB control number 0910-0073; the collections of
information in 21 CFR 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.
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
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 Mycobacterium
tuberculosis Cell-Mediated Immune Response Assay in the new 21 CFR
866.3371, under which these qualitative TB immune response 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. P010033 Approval Order, available at: <a href="https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P010033">https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P010033</a>.
* 2. October 11-12, 2001: Microbiology Devices Panel Meeting Summary
(available at <a href="https://wayback.archive-it.org/7993/20170405192838/https:/www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/MicrobiologyDevicesPanel/ucm124771.htm">https://wayback.archive-it.org/7993/20170405192838/https:/www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/MicrobiologyDevicesPanel/ucm124771.htm</a>).
* 3. P010033 Summary of Safety and Effectiveness, available at:
<a href="https://www.accessdata.fda.gov/cdrh_docs/pdf/P010033B.pdf">https://www.accessdata.fda.gov/cdrh_docs/pdf/P010033B.pdf</a>.
* 4. P180047 Summary of Safety and Effectiveness, available at:
<a href="https://www.accessdata.fda.gov/cdrh_docs/pdf18/P180047B.pdf">https://www.accessdata.fda.gov/cdrh_docs/pdf18/P180047B.pdf</a>.
* 5. P070006 Summary of Safety and Effectiveness, available at:
<a href="https://www.accessdata.fda.gov/cdrh_docs/pdf7/P070006B.pdf">https://www.accessdata.fda.gov/cdrh_docs/pdf7/P070006B.pdf</a>.
* 6. June 29, 2011: Meeting Materials of the Microbiology Devices
Panel (available at <a href="https://wayback.archive-it.org/7993/20170403223442/https:/www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/MicrobiologyDevicesPanel/ucm260517.htm">https://wayback.archive-it.org/7993/20170403223442/https:/www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/MicrobiologyDevicesPanel/ucm260517.htm</a>).
* 7. September 7-8, 2023: Microbiology Devices Panel of the Medical
Devices Advisory Committee Meeting Announcement (available at
<a href="https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-7-8-2023-microbiology-devices-panel-medical-devices-advisory-committee-meeting#event-materials">https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-7-8-2023-microbiology-devices-panel-medical-devices-advisory-committee-meeting#event-materials</a>).
8. Official American Thoracic Society/Infectious Diseases Society of
America/Centers for Disease Control and Prevention Clinical Practice
Guidelines: Diagnosis of Tuberculosis in Adults and Children
[verbar] Clinical Infectious Diseases [verbar] Oxford Academic
<a href="https://academic.oup.com/cid/article/64/2/e1/2629583?login=true">https://academic.oup.com/cid/article/64/2/e1/2629583?login=true</a>.
<a href="http://doi.org/10.1093/cid/ciw694">doi.org/10.1093/cid/ciw694</a>. Accessed March 18, 2026.
9. Official American Thoracic Society/Centers for Disease Control
and Prevention/Infectious Diseases Society of America Clinical
Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis
[verbar] Clinical Infectious Diseases [verbar] Oxford Academic
<a href="https://academic.oup.com/cid/article/63/7/e147/2196792">https://academic.oup.com/cid/article/63/7/e147/2196792</a>. <a href="http://doi.org/10.1093/cid/ciw376">doi.org/10.1093/cid/ciw376</a>. Accessed March 18, 2026.
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. 866.3371 to subpart D to read as follows:
Sec. 866.3371 Qualitative Mycobacterium tuberculosis Cell-Mediated
Immune Response Assay.
(a) Identification. A qualitative Mycobacterium tuberculosis cell-
mediated immune response assay is identified as a prescription in vitro
diagnostic device intended to aid in the diagnosis of Mycobacterium
tuberculosis infection. Qualitative Mycobacterium tuberculosis cell-
mediated immune response assays measure the production of interferon-
gamma or other cytokines by human lymphocytes in response to
stimulation antigens. The assay is intended for use by a licensed
healthcare professional as an aid in the diagnosis of Mycobacterium
tuberculosis infection in conjunction with risk assessment,
radiographic imaging, and other medical and diagnostic evaluations.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) The labeling must include:
(i) A prominent statement that the assay is an indirect test for
tuberculosis and that results must be interpreted by a licensed
healthcare professional in conjunction with risk assessment,
radiographic imaging, and other medical and diagnostic evaluations to
assist the licensed healthcare professional in making individual
patient management decisions.
(ii) A detailed explanation of the interpretation of results,
including, as applicable, descriptions of borderline, equivocal,
indeterminate, and invalid results.
(iii) Warnings and limitations that include statements that
indicate, as applicable:
(A) Diagnosis or exclusion of tuberculosis disease and assessment
of the probability of latent tuberculosis infection is based on a
combination of epidemiological, clinical, and diagnostic findings.
(B) Licensed healthcare professionals are directed to consult
resources from appropriate public health authorities that assist in
diagnosing tuberculosis infection.
(C) The species of nontuberculous mycobacterium that may generate
false positive results, as applicable.
[[Page 15582]]
(D) Negative test results do not exclude the possibility of
exposure to, or infection with, Mycobacterium tuberculosis. A negative
result must be considered with the individual's medical and historical
data relevant to probability of Mycobacterium tuberculosis infection
and potential risk of progression to tuberculosis disease, particularly
for individuals with impaired immune function. Negative predictive
values may be low for individuals suspected to have Mycobacterium
tuberculosis disease.
(E) Positive results do not confirm the diagnosis of active
tuberculosis disease.
(F) Assay results are qualitative and the magnitude of the measured
assay numeric values cannot be correlated to stage or degree of
infection, level of immune responsiveness, or likelihood for
progression to active disease.
(G) Heterophilic antibodies, circulating interferon gamma, and
other circulating factors may cause inaccurate results.
(H) Patient populations in which test performance characteristics
have not been established, or patient populations where test
performance may be affected.
(2) Design verification and validation must include the following:
(i) A detailed device description, including the computational path
from collected raw data to reported result (e.g., how collected raw
signals are converted into a reported result), and rationale used to
select stimulation antigens.
(ii) Documentation and characterization of all critical reagents
(e.g., determination of the identity, supplier, purity, and stability)
and protocols for maintaining product integrity.
(iii) Final lot 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.
(iv) Risk analysis and documentation demonstrating how risk control
measures are implemented to address device hazards, such as Failure
Modes Effects Analysis and/or Hazard Analysis.
(v) Detailed documentation of analytical studies, including
reproducibility, precision (including lot-to-lot precision studies, as
appropriate), interference, cross reactivity, carryover, hook effect,
sample and reagent stability, and other studies relevant to the
technology and intended use (e.g., linearity), as applicable.
(vi) Detailed documentation of device performance data from a
multisite clinical study in geographically diverse areas with a design
and performance that is appropriate for the intended use of the device.
The study must be performed on populations consistent with the intended
use population and compare the device performance to results obtained
from a reference or comparator method that FDA has determined is
appropriate. The clinical study must include testing of unique
prospective (sequentially collected) samples and may, when determined
to be acceptable by FDA, include additional characterized clinical
samples. The clinical study must include a cohort of subjects with
culture-confirmed or FDA-cleared or approved nucleic acid amplification
test confirmed active tuberculosis infection, a cohort of subjects with
no known risk factors for tuberculosis infection, and a mixed risk
cohort of subjects with at least one known risk factor for tuberculosis
and/or risk for latent tuberculosis infection. Enrolled subjects must
include individuals who are immunosuppressed, individuals who have
received the bacille Calmette-Gu[eacute]rin vaccine, or individuals
with nontuberculous mycobacterial infections, as applicable.
Documentation from the study must include a detailed study report that
contains a study description, a summary of testing results, and results
of all statistical analyses.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2026-06064 Filed 3-27-26; 8:45 am]
BILLING CODE 4164-01-P
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