[Federal Register Volume 91, Number 157 (Monday, August 17, 2026)]
[Rules and Regulations]
[Pages 53184-53191]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2026-16727]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 864
[Docket No. FDA-2025-N-1243]
Hematology and Pathology Devices; Reclassification of In Situ
Hybridization Test Systems for Use With a Corresponding Approved
Oncology Therapeutic Product
AGENCY: Food and Drug Administration, HHS.
ACTION: Final amendment; final order.
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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
issuing a final order reclassifying in situ hybridization (ISH) test
systems indicated for use with a corresponding approved oncology
therapeutic product (product codes NYQ, MVD, OWE, and PNK), all
postamendments class III (premarket approval) devices, into class II
(special controls), subject to premarket notification. FDA is also
establishing a new device classification regulation, along with the
special controls that are necessary to provide a reasonable assurance
of safety and effectiveness of this device type.
DATES: This order is effective September 16, 2026. See further
discussion in section IV, ``Implementation Strategy.''
FOR FURTHER INFORMATION CONTACT: Soma Ghosh, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 3316, Silver Spring, MD 20993, 240-402-5333,
[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 introduced or delivered for introduction into
interstate commerce for commercial distribution prior to May 28, 1976
(generally referred to as postamendments devices) are automatically
classified by section 513(f)(1) of the FD&C Act into class III without
any FDA rulemaking process. Those devices remain in class III and
require approval of a premarket approval application (PMA), unless and
until: (1) the Food and Drug Administration (FDA) reclassifies the
device into class I or class II; or (2) FDA issues an order finding the
device to be substantially equivalent, in accordance with section
513(i) of the FD&C Act, to a predicate device that does not require
premarket approval. FDA determines whether new devices are
substantially equivalent to predicate devices by means of 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) 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 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 stated in section
513(a)(3) of the FD&C Act and defined in 21 CFR
[[Page 53185]]
860.7(c)(2), in the classification process to determine the level of
regulation for devices. To be considered in the reclassification
process, the ``valid scientific evidence'' upon which the Agency relies
generally 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))). Section 520(h)(4) of the FD&C Act (21 U.S.C.
360j(h)(4)) 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.\2\
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\2\ Since the publication of the proposed order, data from one
additional PMA and several PMA supplements have become available for
consideration by FDA in accordance with section 520(h)(4) of the
FD&C Act. FDA has determined that the data from the additional PMA
and PMA supplements are cumulative of, and consistent with, the
information addressed in the proposed order and do not raise any new
or different questions regarding the safety and effectiveness of
oncology therapeutic ISH-based test systems.
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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 June 11, 2025, FDA published a proposed order \3\ in the Federal
Register (90 FR 24540) (``proposed order'') to reclassify in situ
hybridization (ISH) test systems indicated for use with a corresponding
approved oncology therapeutic product (product codes NYQ, MVD, OWE, and
PNK) \4\ (hereinafter referred to as oncology therapeutic ISH-based
test systems) from class III to class II. FDA has considered the
information available to the Agency, as described in the June 11, 2025,
proposed order, and considered 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 (updated as
discussed in section II of this document). FDA has also determined
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\ FDA notes that the ``ACTION'' caption for the 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 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 assist in accurate identification and tracking of
current medical devices and to allow for tracking of and easy
reference to predicate device types. A medical device product code
consists of a three-letter combination which associates a device's
type with a product classification designated for the application.
The three-digit classification product codes in CDRH's Product
Classification Database carry no other significance. See FDA
guidance titled ``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.
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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 to reclassify
oncology therapeutic ISH-based test systems from class III to class II
(special controls).\5\ Absent the special controls identified in this
final order, general controls applicable to the device type are
insufficient to provide a reasonable assurance of safety and
effectiveness. Specifically, general controls are insufficient to
effectively mitigate the risks identified for this device type, such as
the risk of false test results (i.e., false positive and false negative
test results), which may negatively influence treatment decisions for
cancer patients--for example, by delaying access to an available and
appropriate alternative therapy. FDA expects that the reclassification
of these devices will enable more manufacturers to develop this type of
device such that patients will benefit from increased access to
oncology therapeutic ISH-based test systems for which there is a
reasonable assurance of safety and effectiveness.
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\5\ 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.
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After the effective date of this order, for these class II devices,
manufacturers may submit a premarket notification and obtain FDA
clearance of the devices before marketing them, as opposed to having to
submit a PMA and receive approval. This action 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. A 510(k) typically
results in a shorter premarket review timeline compared to a PMA, which
ultimately provides patients with more timely access to this type of
device.
II. Comments on the Proposed Order and FDA Responses
A. Introduction
FDA received comments from fewer than 5 commenters on the proposed
order published in the Federal Register on June 11, 2025. The comment
period on the proposed order closed on August 11, 2025. The majority of
the comments received by the close of the comment period came from
members of the medical device industry. Some commenters provided
multiple comments on one or more issues. All commenters provided
support for the proposed reclassification with some comments also
providing recommendations or proposed modifications 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 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 separated
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 supporting the proposed
reclassification of oncology therapeutic ISH-based test systems, from
class III to class II, subject to special controls. Citing, among other
things, ISH as a long-established technology, commenters stated they
believe that special controls could be established to provide
reasonable assurance of the safety and effectiveness of these devices.
In addition, commenters noted that the decreased regulatory burden
resulting from the reclassification could increase development and
availability of these tests, thus offering better diagnostic options
for clinicians and improving patient access to diagnostics and
therapies.
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(Response 1) FDA agrees with the comments supporting this
reclassification. Based on the information the Agency considered and
analyzed in proposing to reclassify these devices, as well as comments
received in response to the proposed order, FDA has determined that
reclassifying oncology therapeutic ISH-based test systems from class
III (premarket approval) into class II (special controls) is
appropriate. Specifically, based on the totality of information
available, FDA has determined that general controls are insufficient to
provide a reasonable assurance of safety and effectiveness for these
devices and there is sufficient information to establish special
controls for these devices that together with general controls will
provide a reasonable assurance of safety and effectiveness. In
addition, FDA also expects that the reclassification of these devices
will enable more manufacturers to develop this type of device such that
health care providers and patients will benefit from increased access
to appropriately safe and effective tests.
(Comment 2) One commenter requested the Agency's guidance and
further deliberation on these matters, either preceding or during a
reclassification panel meeting.
(Response 2) FDA has determined that a classification panel is
unnecessary to reclassify oncology therapeutic ISH-based test systems
from class III to class II. Section 513(f)(3) of the FD&C Act provides
that FDA may ask an appropriate panel to review information and make a
recommendation before issuing an order reclassifying a postamendments
device (see also 21 CFR 860.134(c)(2)). FDA is reclassifying these
postamendments class III devices on its own initiative and does not
believe a panel recommendation is needed to help determine whether
these devices should be reclassified from class III to class II nor to
identify appropriate special controls. FDA has determined, based on the
information discussed in the preamble to the proposed order and FDA's
consideration of public comments, that the standard in section
513(a)(1)(B) of the FD&C Act is met. Specifically, FDA has determined
that general controls are insufficient to provide a reasonable
assurance of safety and effectiveness, and there is sufficient
information to establish special controls, which with general controls
will provide a reasonable assurance of the safety and effectiveness
when applied to these devices.
(Comment 3) One commenter expressed appreciation for the Agency's
use of the least burdensome approach through discussion of
predetermined change control plans (PCCPs) in the preamble to the
proposed order. The commenter requested the Agency allow applicants to
seek FDA's alignment on device-specific PCCPs via pre-submission rather
than a pre-market notification and further requested that the Agency
consider permitting PCCPs for a planned modification to already PMA-
approved devices to include artificial intelligence (AI)/machine
learning (ML) driven digital pathology (DP) algorithms intended to aid
the end user or seek aid from the end user for end result generation,
via PCCPs.
(Response 3) The new classification regulation at Sec. 864.1890
(21 CFR 864.1890) applies to previously approved oncology therapeutic
ISH-based test systems and new devices that are determined to be
substantially equivalent. We note that, at the time of publication of
this final order, FDA has not classified, cleared, approved, or granted
authorization for any oncology therapeutic ISH-based test systems that
incorporate DP devices, including AI/ML algorithm-assisted DP devices.
As described in the preamble of the proposed order, manufacturers
may wish to use 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 \6\ while continuing to provide
reasonable assurance of device safety and effectiveness. 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 (see section 515C of the FD&C Act (21 U.S.C.
360e-4)). Thus, FDA's consideration of a device-specific PCCP, and the
determination of whether the inclusion of a device modification, to
include a modification to an AI/ML-enabled device via a PCCP is
appropriate, will be based on the Agency's review and consideration of
the information submitted at the time of a premarket submission. FDA
encourages manufacturers to leverage the Q-Submission program to obtain
FDA feedback on their approach to using a PCCP for a device prior to
submitting a marketing submission. Additional information regarding the
Q-Submission program can be found in FDA's final guidance document
titled ``Requests for Feedback and Meetings for Medical Device
Submissions: The Q-Submission Program'' (Ref. 1). For additional
information regarding marketing submissions that include a PCCP for AI/
ML-enabled devices, see FDA's guidance, ``Marketing Submission
Recommendations for a Predetermined Change Control Plan for Artificial
Intelligence-Enabled Device Software Functions'' (Ref. 2).
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\6\ 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 Sec.
807.81(a)(3).
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(Comment 4) One comment recommended the Agency reference and
``include the principles'' of FDA's guidance, ``Replacement Reagent and
Instrument Family Policy for In Vitro Diagnostic Devices'' in this
final order.
(Response 4) FDA appreciates this comment and acknowledges that the
guidance ``Replacement Reagent and Instrument Family Policy for In
Vitro Diagnostic Devices'' may be applicable under certain
circumstances to oncology therapeutic ISH-based test systems (Ref. 3).
When evaluating the applicability of this guidance to specific
modifications to a particular test system, interested parties should
follow the logic scheme and recommendations contained in the guidance.
(Comment 5) One commenter requested several changes to the proposed
classification regulation. The commenter recommended revising the
proposed codified text for Sec. 864.1890 by adding a new paragraph
titled ``Device Description and Principle of Operation,'' as Sec.
864.1890(b). The suggested language would require, presumably in a
submission to FDA and/or in the device labeling, detailed elements of a
device's intended use/indication for use including specifications for
the intended use population(s), biomarker lists, specimen type(s),
system components, biomarker definitions as used in the therapeutic
product trials and as detected by the test, along with the
corresponding therapeutic product(s) or therapeutic product group, and
a description of whether the device is qualitative, semi-quantitative,
or quantitative. The commenter also proposed renumbering the
identification provision as paragraph (a) and classification provision
as paragraph (c).
The commenter also recommended adding a new labeling special
control, to be incorporated as Sec. 864.1890(c)(2)(i), which would
require Sec. 809.10 (21 CFR 809.10) compliant labeling and any product
information and test output generated to include the intended use
statement as outlined in the commenter's proposed Sec. 864.1890(b).
(Response 5) While FDA agrees that labeling special controls, in
addition to general controls, are needed to assure the safety and
effectiveness of oncology therapeutic ISH-based test systems, FDA
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disagrees that the commenter's proposed edits to Sec. 864.1890 are
necessary. FDA believes the labeling special controls proposed by the
Agency, in combination with the applicable general controls, which
include general in vitro diagnostic (IVD) product labeling requirements
under Sec. 809.10, are sufficient for the labeling of this device
type.
FDA declines to adopt the proposed revisions at Sec. 864.1890(b)
to the codified text. Much of this information is already required to
be submitted to FDA under existing general controls. For example, Sec.
809.10(b)(2) requires the type of procedure to be included in labeling
(e.g., qualitative or quantitative) and Sec. 807.87(e) requires
submission of the device's proposed labeling as part of a 510(k). FDA
does not believe that an additional requirement mandating submission of
all of this information is necessary for all devices in this device
type. Moreover, and as discussed further below, FDA does not believe
all of this information needs to be included in the device's intended
use/indications for use statement found in the device's labeling to
provide reasonable assurance of the safety and effectiveness of these
devices. Accordingly, FDA is not adding the proposed paragraph to Sec.
864.1890, nor is FDA renumbering the identification and classification
paragraphs as proposed.
FDA also declines to incorporate the commenter's proposed edits to
the labeling special control. The suggested revisions would require
labeling to include an intended use statement referencing the
commenter's proposed Sec. 864.1890(b), which FDA is not adopting for
the reasons described in the previous paragraph. Moreover, the
commenter's suggested requirements duplicate or overlap with existing
regulatory requirements under Sec. 809.10 and part 801 (21 CFR part
801), as well as the labeling elements already encompassed by the
Agency's proposed special controls. The Agency's proposed special
controls, along with applicable statutory and regulatory requirements,
address all of the necessary intended use statements and operational
descriptions (e.g., summary and explanation of the test) that are to be
included in labeling, without the need for the additional codified
requirements. FDA believes the special controls, as finalized, along
with general controls, will ensure the device's risks to health are
appropriately mitigated and provide a reasonable assurance of the
safety and effectiveness of oncology therapeutic ISH-based test
systems.
(Comment 6) One comment acknowledged the suitability of the
analytical performance tests outlined in the proposed order but
recommended that FDA consider incorporating surrogate samples for use
in the precision/reproducibility data generation, where the sample type
can be supported as representative. This would apply to situations
where sufficient clinical specimens for the intended use specimen
type(s) are unavailable for analytical validation testing. The comment
stated that such an inclusion would facilitate manufacturers' ability
to conduct adequate verification testing by using surrogate samples
that are morphologically comparable to the intended-use clinical
specimens.
(Response 6) Based on the information FDA considered and analyzed
in proposing to reclassify these devices, as well as comments received
in response to the proposed order, FDA acknowledges that certain
exceptional clinical circumstances may warrant consideration of
alternative approaches to the use of clinical specimens for the purpose
of analytical validation testing (e.g., rare cancer(s) or tumor type(s)
where obtaining sufficient clinical specimens presents a significant
challenge). However, FDA maintains that precision studies represent a
fundamental device performance requirement that is essential for
demonstrating analytical performance and ensuring consistent and
reliable device function. Upon further consideration, FDA has decided
to modify the special control related to this comment (see Sec.
864.1890(b)(1)(v)) to consider surrogate samples that adequately
represent the intended use specimen type(s) and intended use
biomarker(s), as appropriate, as determined by FDA, to supplement
clinical specimens. For example, FDA will determine the appropriateness
of surrogate samples based on clinical and scientific data and/or
justification available to the Agency.
In addition to the above modification, FDA, based in part on the
comments received, has also removed the special control requiring
device performance data demonstrating appropriate reagent stability.
Upon further review of the information the Agency considered and
analyzed in proposing to reclassify these devices, such as postmarket
safety data from medical device reports and recalls, as well as
comments received on the proposed special controls, FDA believes that a
special control requiring reagent stability data is not necessary and
that general controls, such as premarket notification (510(k))
requirements and quality system requirements set forth under part 820
(21 CFR part 820) are sufficient to ensure that reagents are
appropriately assessed and labeled such that this special control is
not necessary. As such, the Agency is removing proposed Sec.
864.1890(b)(1)(viii).
(Comment 7) One comment recommended FDA revise the
``Identification'' language of proposed Sec. 864.1890 to include the
term ``companion.''
(Response 7) FDA disagrees with the recommended edit and is
finalizing the identification language in this final order without
change. The comment did not provide context to support the suggested
revision, and FDA continues to believe that the identification, as
proposed, provides an appropriate level of clarity regarding the type
of device intended to fall within the scope of Sec. 864.1890.
(Comment 8) One comment expressed a desire to work with the Agency
to address nuanced clinical performance adequacy scenarios as
potentially applicable to future devices either via a pre-submission
route or alternative mechanism.
(Response 8) FDA agrees that questions of this nature may be
appropriate topics to discuss with the Agency through the Q-Submission
program. Prior to submission, a sponsor may seek FDA input on specific
questions regarding review topics relevant to a planned marketing
submission by utilizing our Q-Submission program. Through the Q-
Submission program FDA may provide input on device-specific
requirements and recommendations intended to support a marketing
submission. Additional information regarding the Q-Submission program
can be found in FDA's final guidance document titled ``Requests for
Feedback and Meetings for Medical Device Submissions: The Q-Submission
Program'' (Ref. 1).
Sponsors may also review information on FDA's Center for Devices
and Radiological Health's (CDRH) website regarding previously approved
oncology therapeutic ISH-based test systems, such as Summary of Safety
and Effectiveness Data (SSED) documents available in FDA's Premarket
Approval Database,\7\ which detail the clinical evidence, risks, and
benefits for medical devices. Additionally, sponsors may consider
reviewing CDRH's 510(k) Decision Summaries, found in FDA's 510(k)
Premarket Notification Database,\8\ which summarize the information
that informed the Agency's substantial
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equivalence decision and that may help inform interested parties
regarding FDA's thinking on the types of performance the Agency might
expect for this type of device. Sponsors also should refer to the
special controls codified at Sec. 864.1890, established as part of
this final order, which set forth requirements that are necessary to
provide a reasonable assurance of safety and effectiveness for these
devices. Comments related to a sponsor's study- or device-specific
questions are outside the scope of this final order.
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\7\ https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm.
\8\ https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm.
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(Comment 9) One comment requested that FDA evaluate other devices
and therapies with comparable risk profiles to determine whether
reclassification may be appropriate, with the goal of broadening
availability of such devices. The comment also requested that FDA
review and update the special controls for oncology therapeutic ISH-
based test systems on a regular basis and ensure that clinical data
supporting the development and implementation of the special controls
is transparent and readily available to interested parties.
(Response 9) The FDA periodically reviews the classification of
devices to ensure they are being regulated in the appropriate class
(class III, II, I) with the necessary level of regulatory controls.
CDRH has previously undertaken reclassification efforts as part of the
Center's systematic approach, including the 2014-2015 Strategic
Priorities,\9\ and as part of CDRH's regular due diligence in
considering the specific classification for a particular device type.
Additionally, in 2024, CDRH announced its intent to initiate the
reclassification process for most high risk IVD devices, reflecting
this ongoing, systematic approach to ensuring appropriate
classification.\10\ FDA intends to continue evaluating the
classification of devices to ensure they are subject to the appropriate
level of regulatory controls.
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\9\ See 81 FR 52445.
\10\ See 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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Further, FDA acknowledges the comment's request that the Agency
regularly review and update the special controls and ensure
transparency. For class II devices, special controls are established to
provide reasonable assurance of safety and effectiveness for the device
type and are developed based on the totality of available scientific
evidence at the time of classification or reclassification. As new
information becomes available, including advances in scientific
knowledge and changes in device technology, FDA may evaluate whether
such developments and device modifications give rise to new benefit-
risk considerations such that new or different special controls, in
addition to general controls, are needed to assure the safety and
effectiveness for the device type.
With respect to transparency, FDA strives to make publicly
available the scientific basis for its regulatory decisions, consistent
with applicable statutes and regulations. In general, the clinical and
scientific information that forms the basis of the special controls is
included in the public docket associated with the classification or
reclassification action, to the extent permitted by law. FDA,
therefore, believes that the current regulatory framework provides an
appropriate mechanism for ensuring the relevance of special controls
and the availability of supporting information. No changes to the final
order have been made in response to this comment.
(Comment 10) One comment proposed edits to Table 1. Risks to Health
and Mitigation Measures in the proposed order. The comment proposed
additional mitigation measures to each of the three identified risks to
health to include, for example, the addition of ``Device Description
and Principle of Operation'' and ``Implementation of Controls,
procedures and user training requirements.''
(Response 10) As discussed in response to comment 5, FDA disagrees
that such line edits or clarifications are needed to the mitigations
identified in the proposed order. The mitigation measures proposed to
be added to table 1 correspond to this commenter's proposed additions
to the codified, as described in comment 5. As noted in response to
comment 5, the language proposed by the commenter is generally already
covered for oncology therapeutic ISH-based test systems by the
regulatory requirements for IVDs under part 801 and Sec. 809.10, as
well as the Agency's proposed special controls. FDA believes that the
special controls set forth in the proposed order with the changes
identified in this final order (see comment 5 and the Agency's
response), together with general controls, are sufficient to
effectively mitigate the risks to health identified in section V of the
proposed order and are necessary to provide a reasonable assurance of
the safety and effectiveness of oncology therapeutic ISH-based test
systems. For these reasons, we decline to incorporate the proposed
edits.
With regards to the commenter's recommendation to include
``Implementation of Controls, procedures and user training
requirements'' in table 1 of the proposed order, FDA also disagrees
that this is necessary. FDA believes that the commenter's proposed
requirement is already encompassed within the Agency's proposed special
controls. Specifically, this proposed recommendation falls within
certain design verification and validation activities required by the
special controls under Sec. 864.1890(b)(1)(i) which indicates that
``[s]pecification for risk mitigation elements intended to mitigate
risks associated with testing and results interpretation, including
controls, procedures, and user training requirements, as appropriate.''
(Comment 11) One comment requested clarification on how FDA's
determination that devices under the relevant oncology therapeutic ISH-
based test system product codes share similar purposes, designs,
functions, and risk profiles would affect their use as predicate
devices under the 510(k) pathway. The commenter also sought general
guidance on how substantial equivalence would be evaluated in cases
where a device's intended use or labeling is expanded, such as to
include a new oncology therapeutic product, clinical indication, or
clinical cut-off.
(Response 11) FDA acknowledges the commenter's request for
clarification regarding the implications of this reclassification on
the use of these devices as predicates under the 510(k) pathway. While
the Agency has determined that devices within the relevant product
codes share similar purposes, designs, functions, and overall risk
profiles for purposes of reclassification, this determination does not
alter the statutory and regulatory requirements applicable to
demonstrating substantial equivalence. For a new device to be
considered substantially equivalent to a predicate device, the new
device must have the same intended use as the predicate device and the
same technological characteristics or different technological
characteristics that do not raise different questions of safety and
effectiveness than the predicate device. Additional information can be
found in FDA's final guidance ``The 510(k) Program: Evaluating
Substantial Equivalence in Premarket Notifications [510(k)]'' (Ref. 4).
In accordance with section 513(i) of the FD&C Act and part 807,
substantial equivalence determinations are made on a case-by-case basis
and depend on the specific intended use and technological
characteristics of the device under review. Any oncology therapeutic
ISH-based test system with a new intended use or technological
characteristics that raise different questions of safety and
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effectiveness compared to legally marketed devices would generally not
be found to be substantially equivalent. However, devices could be used
as predicate devices to support a substantial equivalence determination
when a device has a new clinical cut-off or a new indication for use
that includes a new therapeutic product if adequate data and
information are provided to demonstrate the new indication(s) for use
fall within the intended use of the predicate device and any
technological differences do not raise different questions of safety
and effectiveness. If a manufacturer has a question regarding a
specific device for which they intend to seek marketing authorization,
the manufacturer may choose to utilize the Q-Submission Program to seek
feedback on the appropriate regulatory pathway for modified devices.
Additional information regarding the Q-Submission program can be found
in FDA's final guidance document titled ``Requests for Feedback and
Meetings for Medical Device Submissions: The Q-Submission Program''
(Ref. 1).
(Comment 12) One comment requested that the Agency clarify that
devices already on the market would be automatically reclassified into
class II without the need for any additional premarket notification or
submission, and that only future devices, or currently marketed devices
with significant modifications, would be required to submit a premarket
notification.
(Response 12) FDA appreciates the need to provide clarification on
the implementation of this final order. To provide such clarification
and assist in the efficient implementation of this final order, the
Agency has added an implementation strategy in section IV of this final
order. Among other things, section IV clarifies that upon its effective
date the final order reclassifies devices that are oncology therapeutic
ISH-based test systems as described within the scope of the proposed
order and adopted as part of this final order, from class III
(premarket approval) into class II (special controls). Oncology
therapeutic ISH-based test systems with prior PMA approval may continue
to be marketed per the previous marketing authorization and would not
require an additional marketing application. For changes or
modifications that could significantly affect the safety or
effectiveness of such devices or a major change or modification in the
intended use of such devices (see Sec. 807.81(a)(3)), FDA expects that
manufacturers will submit a 510(k) for the modified device.
(Comment 13) One comment encouraged FDA to issue a detailed
guidance regarding the special controls described in the proposed order
at the same time as the publication of this final order in the Federal
Register.
(Response 13) At this time, FDA does not intend to issue a guidance
document regarding compliance with the special controls identified in
this final order. For the reasons discussed in the proposed order, the
Agency believes that the special controls, as stated in Sec.
864.1890(b), provide sufficiently clear and appropriate requirements,
at a level of detail necessary to reasonably assure the safety and
effectiveness of this device type. Should FDA determine in the future
that further information is warranted, the Agency may consider issuing
guidance. The Agency also believes information available to sponsors
through other resources will be helpful in preparing 510(k)s for
submission and complying with special controls. For example, sponsors
may review information on CDRH's website regarding previously approved
oncology therapeutic ISH-based test systems such as SSED documents
available in FDA's Premarket Approval Database, which detail the
clinical evidence, risks, and benefits for approved devices. In
addition, the performance data and related valid scientific evidence
included in 510(k)s reviewed by FDA may be a helpful resource. Once
available, sponsors may consider reviewing the 510(k) Decision
Summaries in FDA's 510(k) Premarket Notification Database to inform the
types of performance the Agency expects for this type of device.
III. The Final Order
In this final order, FDA is adopting relevant findings, including
the reasoning that supports those findings, from the June 11, 2025,
proposed order. FDA has made revisions in this final order based, in
part, on the comments received (see section II). FDA is issuing this
final order to reclassify oncology therapeutic ISH-based test systems
from class III into class II under a new device classification
regulation with the name In Situ Hybridization Test Systems for Use
with a Corresponding Approved Oncology Therapeutic Product, and to
establish special controls by revising 21 CFR part 864 (adding Sec.
864.1890).
Further, in this final order, FDA 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 for oncology therapeutic ISH-based test systems. As
described in section II of this document, FDA has made revisions to the
special controls as previously described in the proposed order. Based,
in part, on comments regarding the proposed order, FDA has revised the
design verification and validation special controls to add to the
existing proposed Sec. 864.1890(b)(1)(v) requirement the consideration
of surrogate samples that adequately represent the intended use
specimen type(s) and intended use biomarker(s), as appropriate, as
determined by FDA, to supplement clinical specimens. Additionally, FDA
has removed the proposed Sec. 864.1890(b)(1)(viii) requiring device
performance data demonstrating reagent stability.
Based on the information discussed in the preambles to the proposed
order and this final order, including the comments received for the
proposed order, FDA concludes that special controls, in addition to
general controls, provide a reasonable assurance of the safety and
effectiveness of oncology therapeutic ISH-based test systems. 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 addition, in this final order, to provide additional
clarification and to efficiently implement this order, the Agency has
added an implementation strategy in section IV.
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 under section
510(m).\11\ FDA has not made this determination for oncology
therapeutic ISH-based test systems and, therefore, this class II device
type is not exempt from 510(k) requirements. Thus, under sections
510(k) and 513(f) of the FD&C Act, persons who intend to market this
device type must submit a 510(k) containing information on the
[[Page 53190]]
oncology therapeutic ISH-based test system that they intend to market
and must obtain FDA clearance of the device prior to marketing it.
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\11\ 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's guidance ``Procedures for Class II
Device Exemptions from Premarket Notification, Guidance for Industry
and CDRH Staff,'' available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/procedures-class-ii-device-exemptions-premarket-notification-guidance-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 864.9.
---------------------------------------------------------------------------
Under this final order, oncology therapeutic ISH-based test systems
are prescription use IVD devices and as such, these tests must satisfy
prescription labeling requirements for IVD products (see Sec.
809.10(a)(4) and (b)(5)(ii)). This device type is 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, of FDA's regulations.
IV. Implementation Strategy
This final order is effective 30 days after the date of its
publication in the Federal Register.
For oncology therapeutic ISH-based test systems that have not been
offered for sale prior to the effective date of the final order,
manufacturers must obtain 510(k) clearance before marketing the device
(and for subsequent modifications to the device, as appropriate).
For oncology therapeutic ISH-based test systems 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 under
the previously issued PMA approval and do not require an additional
marketing authorization.
For devices that have been legally marketed via PMA before the
effective date of this final order, FDA expects that manufacturers will
submit a 510(k) premarket notification when making a change or
modification that could significantly affect the safety or
effectiveness of the device or a major change or modification in the
intended use of the device. See Sec. 807.81(a)(3).
V. Analysis of Environmental Impact
The Agency has determined under 21 CFR 25.34(b) that this action is
of a type that does not normally have a significant effect on the human
environment. Therefore, neither an environmental assessment nor an
environmental impact statement is required.
VI. Paperwork Reduction Act of 1995
This final administrative order refers to previously approved
collections of information found in FDA regulations. 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 (44 U.S.C. 3501-3521). The collections of information in part 820
(Quality Management System Regulation) have been approved under OMB
control number 0910-0073; the collections of information in 21 CFR part
812 (Investigational Device Exemptions) have been approved under OMB
control number 0910-0078; the collections of information in 21 CFR part
814, subparts A through E (Premarket Approval of Medical Devices) have
been approved under OMB control number 0910-0231; 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 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 In Situ
Hybridization Test Systems for Use with a Corresponding Approved
Oncology Therapeutic Product in the new Sec. 864.1890, under which
these oncology therapeutic ISH-based test systems are reclassified from
class III into class II.
VIII. References
The following references 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 are also available electronically at https://www.regulations.gov.
Although FDA verified the website addresses in this document, please
note that websites are subject to change over time.
1. FDA, ``Requests for Feedback and Meetings for Medical Device
Submissions: The Q-Submission Program; Guidance for Industry and
Food and Drug Administration Staff,'' May 29, 2025. (Available at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program.)
2. FDA, ``Marketing Submission Recommendations for a Predetermined
Change Control Plan for Artificial Intelligence-Enabled Device
Software Functions; Guidance for Industry and Food and Drug
Administration Staff,'' August 18, 2025. (Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/marketing-submission-recommendations-predetermined-change-control-plan-artificial-intelligence.)
3. FDA, ``Replacement Reagent and Instrument Family Policy for In
Vitro Diagnostic Devices; Guidance for Industry and Food and Drug
Administration Staff,'' August 17, 2022. (Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/replacement-reagent-and-instrument-family-policy-in-vitro-diagnostic-devices.)
4. FDA, ``The 510(k) Program: Evaluating Substantial Equivalence in
Premarket Notifications [510(k)]; Guidance for Industry and Food and
Drug Administration Staff,'' July 28, 2014. (Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/510k-program-evaluating-substantial-equivalence-premarket-notifications-510k.)
List of Subjects in 21 CFR Part 864
Blood, Medical devices, Packaging and containers.
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 864 is amended as follows:
PART 864--HEMATOLOGY AND PATHOLOGY DEVICES
0
1. The authority citation for part 864 continues to read as follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.
0
2. Add Sec. 864.1890 to subpart B to read as follows:
Sec. 864.1890 In situ hybridization test systems for use with a
corresponding approved oncology therapeutic product.
(a) Identification. In situ hybridization (ISH) test systems
indicated for use with a corresponding approved oncology therapeutic
product are identified as prescription in vitro diagnostic devices
consisting of nucleic acid probes intended for the qualitative or
quantitative detection of specific nucleic acid sequences in human
clinical specimens to provide information related to the use of a
corresponding approved oncology therapeutic product as described in the
corresponding approved oncology therapeutic product labeling.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) Design verification and validation must include:
(i) Specification for risk mitigation elements intended to mitigate
risks
[[Page 53191]]
associated with testing and results interpretation, including controls,
procedures, and user training requirements, as appropriate.
(ii) Specification of the criteria for test result interpretation
and reporting, including device cut-off(s) (i.e., clinical threshold(s)
or the medical decision point(s) between positive and negative results)
or other relevant criteria that distinguishes positive and negative or
quantitative results. This information must include the rationale for
the chosen cut-off(s) to include the upper reference of normal, or
other relevant criteria and results supporting validation of the cut-
off(s) evaluating borderline samples around the clinical threshold(s).
Scoring criteria for all applicable signals must be included.
(iii) Device performance data demonstrating appropriate analytical
sensitivity from studies using interphase nuclei from intended use
specimen type(s) that are considered karyotypically normal, or through
an alternative approach, as determined to be appropriate by FDA (e.g.,
probe sensitivity and probe limits).
(iv) Device performance data demonstrating appropriate analytical
specificity of the device for the intended use specimen type(s), as
determined to be appropriate by FDA (e.g., probe specificity,
interference study, cross-reactivity and cross contamination testing).
(v) Device performance data demonstrating appropriate precision and
reproducibility of the device using clinical specimens representing the
intended use specimen type(s) and intended use biomarker(s) from the
intended use population and investigating major sources of variability
(e.g., multiple reagent lots, operators, instruments over multiple
days, and inter- and intra-reader precision). Surrogate samples that
adequately represent the intended use specimen type(s) and intended use
biomarker(s) may be appropriate, as determined by FDA, to supplement
clinical specimens. If the device will be used at more than one site,
data must demonstrate adequate reproducibility across multiple intended
use sites. Additionally, precision and reproducibility of the device
must be evaluated with specimens near the clinical decision
threshold(s) and near the limits of reportable range. Additionally,
device performance data demonstrating appropriate precision must be
included from studies evaluating the different signals and associated
cut-offs and controls, as determined to be appropriate by FDA.
Furthermore, precision of the device must be evaluated per specimen and
in aggregate.
(vi) Device performance data demonstrating appropriate device
robustness, as determined to be appropriate by FDA. The study must
assess the tolerance ranges for various critical test and specimen
parameters, as applicable.
(vii) Device performance data demonstrating linearity of
quantitative results using samples covering the device measuring range,
as applicable.
(viii) Device performance data demonstrating appropriate specimen
stability based on the intended use specimen type(s) of the device, as
applicable.
(ix) Clinical data generated using well-characterized clinical
specimens representative of the intended use population demonstrating
appropriate clinical performance of the device for its intended use, as
determined to be appropriate by FDA.
(2) Labeling must include:
(i) An appropriate summary, as determined by FDA, of the
performance studies performed and the results of those studies,
including those that relate to all design verification and validation
special controls.
(ii) A limiting statement, as appropriate, that explains that the
test results are intended to be interpreted by a qualified or
appropriately trained reader in conjunction with other diagnostic
laboratory test results and/or pathology test results, relevant
clinical information, and proper controls.
(iii) Language indicating that the test system is indicated for use
with a corresponding FDA-approved oncology therapeutic product and
device labeling must be consistent with the information set forth in
the corresponding FDA-approved oncology therapeutic product labeling.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2026-16727 Filed 8-14-26; 8:45 am]
BILLING CODE 4164-01-P