Proposed Rule2025-10549
Hematology and Pathology Devices; Reclassification of In Situ Hybridization Test Systems for Use With a Corresponding Approved Oncology Therapeutic Product
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Published
June 11, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA) is proposing 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) from class III (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 this device type.
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<title>Federal Register, Volume 90 Issue 111 (Wednesday, June 11, 2025)</title>
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[Federal Register Volume 90, Number 111 (Wednesday, June 11, 2025)]
[Proposed Rules]
[Pages 24540-24549]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-10549]
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Proposed Rules
Federal Register
________________________________________________________________________
This section of the FEDERAL REGISTER contains notices to the public of
the proposed issuance of rules and regulations. The purpose of these
notices is to give interested persons an opportunity to participate in
the rule making prior to the adoption of the final rules.
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Federal Register / Vol. 90, No. 111 / Wednesday, June 11, 2025 /
Proposed Rules
[[Page 24540]]
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: Proposed amendment; proposed order; request for comments.
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SUMMARY: The Food and Drug Administration (FDA) is proposing 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) from class III (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 this device type.
DATES: Either electronic or written comments on the proposed order must
be submitted by August 11, 2025. Please see section X of this document
for the proposed effective date when the new requirements apply and for
the proposed effective date of a final order based on this proposed
order.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The <a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of August 11, 2025. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are received on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal Rulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
<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-2025-N-1243 for ``Hematology and Pathology Devices;
Reclassification of In Situ Hybridization Test Systems for Use with a
Corresponding Approved Oncology Therapeutic Product.'' Received
comments, those filed in a timely manner (see ADDRESSES), will be
placed in the docket and, except for those submitted as ``Confidential
Submissions,'' publicly viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday Eastern Time, 240-402-7500.
<bullet> Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents, the
plain language summary of the proposed order of not more than 100 words
consistent with the ``Providing Accountability Through Transparency
Act,'' or the electronic and written/paper comments received, go to
<a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the docket number, found in
brackets in the heading of this document, into the ``Search'' box and
follow the prompts and/or go to the Dockets Management Staff, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: 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,
<a href="/cdn-cgi/l/email-protection#81d2eeece0afc6e9eef2e9c1e7e5e0afe9e9f2afe6eef7"><span class="__cf_email__" data-cfemail="9bc8f4f6fab5dcf3f4e8f3dbfdfffab5f3f3e8b5fcf4ed">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
[[Page 24541]]
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 (general controls and special controls), and class
III (general controls and premarket approval).
Section 513(a)(1) of the FD&C Act defines the three classes of
devices. Class I devices are those devices for which the general
controls of the FD&C Act (controls authorized by or under sections 501,
502, 510, 516, 518, 519, or 520 (21 U.S.C. 351, 352, 360, 360f, 360h,
360i, or 360j) or any combination of such sections) are sufficient to
provide reasonable assurance of safety and effectiveness 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, but 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 the Agency deems
necessary to provide such assurance (section 513(a)(1)(B) of the FD&C
Act).
Class III devices are those devices for which insufficient
information exists to determine that general controls and special
controls would provide a reasonable assurance of safety and
effectiveness, and are purported or represented to be for a use in
supporting or sustaining human life or for a use which is of
substantial importance in preventing impairment of human health, or
present a potential unreasonable risk of illness or injury (section
513(a)(1)(C) of the FD&C Act).
Devices that were not introduced or delivered for introduction into
interstate commerce for commercial distribution before May 28, 1976
(generally referred to as ``postamendments devices'') are classified
automatically by section 513(f)(1) of the FD&C Act into class III
without any action taken by FDA (Agency or we). 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, 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 the regulations (21 CFR part 807).
A postamendments device that has initially been 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 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 defined in section
513(a)(3) of the FD&C Act and 21 CFR 860.7(c)(2), in the classification
process to determine the level of regulation for devices.\2\ In
general, to be considered in the reclassification process, the ``valid
scientific evidence'' upon which the Agency relies must be publicly
available (see section 520(c) of the FD&C Act (21 U.S.C. 360j(c))).
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 postamendments class III ISH-
based test systems indicated for use with a corresponding approved
oncology therapeutic product (product codes NYQ, MVD, OWE, and PNK),\3\
hereafter collectively referred to as oncology therapeutic ISH-based
test systems, into class II (special controls) subject to premarket
notification under a new device classification regulation with the name
``In Situ Hybridization Test Systems Indicated for Use with a
Corresponding Approved Oncology Therapeutic Product.''
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\3\ FDA's Center for Devices and Radiological Health (CDRH) uses
product codes to help categorize and assure consistent regulation of
medical devices. A product code consists of three characters that
are assigned at the time a product code is generated and is unique
to a product type. The three characters carry no other significance
and are not an abbreviation.
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Oncology therapeutic ISH-based test systems, currently designated
under product codes NYQ, MVD, OWE, and PNK, are prescription in vitro
diagnostic (IVD) devices that utilize ISH technology to qualitatively
or quantitatively detect specific nucleic acid sequences in human
specimens and are indicated for use with a corresponding approved
oncology therapeutic product. These test systems include companion
diagnostic (CDx) devices, which are devices that provide information
that is essential for the safe and effective use of a corresponding
approved therapeutic product and the use of which is stipulated in the
instructions for use in the labeling of both the diagnostic device and
the corresponding therapeutic product (Ref. 1). Although the devices
within the different product codes have distinct characteristics in
certain respects--for example, each product code generally represents
devices with a distinct ISH technique, specific biomarker(s) detected
by the test system, specimen type(s) tested, and/or specific FDA
approved therapeutic product(s) for which the device is indicated for
use--FDA has determined that these devices have the same or a similar
risk profile and sufficiently similar purposes, designs, functions, and
other features related to safety and effectiveness such that the same
regulatory controls are necessary and sufficient to provide reasonable
assurance of safety and effectiveness. For these reasons and
considering that FDA did not identify
[[Page 24542]]
any unique risks associated with the distinctions across these devices,
FDA is proposing a single classification regulation to classify all
oncology therapeutic ISH-based test systems into class II. Previously
approved devices remain under their respective product codes (i.e.,
NYQ, MVD, OWE, or PNK) and future oncology therapeutic ISH-based test
systems would either be assigned to one of the currently existing
product codes or a new product code, as appropriate. The new
classification regulation would classify oncology therapeutic ISH-based
test systems, currently designated under product codes NYQ, MVD, OWE,
and PNK, as well as future oncology therapeutic ISH-based test systems.
Based upon the extensive PMA data available to FDA in accordance
with section 520(h)(4) of the FD&C Act,<SUP>4 5</SUP> published peer-
reviewed literature studying this longstanding and well-understood
technology, and data available to the Agency demonstrating a lack of
significant postmarket safety signals, 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, ``In Situ
Hybridization Test Systems for Use with a Corresponding Approved
Oncology Therapeutic Product,'' and classify this device type into
class II along 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 oncology therapeutic ISH-based
test systems from class III to class II, FDA, on its own initiative,
relied on data from relevant PMAs and a relevant PMA panel-track
supplement, available to FDA with product codes of NYQ, MVD, OWE,
and PNK, 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's guidance
``Guidance on Section 216 of the Food and Drug Administration
Modernization Act of 1997--Guidance for Industry and for FDA
Reviewers [verbar] FDA''). This data was from relevant PMAs and a
PMA panel-track supplement approved after November 28, 1990, and
before August 30, 2018, 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
``amends'' the Code of Federal Regulations. The change was made in
accordance with the Office of the Federal Register's (OFR)
interpretations of the Federal Register Act (44 U.S.C. chapter 15),
its implementing regulations (1 CFR 5.9 and parts 21 and 22), and
the Document Drafting Handbook.
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Section 510(m) of the FD&C Act provides that FDA may exempt a class
II device from the premarket notification requirements under section
510(k) of the FD&C Act, if FDA determines that premarket notification
is not necessary to provide reasonable assurance of the safety and
effectiveness of the device. FDA has determined that premarket
notification is necessary to provide a reasonable assurance of the
safety and effectiveness of oncology therapeutic ISH-based test
systems, therefore, the Agency does not intend to exempt these proposed
class II devices from the premarket notification (510(k)) submission
requirement as provided under section 510(m) of the FD&C Act.\7\ If
this proposed order is finalized, persons who intend to market this
type of device must submit to FDA a premarket notification under
section 510(k) of the FD&C Act prior to marketing the device.
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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, entitled ``Procedures for Class II
Device Exemptions from Premarket Notification, Guidance for Industry
and CDRH Staff'' 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 864.9.
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II. Regulatory History of the Devices
In accordance with section 513(f)(1) of the FD&C Act, oncology
therapeutic ISH-based test systems were automatically classified into
class III because they were not introduced or delivered for
introduction into interstate commerce for commercial distribution
before May 28, 1976, and have not been found substantially equivalent
to a device placed in commercial distribution after May 28, 1976, which
was subsequently classified or reclassified into class I or class II.
Therefore, these devices are subject to the PMA requirements under
section 515 of the FD&C Act (21 U.S.C. 360e).
On December 31, 2001, FDA approved, through a panel-track
supplement \8\ to an original PMA, the first oncology therapeutic ISH-
based test system, a CDx device, PathVysion HER-2 DNA Probe Kit
(P980024/S001) (product code MVD), designed to detect amplification of
the HER-2/neu gene via fluorescence ISH (FISH) in formalin-fixed
paraffin-embedded (FFPE) human breast cancer tissue for use as an aid
in the assessment of patients for whom trastuzumab is being considered
(Ref. 2). In a November 6, 2002, Federal Register notice (67 FR 67629),
FDA announced the approval order and the availability of the Summary of
Safety and Effectiveness Data (SSED) for the device.
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\8\ The term ``panel-track supplement'' is defined in section
737(4)(B) of the FD&C Act as, ``a supplement to an approved
premarket application or premarket report under section 515 that
requests a significant change in design or performance of the
device, or a new indication for use of the device, and for which
substantial clinical data are necessary to provide a reasonable
assurance of safety and effectiveness.''
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Since the first approval order for an oncology therapeutic ISH-
based test system, FDA has reviewed and approved 7 original PMAs and
approximately 130 PMA supplements for oncology therapeutic ISH-based
test systems under product codes NYQ, MVD, OWE, and PNK.\9\ 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)) (Ref. 3), FDA considered data
contained in the following 6 original PMAs and 1 panel-track supplement
to an original PMA, representing devices from all 4 product codes
(i.e., NYQ, MVD, OWE, and PNK) for oncology therapeutic ISH-based test
systems: PathVysion HER-2 DNA Probe Kit (P980024/S001) (product code
MVD) (Ref. 2), DakoCytomation HER2 FISH pharmDX Kit (P040005) (product
code MVD) (Ref. 4), SPOT-Light HER2 CISH Kit (P050040) (product code
NYQ) (Ref. 5), HER2 CISH pharmDx Kit (P100024) (product code NYQ) (Ref.
6), INFORM HER2 Dual ISH DNA Probe Cocktail (P100027) (product code
NYQ) (Ref. 7), Vysis ALK Break Apart FISH Probe Kit (P110012) (product
code OWE) (Ref. 8), and Vysis CLL FISH Probe Kit (P150041) (product
code PNK) (Ref. 9). As of August 30, 2024, fewer than 6 years have
passed since FDA's approval
[[Page 24543]]
of the PMA and PMA supplements for VENTANA HER2 Dual ISH DNA Probe
Cocktail (P190031) and several PMA supplements associated with the 7
identified PMAs. Therefore, no information from those documents has
been used in support of this proposed order to reclassify oncology
therapeutic ISH-based test systems into class II (see section 520(h)(4)
of the FD&C Act (21 U.S.C. 360j(h)(4))).\10\
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\9\ FDA has determined that the devices assigned to product
codes NYQ, MVD, OWE, and PNK all utilize ISH-based technology for
use with a corresponding approved oncology therapeutic product, have
sufficiently similar purposes, designs, functions, and other
features related to safety and effectiveness such that all oncology
therapeutic ISH-based test systems have the same or a similar risk
profile. Further, FDA has not identified any unique risks associated
with the distinctions across these devices.
\10\ 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.
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A review of data from FDA's Manufacturer and User Facility Device
Experience (MAUDE) database, which contains Medical Device Reports
(MDRs) of adverse events, indicates that as of July 12, 2024, there
have been 14 reported events for oncology therapeutic ISH-based test
systems under the product codes NYQ (N = 9 MDRs), OWE (N = 3 MDRs), and
MVD (N = 2 MDRs) since the approval of the first oncology therapeutic
ISH-based test system in 2001. There have been no MDRs reported under
the product code PNK.
A significant majority (over 80 percent) of the MDRs reported under
the product codes listed have identified no known impact or consequence
to patient, no patient involvement, and/or no clinical signs, symptoms,
or conditions. After review of the data, the Agency has determined that
broken control slides account for the device problem associated with
nearly one-third of the MDR reported events, with other reported device
problems including, for example, communication or transmission problem,
false negative result, false positive result, and device operates
differently than expected.
A search of these product codes in FDA's Medical Device Recalls
database indicates that as of July 12, 2024, there have been 3 class II
recalls \11\ and no class I or III recalls \12\ involving oncology
therapeutic ISH-based test systems. The class II recalls occurred
between 2011 and 2016 and have since been terminated. The recalls were
due to an incorrect probe concentration, weak red chromogenic signals,
and possible fungal contamination of a reagent potentially leading to
false test results. This postmarket data, coupled with the fact that
none of the recalls and only 1 MDR were reported to have caused or led
to patient harm, indicate a generally good safety record for these
device types. These events reflect the risks to health identified in
section V of this proposed order, which FDA believes can effectively be
mitigated through general controls and the implementation of the
special controls proposed herein.
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\11\ The database searches initially identified 6 class II
recalls. However, after manual review of the data it has been
determined that 3 of the recalls were improperly reported. The 3
improperly reported class II recalls were instead related to device
product codes that fall outside the scope of this proposed order. As
such, for the purpose of this proposed order the data related to
these recalls have been excluded from the Agency's postmarket
surveillance analysis and discussion surrounding recall data.
\12\ Class I, II, and III recalls are defined in 21 CFR 7.3(m).
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III. Device Description
Oncology therapeutic ISH-based test systems are postamendments
devices classified into class III under section 513(f)(1) of the FD&C
Act. These oncology therapeutic ISH-based test systems are prescription
IVDs intended for the qualitative or quantitative detection of specific
nucleic acid sequences in human specimens using ISH technology, with
either chemical- or fluorescent-labeled probes, through manual
techniques, automated instrumentation, or a combination of manual
techniques and automated instrumentation, and are indicated for use
with a corresponding approved oncology therapeutic product. These ISH-
based test systems include IVD CDx devices which are devices that
provide information that is essential for the safe and effective use of
a corresponding therapeutic product.\13\ The use of an IVD CDx device
with a therapeutic product is stipulated in the instructions for use in
the labeling of both the diagnostic device and the corresponding
therapeutic product, including the labeling of any generic equivalents
of the therapeutic product.\14\ An IVD CDx device could be essential
for the safe and effective use of a corresponding therapeutic product
to:
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\13\ FDA, ``In Vitro Companion Diagnostic Devices--Guidance for
Industry and Food and Drug Administration Staff,'' August 6, 2014.
Available at <a href="https://www.fda.gov/media/81309/download">https://www.fda.gov/media/81309/download</a>.
\14\ Id.
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<bullet> Identify patients who are most likely to benefit from the
therapeutic product;
<bullet> Identify patients likely to be at increased risk for
serious adverse reactions as a result of treatment with the therapeutic
product;
<bullet> Monitor response to treatment with the therapeutic product
for the purpose of adjusting treatment (e.g., schedule, dose,
discontinuation) to achieve improved safety or effectiveness;
<bullet> Identify patients in the population for whom the
therapeutic product has been adequately studied, and found safe and
effective, i.e., there is insufficient information about the safety and
effectiveness of the therapeutic product in any other population.
FDA does not include in this definition IVD devices that are not
essential to the safe and effective use of a therapeutic product.\15\
For more information on CDx devices, see FDA's guidance titled ``In
Vitro Companion Diagnostic Devices--Guidance for Industry and Food and
Drug Administration Staff'' (Ref. 1).
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\15\ Id.
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FDA proposes to revise 21 CFR part 864 to create a new device
classification regulation with the name ``In Situ Hybridization Test
Systems for Use with a Corresponding Approved Oncology Therapeutic
Product.'' ISH test systems indicated for use with a corresponding
approved oncology therapeutic product are identified as prescription
IVD 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.
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 oncology
therapeutic ISH-based test systems from class III into class II,
subject to premarket notification (510(k)) requirements. FDA believes
that there is sufficient information to establish special controls, and
that these special controls, together with general controls, would
effectively mitigate the risks to health identified in section V and
are necessary to provide a reasonable assurance of the safety and
effectiveness of oncology therapeutic ISH-based test systems. Oncology
therapeutic ISH-based test systems are prescription IVD devices, and
under this proposed order, if finalized, they will be identified as
such. Therefore, these devices are subject to the prescription labeling
requirements for IVD products (see 21 CFR 809.10(a)(4) and (b)(5)(ii)).
Section 510(m) of the FD&C Act provides that FDA may exempt a class
II device from the premarket notification requirements under section
510(k) of the FD&C Act, if FDA determines that premarket notification
is not necessary to provide reasonable assurance of the safety and
effectiveness of the device. For oncology therapeutic ISH-based test
[[Page 24544]]
systems, FDA has determined that premarket notification is necessary to
provide a reasonable assurance of the safety and effectiveness of these
devices.\16\ Therefore, the Agency does not intend to exempt these
proposed class II devices from 510(k) requirements. If this proposed
order is finalized, persons who intend to market an oncology
therapeutic ISH-based test system will need to submit to FDA a 510(k)
and receive clearance prior to marketing the device.
---------------------------------------------------------------------------
\16\ See supra note 8.
---------------------------------------------------------------------------
This proposed order, if finalized, will decrease regulatory burden
on industry, as manufacturers will no longer have to submit a PMA for
these types of devices but can instead submit a 510(k) to the Agency
for review prior to marketing their device. 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
application required by FDA. A 510(k) typically results in a shorter
premarket review timeline compared to a PMA, which ultimately may
provide more timely access of these types of devices to patients. FDA
expects that the reclassification of these devices would enable more
manufacturers to develop these types of devices 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 \17\ while continuing to provide a
reasonable assurance of device safety and effectiveness.\18\ 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.\19\
---------------------------------------------------------------------------
\17\ 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).
\18\ 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.
\19\ Sections 513 and 515 of the FD&C Act. See also, FDA's
guidance ``The Least Burdensome Provisions: Concept and Principles
[verbar] FDA.''
---------------------------------------------------------------------------
FDA believes that there is sufficient information available to FDA
through the PathVysion HER-2 DNA Probe Kit (P980024/S001) PMA panel-
track supplement and DakoCytomation HER2 FISH pharmDx Kit (P040005),
SPOT-Light HER2 CISH Kit (P050040), HER2 CISH pharmDx Kit (P100024),
INFORM HER2 Dual ISH DNA Probe Cocktail (P100027), Vysis ALK Break
Apart FISH Probe Kit (P110012), and Vysis CLL FISH Probe Kit (P150041)
PMAs \20\ (Refs. 2 and 4-9), published peer-reviewed literature on ISH
technology, and FDA's publicly available MAUDE and Medical Device
Recalls databases to establish special controls that effectively
mitigate the risks to health identified in section V. More
specifically, in evaluating these data sources, FDA has identified the
risks to health for inclusion in the overall risk assessment for
oncology therapeutic ISH-based test systems. The Agency has considered
the risks to health identified by these sources and used certain
information from these sources in establishing special controls that
include mitigation measures for each of the risks to health identified
in section V. Accordingly, these devices should continue to demonstrate
safety and effectiveness upon their reclassification from class III to
class II when conformity with the special controls is demonstrated.
Absent the special controls identified in this proposed order, general
controls applicable to these devices are insufficient to provide
reasonable assurance of the safety and effectiveness of oncology
therapeutic ISH-based test systems.
---------------------------------------------------------------------------
\20\ 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.
---------------------------------------------------------------------------
V. Risks to Health
FDA is providing a substantive summary of the valid scientific
evidence concerning the public health benefits of the use of oncology
therapeutic ISH-based test systems, and the risks to health of these
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 6 PMAs and 1 PMA panel-track supplement available
to FDA under section 520(h)(4) of the FD&C Act, published peer-reviewed
literature on ISH technology, and postmarket information regarding
oncology therapeutic ISH-based test systems.
Cancer continues to be one of the two leading causes of death in
the United States (Ref. 10). Biomarker tests for molecularly targeted
cancer therapies aim to provide information for health care providers
to target and/or tailor cancer treatment based on identifiable
molecular differences between patients, with the goal of improving
patient outcomes while minimizing risks related to treatment side
effects. Oncology therapeutic ISH-based test systems provide a benefit
to the public health by aiding in oncology therapeutic product
treatment decisions. These test systems may provide information that is
essential for the safe and effective use of a corresponding approved
therapeutic product. For example, health care providers may use a
relevant oncology therapeutic ISH-based test system to select the
appropriate therapy for a patient or to monitor a particular patient's
response to an approved oncology therapeutic product for the purpose of
optimizing a dosing regimen. These devices can be used to enable
personalization of oncology care by identifying patients who are most
likely to benefit from a specific therapy and yield improved clinical
outcomes, or who are at varying degrees of risk for a particular side
effect related to the use of a specific therapy. Ultimately, the use of
these devices informs treatment decisions and has a significant public
health impact for cancer patients.
The Agency has identified the following risks to health associated
with the use of oncology therapeutic ISH-based test systems:
<bullet> False negative test results or false positive test
results. False negative test results or false positive test results may
negatively influence oncology therapeutic product treatment decisions
for cancer patients. For example, false positive test results may
result in the withholding of appropriate oncology therapeutic
treatment, delayed treatment from an available appropriate alternative
therapy, or receiving inappropriate therapy with varying degrees of
consequence (e.g., failing to adjust therapy to achieve optimal
clinical outcome or exposing a patient to otherwise avoidable serious
adverse health risks caused by the therapeutic product).
<bullet> Failure of the test system to perform as intended or
indicated. Failure of the test system to perform as intended or
indicated may result in inappropriate
[[Page 24545]]
clinical management, due to, among other things, the potential need to
rerun the test, leading to a delay in effective treatment or
inappropriate treatment for a patient based on delayed results that are
essential for the safe and effective use of a corresponding therapeutic
product.
<bullet> Failure to correctly interpret test results. Failure to
correctly interpret test results, such as, incorrect interpretation/
reading of the stained slides, may result in the same negative outcomes
associated with false negative or false positive test results as
previously discussed. For example, incorrectly interpreting the test
results as positive (i.e., false positive) may lead to a patient
receiving ineffective or unnecessary treatment that may unnecessarily
expose them to treatment toxicities.
VI. Summary of Data Upon Which the Reclassification Is Based
The safety and effectiveness of this device type has become well
established since the initial approval of the first oncology
therapeutic ISH-based test system in 2001. FDA believes that oncology
therapeutic ISH-based test systems should be reclassified from class
III (premarket approval) into class II (special controls) because
special controls can be established to mitigate the risks to health
identified in section V and, in addition to general controls, 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 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 believes, that when
used as indicated, oncology therapeutic ISH-based test systems can
provide significant benefits to health care providers and patients.
In proposing to reclassify and establish special controls for
oncology therapeutic ISH-based test systems, FDA has considered and
analyzed the following information: (1) data from 6 PMAs and 1 PMA
panel-track supplement for oncology therapeutic ISH-based test systems
available to FDA in accordance with section 520(h)(4) of the FD&C Act,
(2) published peer-reviewed literature on ISH technology, and (3) MDR
and recall data from the Agency's publicly available MAUDE and Medical
Device Recalls databases. The available evidence demonstrates that
there are public health benefits derived from the use of oncology
therapeutic ISH-based test systems which provide information related to
the use of a corresponding approved oncology therapeutic product, such
as information that is essential for the safe and effective use of a
corresponding approved oncology therapeutic product. 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 oncology therapeutic
ISH-based test systems through review of PMA data going back to the
initial approval of the first oncology therapeutic ISH-based test
system in 2001, under product code MVD (Ref. 2). Subsequently, between
2005 and 2020, FDA approved 7 PMAs for oncology therapeutic ISH-based
test systems under the product codes NYQ, MVD, PNK, and OWE. For the
purpose of this reclassification, of the 7 original PMAs and 1 PMA
panel-track supplement that the Agency has approved for oncology
therapeutic ISH-based test systems, FDA was able to consider data from
the following 6 original PMAs and 1 panel-track supplement to an
original PMA in accordance with section 520(h)(4) of the FD&C Act:
PathVysion HER-2 DNA Probe Kit (P980024/S001), DakoCytomation HER2 FISH
pharmDx Kit (P040005), SPOT-Light HER2 CISH Kit (P050040), HER2 CISH
pharmDx Kit (P100024), INFORM HER2 Dual ISH DNA Probe Cocktail
(P100027), Vysis ALK Break Apart FISH Probe Kit (P110012), and Vysis
CLL FISH Probe Kit (P150041) (Ref. 2 and 4-9).\21\
---------------------------------------------------------------------------
\21\ As previously noted, as of August 30, 2024, fewer than 6
years have passed since FDA's approval of the PMA and PMA
supplements for VENTANA HER2 Dual ISH DNA Probe Cocktail (P190031).
Therefore, no information from those documents has been used in
support of this proposed order to reclassify oncology therapeutic
ISH-based test systems into class II (see section 520(h)(4) of the
FD&C Act (21 U.S.C. 360j(h)(4))).
---------------------------------------------------------------------------
As part of the Agency's analysis in proposing to reclassify
oncology therapeutic ISH-based test systems, FDA reviewed and
considered information provided within each of these applications, to
include information available in the SSEDs and device labeling for each
application, which demonstrated a 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 those risks to health identified in section V and
can provide a reasonable assurance of the safety and effectiveness for
oncology therapeutic ISH-based test systems. Additionally, FDA
identified the potential adverse effects or risks to health of the
devices based on information provided within the applications, to be
false test results (i.e., false positive and false negative test
results), failure to correctly interpret test results, and failure of
the test system to perform as intended or indicated. Based on data
collected in the corresponding clinical studies submitted in support of
the approvals and given that oncology therapeutic ISH-based test
systems are diagnostic devices, the adverse event profile for these
devices was generally deemed acceptable as there were no direct adverse
effects or additional safety hazards to the patients being tested
beyond routine procedures performed for a cancer diagnosis.
While the devices that are the subject of the 6 PMAs and 1 PMA
panel-track supplement have unique device attributes in certain
respects (e.g., specific ISH technique utilized, specific biomarker(s)
detected by the test system, specimen type(s), and/or specific FDA
approved therapeutic product(s) for which the device is indicated for
use), FDA has determined that these devices have sufficiently similar
purposes, designs, functions, and other features related to safety and
effectiveness such that the information and data reviewed and analysis
conducted by FDA was analogous across all 7 applications available to
the Agency in accordance with section 520(h)(4) of the FD&C Act. As
such, and in order to avoid redundancy, the following two summaries are
intended to provide examples that are representative of the PMA
information and data that was reviewed and considered by FDA across the
7 applications in proposing to reclassify oncology therapeutic ISH-
based test systems from class III (premarket approval) into class II
(special controls).
On December 31, 2001, FDA approved, through a panel-track
supplement to an original PMA, the first oncology therapeutic ISH-based
test system, a CDx device, PathVysion HER-2 DNA Probe Kit with an
intended use to detect amplification of the HER-2/neu gene via FISH in
FFPE human breast cancer tissue specimens and for use as an aid in the
assessment of patients for whom trastuzumab is being considered
(product code MVD) (P980024/S001) (Ref. 2). The Agency considered the
submitted studies and data in the approved submission, which
demonstrated that the PathVysion HER-2 DNA Probe Kit has acceptable
performance on FFPE human breast
[[Page 24546]]
cancer tissue sections with varying levels of gene amplification. Such
studies include clinical studies demonstrating that the PathVysion HER-
2 DNA Probe Kit, when compared to the reference methods
immunohistochemistry (IHC) and clinical trial assay (CTA), has similar
ability to detect HER-2/neu amplification in specimens from patients
with stage II, node positive breast cancer. Potential adverse effects
of the device include the identified risks of false positive or false
negative test results and the misassignment of patients to receive a
more aggressive therapy with the potential exposure to serious side
effects or excluding a patient from receiving a therapy for which they
might benefit. FDA's review of the PMA panel-track supplement
determined that the rate of false positivity and false negativity are
within acceptable limits compared to the reference methods and 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. Beyond the risk of false positive or false negative test
results, the PathVysion HER-2/neu DNA Probe assay involves testing on
FFPE human breast cancer tissue sections for which such procedures are
routinely performed for breast cancer diagnosis. The test, therefore,
presents no additional safety hazard to the patient being tested.
Additionally, on August 26, 2011, FDA approved P110012, for the
Vysis ALK Break Apart FISH Probe Kit PMA (product code OWE) (Ref. 8).
The Vysis ALK Break Apart FISH Probe Kit test system is a qualitative
test intended to detect rearrangements involving the ALK gene via FISH
in FFPE non-small cell lung cancer (NSCLC) tissue specimens to aid in
identifying patients eligible for treatment with Xalkorie (crizotinib).
Analytical and clinical data provided in this PMA supported that there
is reasonable assurance of safety and effectiveness of this device for
use in the assessment of ALK gene rearrangements (e.g., translocations,
inversions, and deletions) and is sufficient to effectively identify
appropriate patients to be considered for crizotinib therapy. These
data included the results of a clinical trial (referred to as Study
1005 in the SSED), which met its primary effectiveness endpoint of
having an objective response rate (ORR) as assessed by the investigator
on a response-evaluable population using Response Evaluation Criteria
in Solid Tumors (RECIST) v 1.0 with 95 percent confidence intervals
(CI) [ORR of 50 percent (95 percent CI: 42, 59)]. The response rate
data from this study was used to support the accelerated approval of
crizotinib and a reasonable assurance of safety and effectiveness of
the Vysis ALK Break Apart FISH Probe Kit with regards to identifying
ALK gene rearrangements in the tumors of patients with previously
treated, advanced (locally or metastatic) NSCLC, for whom crizotinib is
being considered. Potential adverse effects of the Vysis ALK Break
Apart FISH Probe Kit include failure of the device to perform as
intended or indicated, failure to correctly interpret test results,
and/or false positive test results or false negative test results that
could lead to improper patient management decisions regarding cancer
treatment. Conclusions drawn from non-clinical and clinical studies
indicated overall acceptable performance including accuracy and
reproducibility demonstrating that the device is reasonably safe and
effective for its intended use. Further, the potential adverse effects
of the device are also based on data collected in the clinical study
conducted to support the PMA approval. As a diagnostic test, the Vysis
ALK Break Apart FISH Probe Kit involved testing on FFPE human NSCLC
cancer tissue sections for which these tissue sections are routinely
removed for NSCLC cancer diagnosis. Therefore, no additional safety
hazard was reported for the patients being tested.
In addition to PMA data from the 6 available PMAs and 1 PMA panel-
track supplement, FDA considered that ISH is a well-established
technology and it has been commonly used in both research and clinical
settings for decades and at this time its general principles are well
understood and widely published in the literature. Over the past five
decades, there have been significant scientific developments aimed at
addressing certain ISH limitations and expanding the applications of
the technology, such as the emergence of non-radioactive labeled probes
and FISH technique. These developments further demonstrate the maturity
of this technology (Refs. 11-14). FDA considered the breadth of
knowledge available regarding ISH as an established technology in
proposing to reclassify oncology therapeutic ISH-based test systems
from class III into class II. This includes, for example, the
establishment of special controls that FDA believes can effectively
mitigate those identified risks to health (discussed in section V) and
can ensure a reasonable assurance of the safety and effectiveness for
these devices.
Finally, a search of FDA's publicly available MAUDE database
revealed 14 reported events for oncology therapeutic ISH-based test
systems under the product codes NYQ, OWE, and MVD. There have been no
MDRs reported under product code PNK. A search of FDA's publicly
available recall database revealed no entries for devices under the
MVD, OWE, and PNK product codes. Notably, only 1 MDR reportedly caused
or led to patient harm. There have been three class II recalls
involving oncology therapeutic ISH-based test systems under the NYQ
product code; 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 generally good safety record for
these device types (see further discussion of the MDR and recall data
in section II of this proposed order).
Based on the Agency's 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 these devices, and that sufficient
information exists to establish such special controls. Therefore, FDA,
on its own initiative, is proposing to reclassify oncology therapeutic
ISH-based test systems from class III (premarket approval) into class
II (special controls) subject to premarket notification (510(k))
requirements.
VII. Proposed 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 oncology
therapeutic ISH-based test systems.
Risks of false negative test results or false positive test
results, failure of the test system to perform as intended or
indicated, and failure to correctly interpret test results (caused by,
for example, failure of the probes, instruments or software, to perform
as expected or failure of the intended user to correctly perform the
test) can be mitigated by special controls, including certain design
verification and validation activities (for example, documentation of
such activities), as well as certain labeling requirements. Examples of
verification and validation information to be included in the design of
the devices includes, for example, documentation of clinical data
demonstrating acceptable performance of the device for its intended use
based on data generated using a dataset representative of the intended
use
[[Page 24547]]
population. Non-clinical performance testing must include specification
of the criteria for test result interpretation and reporting and
supporting validation of the device's cut-off(s) or clinical decision
threshold(s). In addition, device design verification and validation
information must include the specifications for risk mitigation
elements intended to mitigate risks associated with testing and results
interpretation, including controls, procedures, and user training
requirements.
Risks of false negative test results and false positive test
results and failure to correctly interpret test results can be further
mitigated by special controls that require specific information in the
labeling for these test systems. For example, specific required
limiting statement(s) can aid in mitigating the risk of incorrect
interpretation/reading of the stained slides leading to false test
results. The risk of failure of the test system to perform as intended
or indicated can be mitigated by labeling special controls that require
an appropriate, as determined by FDA, summary of the performance
studies performed and the results of those studies, thus informing the
user of the expected performance of the device. Table 1 shows how FDA
believes such risks to health described in section V would be mitigated
by the proposed special controls.
Table 1--Risks to Health and Mitigation Measures for Oncology
Therapeutic ISH-Based Test Systems
------------------------------------------------------------------------
Identified risks to health Mitigation measures
------------------------------------------------------------------------
False negative test results or Certain design verification and
false positive test results. validation activities, including
certain analytical validation and
clinical validation data.
Certain labeling information,
including certain limiting
statement(s) and certain
performance information.
Failure of the test system to Certain design verification and
perform as intended or indicated. validation activities, including
certain analytical validation and
clinical validation data.
Certain labeling information,
including certain limiting
statement(s), and certain
performance information.
Failure to correctly interpret Certain design verification and
test results. validation activities, including
certain analytical validation and
clinical validation data.
Certain labeling information,
including certain limiting
statement(s), and certain
performance information.
------------------------------------------------------------------------
If this proposed order is finalized, oncology therapeutic ISH-based
test systems will be identified as prescription IVD devices. Therefore,
these devices would continue to 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, oncology therapeutic ISH-based
test systems will be reclassified into class II (general controls and
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 the new classification regulation 21 CFR 864.1890. Firms will be
required to comply with the particular mitigation measures set forth in
the special controls in their premarket notification submissions and
upon clearance of their devices. Adherence to the special controls, in
addition to the general controls, is necessary to provide a reasonable
assurance of safety and effectiveness of oncology therapeutic ISH-based
test systems.
VIII. Analysis of Environmental Impact
We have determined under 21 CFR 25.34(b) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
IX. Paperwork Reduction Act of 1995
While this proposed order contains no new collections of
information, it does refer to previously approved FDA collections of
information. The previously approved 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 System
Regulation) have been approved under OMB control number 0910-0073; the
collections of information in part 807, subpart E (Premarket
Notification Procedures), have been approved under OMB control number
0910-0120; and the collections of information in 21 CFR parts 801 and
809 (Device Labeling) have been approved under OMB control number 0910-
0485.
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 In Situ Hybridization Test
Systems for Use with a Corresponding Approved Oncology Therapeutic
Product in the new 21 CFR 864.1890, under which these oncology
therapeutic ISH-based test systems 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. In Vitro Companion Diagnostic Devices--Guidance for Industry
and Food and Drug Administration Staff, issued August
[[Page 24548]]
6, 2014 (available at <a href="https://www.fda.gov/media/81309/download">https://www.fda.gov/media/81309/download</a>).
* 2. P980024/S001 Summary of Safety and Effectiveness, 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>?id=P980024.
* 3. ``Guidance for Industry and for FDA Reviewers: Guidance on
Section 216 of the Food and Drug Administration Modernization Act of
1997,'' issued on August 9, 2000 (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>).
* 4. P040005 Summary of Safety and Effectiveness, available at:
<a href="https://www.accessdata.fda.gov/cdrh_docs/pdf4/P040005B.pdf">https://www.accessdata.fda.gov/cdrh_docs/pdf4/P040005B.pdf</a>.
* 5. P050040 Summary of Safety and Effectiveness, available at:
<a href="https://www.accessdata.fda.gov/cdrh_docs/pdf5/P050040B.pdf">https://www.accessdata.fda.gov/cdrh_docs/pdf5/P050040B.pdf</a>.
* 6. P100024 Summary of Safety and Effectiveness, available at:
<a href="https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100024B.pdf">https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100024B.pdf</a>.
* 7. P100027 Summary of Safety and Effectiveness, available at:
<a href="https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100027B.pdf">https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100027B.pdf</a>.
* 8. P110012 Summary of Safety and Effectiveness, available at:
<a href="https://www.accessdata.fda.gov/cdrh_docs/pdf11/P110012B.pdf">https://www.accessdata.fda.gov/cdrh_docs/pdf11/P110012B.pdf</a>.
* 9. P150041 Summary of Safety and Effectiveness, available at:
<a href="https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150041B.pdf">https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150041B.pdf</a>.
10. Curtin, SC, Tejada-Vera, B, Bastian, Deaths: Leading Causes for
2021. National Center for Health Statistics. Vital Health Stat
73(4). 2024.
11. Chu YH, Hardin H, Zhang R, Guo Z, Lloyd RV. In situ
hybridization: Introduction to techniques, applications and pitfalls
in the performance and interpretation of assays. Semin Diagn Pathol.
2019;36(5):336-341. doi:10.1053/j.semdp.2019.06.004.
12. du Sart, D., Andy Choo, K.H. (1998). The Technique of In Situ
Hybridization. In: Rapley, R., Walker, J.M. (eds) Molecular
Biomethods Handbook. Springer Protocols Handbooks. Humana Press.
doi:10.1007/978-1-59259-642-3_51.
13. Manning JE, Hershey ND, Broker TR, Pellegrini M, Mitchell HK,
Davidson N. A new method of in situ hybridization. Chromosoma.
1975;53(2):107-117. doi:10.1007/BF00333039.
14. Bauman JG, Wiegant J, Borst P, van Duijn P. A new method for
fluorescence microscopical localization of specific DNA sequences by
in situ hybridization of fluorochromelabelled RNA. Exp Cell Res.
1980;128(2):485-490. doi:10.1016/0014-4827(80)90087-7.
List of Subjects in 21 CFR Part 864
Blood, Medical devices, Packaging and containers.
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 864 be 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 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 provided.
(iii) Device performance data demonstrating appropriate analytical
sensitivity provided 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). 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 provided 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 reagent
stability for real-time and in-use stability; post-hybridization signal
stability; and photostability of probe, as applicable.
(ix) Device performance data demonstrating appropriate specimen
stability based on the intended use specimen type(s) of the device, as
applicable.
(x) 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
[[Page 24549]]
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.
Dated: June 5, 2025.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-10549 Filed 6-10-25; 8:45 am]
BILLING CODE 4164-01-P
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