Proposed Rule2025-21071
Immunology and Microbiology Devices; Reclassification of Nucleic Acid-Based Test Systems for Use With a Corresponding Approved Oncology Therapeutic Product; Proposed Amendment; Proposed Order; Request for Comments
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Published
November 25, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA) is proposing to reclassify certain postamendments class III nucleic acid-based test systems indicated for use with a corresponding approved oncology therapeutic product (product codes OWD, PJG, PQP, and SFL) 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 these devices.
Full Text
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<title>Federal Register, Volume 90 Issue 225 (Tuesday, November 25, 2025)</title>
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[Federal Register Volume 90, Number 225 (Tuesday, November 25, 2025)]
[Proposed Rules]
[Pages 53261-53274]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-21071]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2025-N-4622]
Immunology and Microbiology Devices; Reclassification of Nucleic
Acid-Based Test Systems for Use With a Corresponding Approved Oncology
Therapeutic Product; Proposed Amendment; Proposed Order; Request for
Comments
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 certain postamendments class III nucleic acid-based test
systems indicated for use with a corresponding approved oncology
therapeutic product (product codes OWD, PJG, PQP, and SFL) 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 these devices.
DATES: Submit electronic or written comments on the proposed order by
January 26, 2026. 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.
[[Page 53262]]
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
midnight 11:59 p.m. Eastern Time at the end of January 26, 2026.
Comments received by mail/hand delivery/courier (for written/paper
submissions) will be considered timely if they are received on or
before that date.
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-4622 for ``Immunology and Microbiology Devices;
Reclassification of Nucleic Acid-Based Test Systems for Use with a
Corresponding Approved Oncology Therapeutic Product; Proposed
Amendment; Proposed Order; Request for Comments.'' 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#b5e6dad8d49bf2dddac6ddf5d3d1d49bddddc69bd2dac3"><span class="__cf_email__" data-cfemail="90c3fffdf1bed7f8ffe3f8d0f6f4f1bef8f8e3bef7ffe6">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background--Regulatory Authorities
The Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended,
establishes a comprehensive system for the regulation of medical
devices intended for human use. Section 513 of the FD&C Act (21 U.S.C.
360c) establishes three classes of devices reflecting the regulatory
controls needed to provide reasonable assurance of their safety and
effectiveness. The three classes of devices are class I (general
controls), class II (special controls), and class III (premarket
approval).
Section 513(a)(1) of the FD&C Act defines the three classes of
devices. Class I devices are those devices for which the general
controls of the FD&C Act (controls authorized by or under section 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). General controls include, but are not
limited to, provisions that relate to establishment registration and
device listing; premarket notification; prohibitions against
adulteration and misbranding (e.g., labeling that fails to bear
adequate directions for use); recordkeeping and reporting, including
adverse event reporting and reporting of corrections and removals
initiated to reduce a risk to health posed by the device or to remedy a
violation of the FD&C Act caused by the device which may present a risk
to health; and current good manufacturing practice (CGMP) requirements.
These controls apply to all devices unless an exemption applies.
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,
[[Page 53263]]
recommendations, and other appropriate actions FDA 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. 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 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
nucleic acid-based test systems indicated for use with a corresponding
approved oncology therapeutic product (product codes OWD, PJG, PQP, and
SFL),\3\ hereafter collectively referred to as oncology therapeutic
nucleic acid-based test systems, into class II (special controls)
subject to premarket notification under a new device classification
regulation with the name ``Nucleic Acid-Based Test Systems 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 ensure consistent regulation of
medical devices. A product code consists of three characters that
are assigned at the time a product code is generated and is unique
to a product type. The three characters carry no other significance
and are not an abbreviation.
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The identification in the proposed classification regulation
characterizes oncology therapeutic nucleic acid-based test systems as
prescription in vitro diagnostic (IVD) devices intended for the
detection of specific genetic variant(s) and/or other nucleic acid
biomarkers in human clinical specimens using nucleic acid amplification
technology (NAAT) and/or sequencing technology, and are indicated for
use with a corresponding approved oncology therapeutic product. These
test systems include companion diagnostic (CDx) test systems, 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 approved therapeutic product
(Ref. 1). These test systems also include those test systems that
provide information about known benefits and/or risks of an approved
therapeutic product, where the use of the test system is referenced in
the product labeling of the corresponding approved therapeutic product
but the test system is not essential for the safe and effective use of
the approved therapeutic product.
As discussed further throughout this proposed order, FDA has issued
PMAs for various oncology therapeutic nucleic acid-based test systems
designated under product codes OWD, PJG, PQP, or SFL. The oncology
therapeutic nucleic acid-based test systems within the different
product codes have distinct characteristics in certain respects, for
example, each product code generally represents devices with a distinct
technology used (e.g., NAAT and/or sequencing technology) and/or
specific analyte(s) detected by the test system. FDA has considered the
distinctions of these test systems across the four product codes and
has determined that these test systems, including those devices that
provide information that is essential for the safe and effective use of
a corresponding approved oncology therapeutic product, as well as test
systems that, while not essential to the safe and effective use of the
corresponding approved oncology therapeutic product, provide
information about known benefits and/or risks related to the use of the
approved oncology therapeutic product, have the same or a similar risk
profile and sufficiently similar purposes, design considerations,
functions, and other features related to safety and effectiveness such
that the same or similar regulatory controls are necessary and
sufficient to provide reasonable assurance of safety and
effectiveness.\4\ For these reasons and considering that FDA did not
identify any unique risks associated with the distinctions across
[[Page 53264]]
these devices, FDA is proposing a single classification regulation to
classify all oncology therapeutic nucleic acid-based test systems into
class II. There would generally not be changes to the product codes
(i.e., OWD, PJG, PQP, and SFL) for previously approved oncology
therapeutic nucleic acid-based test systems, and future oncology
therapeutic nucleic acid-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 apply to both
current and new devices that are oncology therapeutic nucleic acid-
based test systems.
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\4\ For example, a specific device could be indicated for and
approved to provide information that is essential for the safe and
effective use of a corresponding approved oncology therapeutic
product and to provide information about known benefits and/or risks
related to the use of a corresponding approved oncology therapeutic
product that is not essential to the safe and effective use of a
corresponding approved oncology therapeutic product. The distinction
is determined by the data from the clinical development program of
the corresponding therapeutic product and how the therapeutic
product is labeled (i.e., whether the use of the IVD device is
essential for the safe and effective use of the therapeutic product
or not essential for the safe and effective use of the therapeutic
product but provides information about known benefits and/or risks
related to the use of the therapeutic product). The devices have
sufficiently similar purposes, design considerations, functions, and
other features related to safety and effectiveness such that the
same or similar regulatory controls are necessary and sufficient to
provide reasonable assurance of safety and effectiveness and the
devices can be part of the same device type.
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Based upon the extensive PMA data available to FDA in accordance
with section 520(h)(4) of the FD&C Act,<SUP>5 6</SUP> published peer-
reviewed literature studying the longstanding and well-understood
technologies, and data available to the Agency demonstrating a lack of
significant postmarket safety signals with oncology therapeutic nucleic
acid-based test systems, 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.\7\ Therefore, FDA is proposing to establish a new device
classification regulation, ``Nucleic Acid-Based 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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\5\ In proposing to reclassify oncology therapeutic nucleic
acid-based test systems from class III to class II, FDA, on its own
initiative, is relying on data from relevant PMAs and a relevant PMA
panel-track supplement (under product codes OWD, PJG and PQP)
available to FDA in accordance with the six-year rule (see section
520(h)(4) of the FD&C Act (21 U.S.C. 360j(h)(4)) (see also, FDA,
``Guidance on Section 216 of the Food and Drug Administration
Modernization Act of 1997--Guidance for Industry and for FDA
Reviewers,'' 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>). This data was from relevant PMAs and a
PMA panel-track supplement approved after November 28, 1990 and
before January 27, 2019 for devices that would fall under 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>.
\6\ 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.
\7\ 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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Under the FD&C Act, premarket notification (510(k)) submissions are
required to provide a reasonable assurance of the safety and
effectiveness of class II devices unless FDA determines that the device
type should be exempt from 510(k) requirements under section 510(m) of
the FD&C Act.\8\ FDA has not made this determination for oncology
therapeutic nucleic acid-based test systems and, therefore, FDA is not
proposing for this class II device type to be exempt from 510(k)
requirements.
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\8\ 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 866.9.
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If this proposed order is finalized, persons who intend to market
this type of device must submit to FDA a premarket notification under
section 510(k) of the FD&C Act prior to marketing the device.
II. Regulatory History of the Devices
In accordance with section 513(f)(1) of the FD&C Act, oncology
therapeutic nucleic acid-based test systems are automatically
classified into class III because they were not introduced or delivered
for introduction into interstate commerce for commercial distribution
before May 28, 1976, have not been reclassified into class I or II, and
have not been found substantially equivalent to a device placed in
commercial distribution after May 28, 1976, which was subsequently
classified or reclassified into class 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 August 17, 2011, FDA approved an original PMA for the first
oncology therapeutic nucleic acid-based test system, the cobas 4800
BRAF V600 Mutation Test (P110020) (product code OWD), a real-time
polymerase chain reaction (PCR) IVD device intended for the qualitative
detection of the BRAF V600E mutation in DNA extracted from human
melanoma tissue and intended to be used as an aid in selecting melanoma
patients for treatment with vemurafenib (Ref. 2). In a January 13,
2012, Federal Register notice (77 FR 2071), FDA announced the approval
order and availability of the Summary of Safety and Effectiveness Data
(SSED) for the device.
Subsequently, on December 19, 2014, FDA approved an original PMA
for the BRACAnalysis CDx under product code PJG (P140020). The
BRACAnalysis CDx is an oncology therapeutic nucleic acid-based test
intended for the qualitative detection and classification of variants
in the protein coding regions and intron/exon boundaries of the BRCA1
and BRCA2 genes using genomic DNA obtained from whole blood specimens.
Single nucleotide variants and small insertions and deletions (indels)
are identified by PCR and Sanger sequencing. Large deletions and
duplications in BRCA1 and BRCA2 are detected using multiplex PCR.
Results of the test are intended to be used as an aid in identifying
ovarian cancer patients eligible for treatment with Lynparza (olaparib)
(Ref. 3). In an April 22, 2015, Federal Register notice (80 FR 22527),
FDA announced the approval order and availability of the SSED for the
device.
FDA subsequently approved an original PMA for FoundationFocus
CDxBRCA Assay under the product code PQP on December 19, 2016
(P160018). FoundationFocus CDxBRCA Assay is an oncology therapeutic
nucleic acid-based test system using next generation sequencing (NGS)
technology, intended for the qualitative detection of BRCA1 and BRCA2
alterations in formalin-fixed paraffin-embedded (FFPE) ovarian tumor
tissues, with results of the test intended to be used as an aid in
identifying ovarian cancer patients for whom treatment with Rubraca
(rucaparib) is being considered (Ref. 4). In a September 25, 2017
Federal Register notice (82 FR 44626), FDA announced the approval order
and availability of the SSED for the FoundationFocus CDxBRCA Assay. FDA
subsequently approved a panel-track supplement \9\ (P160018/S001), on
April
[[Page 53265]]
6, 2018, expanding the indications for use of this test to include the
qualitative detection of genomic loss of heterozygosity (LOH) from FFPE
ovarian tumor tissue for which positive homologous recombination
deficiency (HRD) status (defined as tBRCA-positive or LOH high) in
ovarian cancer patients is associated with improved progression-free
survival (PFS) from Rubraca (rucaparib) maintenance therapy (Ref.
5).\10\ This new indication for use, while not essential to the safe
and effective use of the corresponding approved oncology therapeutic
product, is to provide information about known benefits related to the
use of the approved oncology therapeutic product. With the approval of
P160018/S001, FDA has thus far approved four oncology therapeutic
nucleic acid-based test systems that provide information about known
benefits and/or risks of an approved oncology therapeutic product,
where the use of the test system is referenced in the product labeling
of the corresponding approved therapeutic product but the test system
is not considered to be essential for the safe and effective use of the
approved therapeutic product.
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\9\ 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.''
\10\ The original device was approved under the trade name
FoundationFocus CDxBRCA Assay (P160018). The sponsor originally
submitted the panel-track PMA supplement application (P160018/S001)
for the same test with an expanded indication for use under the
trade name FoundationFocus CDxBRCA <INF>HRD</INF>. However, through
the review process, the sponsor decided to change the name to
FoundationFocus CDxBRCA <INF>LOH</INF>. Consistent with the
authorized device trade name for P160018/S001, the name used
throughout this reclassification proposed order is FoundationFocus
CDxBRCA <INF>LOH</INF>.
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Finally, on August 15, 2025, FDA approved an original PMA for the
Idylla CDx MSI Test under product code SFL (P250005). The Idylla CDx
MSI Test is an oncology therapeutic nucleic acid-based test intended
for the qualitative detection of a panel of seven monomorphic
biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A and SULF2) for
identification of microsatellite instability (MSI) in colorectal cancer
(CRC) tissue. The Idylla CDx MSI Test uses FFPE tissue sections from
patients with CRC, from which nucleic acids are extracted and then
analyzed using PCR amplification and subsequent melt-curve
analysis.\11\ The Idylla CDx MSI Test reports MSI status as either
Microsatellite Stable (MSS), Microsatellite Instability-High (MSI-H),
or invalid. The test is intended as a companion diagnostic to identify
CRC patients with MSI-H status, who may benefit from treatment with
OPDIVO (nivolumab) as a monotherapy and/or treatment with OPDIVO
(nivolumab) in combination with YERVOY (ipilimumab).\12\
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\11\ As noted above, FDA has determined that the tests assigned
to product codes OWD, PJG, PQP, and SFL all utilize NAAT and/or
sequencing-based technology for use with a corresponding approved
oncology therapeutic product, and have sufficiently similar
purposes, design considerations, functions, and other features
related to safety and effectiveness such that all oncology
therapeutic nucleic acid-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 tests.
\12\ As of the date of issuance of this proposed order, fewer
than 6 years have transpired since FDA's approval of the Idylla CDx
MSI Test (PMA P250005). Therefore, no information from this document
has been used in support of this proposed order to reclassify
oncology therapeutic nucleic acid-based test systems into class II
(see section 520(h)(4) of the FD&C Act (21 U.S.C. 360j(h)(4))).
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Since the first approval order for an oncology therapeutic nucleic
acid-based test system, FDA has reviewed and approved an additional 18,
2, 13, and 1 original PMAs under the product codes OWD, PJG, PQP, and
SFL, respectively, and approximately 200, 29, 174, and 0 PMA
supplements, respectively, for therapeutic nucleic acid-based test
systems under product codes OWD, PJG, PQP, and SFL.\13\
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\13\ FDA has determined that the tests assigned to product codes
OWD, PJG, PQP, and SFL all utilize NAAT and/or sequencing-based
technology for use with a corresponding approved oncology
therapeutic product, and have sufficiently similar purposes, design
considerations, functions, and other features related to safety and
effectiveness such that all oncology therapeutic nucleic acid-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 tests.
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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. 6), FDA
considered data contained in the following 17 original PMAs and one
panel-track supplement to an original PMA, representing oncology
therapeutic nucleic acid-based test systems from three of the four
product codes (i.e., OWD, PJG, and PQP) for oncology therapeutic
nucleic acid-based test systems: cobas 4800 BRAF V600 Mutation Test
(P110020) (product code OWD) (Ref. 2), therascreen KRAS RGQ PCR Kit
(P110027) (product code OWD) (Ref. 7), therascreen KRAS RGQ PCR Kit
(P110030) (product code OWD) (Ref. 8), THxID BRAF Kit (P120014)
(product code OWD) (Ref. 9), cobas EGFR Mutation Test (P120019)
(product code OWD) (Ref. 10), therascreen EGFR RGQ PCR Kit (P120022)
(product code OWD) (Ref. 11), BRACAnalysis CDx (P140020) (product code
PJG) (Ref. 3), cobas KRAS Mutation Test (P140023) (product code OWD)
(Ref. 12), cobas EGFR Mutation Test v2 (P150044) (product code OWD)
(Ref. 13), cobas EGFR Mutation Test v2 (P150047) (product code OWD)
(Ref. 14), FoundationFocus CDxBRCA Assay (P160018) (product code PQP)
(Ref. 4), FoundationFocus CDxBRCA <INF>LOH</INF> (P160018/S001)
(product code PQP) (Ref. 5), Praxis Extended RAS Panel (P160038)
(product code PQP) (Ref. 15), LeukoStrat CDx FLT3 Mutation Assay
(P160040) (product code OWD) (Ref. 16), Oncomine Dx Target Test
(P160045) (product code PQP) (Ref. 17), Abbott RealTime IDH2 (P170005)
(product code OWD) (Ref. 18), FoundationOne CDx (P170019) (product code
PQP) (Ref. 19), and Abbott RealTime IDH1 (P170041) (product code OWD)
(Ref. 20). No information from PMAs and PMA supplements for which fewer
than six years have passed since FDA's approval has been used in
support of this proposed order to reclassify oncology therapeutic
nucleic acid-based test systems into class II (see section 520(h)(4) of
the FD&C Act (21 U.S.C. 360j(h)(4))).\14\
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\14\ 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.
---------------------------------------------------------------------------
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 September 8, 2025 there
have been 147 reported events for oncology therapeutic nucleic acid-
based test systems under product codes OWD (N= 139 MDRs), PJG (N= 1
MDR), PQP (N= 7 MDRs), and SFL (N= 0 MDR) since the approval of the
first oncology therapeutic nucleic acid-based test system in 2011.
After review of the data, the Agency has determined that false
positive results account for the device problem associated with a
significant number (over 80 percent) of the MDR reported events. Other
device problems that were less frequently reported include, for
example, incorrect, inadequate or imprecise result or readings, non-
reproducible results, output problem, and false negative results.
Notably, a significant majority (over 95 percent) of the MDRs reported
under these product codes listed identified no clinical signs,
symptoms, or conditions; no known impact or consequence to the patient;
and/or no patient involvement. Other less frequently reported health
impacts, include, for example, inadequate/
[[Page 53266]]
inappropriate treatment or diagnostic exposure; minor injury/illness/
impairment; and delay to treatment/therapy.
A search of these product codes in FDA's Medical Device Recalls
database indicates that as of September 8, 2025, there have been four
class III recalls, 23 class II recalls,\15\ and no class I recalls \16\
involving oncology therapeutic nucleic acid-based test systems. Of the
23 class II recalls, 12 occurred between 2014 and 2022, have since been
terminated, and were determined to be due to non-specific molecular
interactions or fluorescence artifacts, nonconforming material/
component, and a process control issue, all of which led to or could
lead to false positive test results. There is 1 class II recall that
was terminated on July 19, 2021, for which the manufacturer's reason
for the recall was potential false positive test results, but the root
cause is still under investigation by the firm. Other reasons for the
class II recalls include erroneous translation of the approved English
labeling to Hungarian, an incorrect or lack of expiration date, and
erroneous test results caused by off-label use or a manufacturing or
design issue of the device.
---------------------------------------------------------------------------
\15\ The database searches initially identified 13 class II
recalls reported under the product code OWD. However, after manual
review of the data it has been determined that there is one recall
that was improperly coded under the product code OWG although the
product listed should fall within the product code OWD. As such, for
the purpose of this proposed order the data related to this recall
has been included in the Agency's postmarket surveillance analysis
and discussion surrounding recall data.
\16\ Class I, II, and III recalls are defined in 21 CFR 7.3(m).
---------------------------------------------------------------------------
Of the four class III recalls, three occurred between 2012 and
2015, have since been terminated, and were determined to be due to a
device design issue leading to the device generating invalid results
and a mix up of materials/components (i.e., incorrect packaging of
internal-use only components and released for distribution). The
remaining class III recall was terminated on December 11, 2017, for
which the manufacturer's reason for the recall was the device
generating false positive results, however, the root cause is still
under investigation by the firm.
This postmarket data, coupled with the relatively low number of
reported events that caused patient harm, indicate a generally good
safety record for these device types. The MDR and recall events provide
information on the risks to health (identified in section V of this
proposed order), which FDA believes can be effectively mitigated
through general controls and the special controls proposed herein.
In response to FDA's announcement that the Agency intended to
initiate the reclassification process for certain IVDs including
companion diagnostic tests (Ref. 21), FDA received a petition on July
25, 2024 from Foundation Medicine Inc., (Docket No. FDA-2024-P-3484)
requesting FDA to reclassify next-generation sequencing oncology panel
devices used for somatic or germline variant detection that include one
or more companion diagnostic indications (under product code PQP) from
class III to class II. As discussed in this proposed order, FDA has
considered the information available to the Agency and believes that
there is sufficient information available to establish special
controls, and that the special controls proposed in section VII,
together with general controls, would provide a reasonable assurance of
the safety and effectiveness of such devices under the PQP product
code, as well as other similar devices under product codes OWD, PJG and
SFL, and is proposing, on its own initiative, that oncology therapeutic
nucleic acid-based test systems, including those under product code
PQP, be reclassified from class III to class II.
III. Device Description
Oncology therapeutic nucleic acid-based test systems are
postamendments devices classified into class III under section
513(f)(1) of the FD&C Act. These oncology therapeutic nucleic acid-
based test systems are prescription IVDs intended for the detection of
specific genetic variant(s) and/or other nucleic acid biomarkers in
human clinical specimens using NAAT (e.g., PCR) and/or sequencing
technology (e.g., NGS), and are indicated for use with a corresponding
approved oncology therapeutic product. These oncology therapeutic
nucleic acid-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 approved therapeutic product.\17\ 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 approved therapeutic product, including the
labeling of any generic equivalents of the therapeutic product.\18\ An
IVD CDx device could be essential for the safe and effective use of a
corresponding approved therapeutic product to:
---------------------------------------------------------------------------
\17\ 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/regulatory-information/search-fda-guidance-documents/in-vitro-companion-diagnostic-devices">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/in-vitro-companion-diagnostic-devices</a>.
\18\ 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 of a CDx device IVD devices
that are not essential to the safe and effective use of a therapeutic
product.\19\ 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).
---------------------------------------------------------------------------
\19\ Id.
---------------------------------------------------------------------------
Additionally, the oncology therapeutic nucleic acid-based test
systems in this proposed order include IVD test systems that provide
information about known benefits and/or risks of patient populations
related to the use of a corresponding approved therapeutic product and
are referenced in the labeling for the corresponding approved
therapeutic product but are not essential for the safe and effective
use of the therapeutic product. For example, such devices can be used
to assess a biomarker-defined population of patients and provide
information regarding the overall survival (OS) rate or objective
response rate for those patients compared to the broader population of
patients for whom the corresponding therapy is indicated. The use of
these devices is not a prerequisite for receiving treatment with the
corresponding therapeutic product but can aid in the benefit-risk
assessment as to the use of the corresponding therapy for those
biomarker-defined patients.
FDA proposes to revise 21 CFR part 866 to create a new device
classification regulation with the name ``Nucleic Acid-Based Test
Systems for Use with a Corresponding Approved Oncology Therapeutic
Product.'' Nucleic acid-based test systems indicated for use with a
corresponding approved
[[Page 53267]]
oncology therapeutic product are identified as prescription IVD devices
intended for the detection of specific genetic variant(s) and/or other
nucleic acid biomarkers in human clinical specimens using NAAT and/or
sequencing technology to provide information related to the use of a
corresponding approved oncology therapeutic product. These test systems
provide information that is essential for the safe and effective use of
a corresponding approved oncology therapeutic product and/or are test
systems that, while not essential to the safe and effective use of the
corresponding approved oncology therapeutic product, provide
information about known benefits and/or risks related to the use of the
corresponding approved oncology therapeutic product.
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 nucleic acid-based test systems from class III into class
II, subject to 510(k) requirements. FDA believes that there is
sufficient information available 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 therapeutic nucleic acid-based test systems.
Under this proposed order, if finalized, oncology therapeutic
nucleic acid-based test systems will be identified as prescription IVD
devices. If the proposed order is finalized, these devices will be
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 nucleic acid-based test systems, FDA has not made
this determination and, therefore, the Agency is not proposing to
exempt these proposed class II devices from 510(k) requirements.\20\ If
this proposed order is finalized, persons who intend to market an
oncology therapeutic nucleic acid-based test system will need to submit
a 510(k) to FDA and receive clearance prior to marketing the device.
---------------------------------------------------------------------------
\20\ 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 pathway. 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 \21\ while continuing to provide a
reasonable assurance of device safety and effectiveness.\22\ 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.\23\
---------------------------------------------------------------------------
\21\ 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).
\22\ 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.
\23\ Sections 513 and 515 of the FD&C Act. See also, FDA, ``The
Least Burdensome Provisions: Concept and Principles--Guidance for
Industry and FDA Staff,'' February 5, 2019. Available at <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/least-burdensome-provisions-concept-and-principles">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/least-burdensome-provisions-concept-and-principles</a>.
---------------------------------------------------------------------------
FDA believes that there is sufficient information available to FDA
through the 17 original PMAs and 1 panel-track supplement for cobas
4800 BRAF V600 Mutation Test (P110020; product code OWD), therascreen
KRAS RGQ PCR Kit (P110027; product code OWD), therascreen KRAS RGQ PCR
Kit (P110030; product code OWD), THxID BRAF Kit (P120014; product code
OWD), cobas EGFR Mutation Test (P120019; product code OWD), therascreen
EGFR RGQ PCR Kit (P120022; product code OWD), BRACAnalysis CDx
(P140020; product code PJG), cobas KRAS Mutation Test (P140023; product
code OWD), cobas EGFR Mutation Test v2 (P150044; product code OWD),
cobas EGFR Mutation Test v2 (P150047; product code OWD),
FoundationFocus CDxBRCA Assay (P160018; product code PQP),
FoundationFocus CDxBRCA <INF>LOH</INF> (P160018/S001; product code
PQP), Praxis Extended RAS Panel (P160038; product code PQP), LeukoStrat
CDx FLT3 Mutation Assay (P160040; product code OWD), Oncomine Dx Target
Test (P160045; product code PQP), Abbott RealTime IDH2 (P170005;
product code OWD), FoundationOne CDx (P170019; product code PQP), and
Abbott RealTime IDH1 (P170041; product code OWD) \24\ (Refs. 2-5, and
7-20), published peer-reviewed literature on nucleic acid-based
detection methods, including NAAT and sequencing technologies, 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 nucleic acid-based
test systems. The Agency has considered the risks to health identified
by these sources and used certain information from these sources in
developing proposed special controls that include mitigation measures
for each of the risks to health identified in section V. Accordingly,
there would continue to be a reasonable assurance of safety and
effectiveness for the devices upon their reclassification from class
III to class II when there is conformity with general and special
controls. Absent the special controls identified in this proposed
order, general controls applicable to these devices are insufficient to
provide
[[Page 53268]]
reasonable assurance of the safety and effectiveness of oncology
therapeutic nucleic acid-based test systems.
---------------------------------------------------------------------------
\24\ 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 nucleic acid-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 17 PMAs and 1 panel-track supplement
available to FDA under section 520(h)(4) of the FD&C Act, published
peer-reviewed literature on nucleic acid-based detection methods,
including NAAT and sequencing technologies, and postmarket information
regarding oncology therapeutic nucleic acid-based test systems.
Cancer continues to be one of the two leading causes of death in
the United States (Ref. 22). Biomarker tests for molecularly targeted
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 nucleic acid-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 and/or provide information about known benefits
and/or risks related to the use of a corresponding approved therapeutic
product that is not essential for its safe and effective use. For
example, health care providers may use a relevant oncology therapeutic
nucleic acid-based test system to identify specific patients who are
eligible for the safe and effective use of a corresponding oncology
therapeutic product, including those patients for which the drug is
contraindicated, or 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 such 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 nucleic acid-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 patients. For those test systems intended to provide information
that is essential for the safe and effective use of a corresponding
approved oncology therapeutic product, this risk 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). For those test systems that provide
information about known benefits and/or risks related to the use of a
corresponding approved oncology therapeutic product but are not
essential for the safe and effective use of the corresponding approved
oncology therapeutic product, this risk may negatively influence
patient management based on a misinformed benefit-risk assessment
related to the use of a corresponding oncology therapeutic product and
could lead to many of the same negative patient outcomes associated
with test systems intended to provide information that is essential for
the safe and effective use of a corresponding approved oncology
therapeutic product as previously described.
<bullet> Failure of the test system to perform as intended or
indicated. For test systems intended to provide information that is
essential for the safe and effective use of a corresponding approved
oncology therapeutic product, failure of the test system to perform as
intended or indicated may result in inappropriate 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 approved oncology therapeutic
product. Similarly, for those test systems that provide information
about known benefits and/or risks related to the use of a corresponding
approved oncology therapeutic product but are not essential for the
safe and effective use of the corresponding approved oncology
therapeutic product, this risk may result in the potential need to
rerun the test, leading to a delay in treatment or inappropriate
treatment for a patient based on delayed results that would provide
important benefit-risk information for a health care provider to aid in
the clinical decision making related to the use of a corresponding
oncology therapeutic product.
<bullet> Failure to correctly interpret test results. Failure to
correctly interpret test results, such as incorrect interpretation of
the biomarker classification or information provided regarding the
therapeutic product, may result in the same negative outcomes
associated with false negative or false positive test results as
previously discussed. For example, for test systems intended to provide
information that is essential for the safe and effective use of a
corresponding approved oncology therapeutic product, incorrectly
interpreting the test results as positive (i.e., false positive test
results) may lead to a patient receiving ineffective or unnecessary
treatment that may unnecessarily expose them to treatment toxicities.
Similarly, for those test systems that provide information about known
benefits and/or risks related to the use of a corresponding approved
oncology therapeutic product but are not essential for the safe and
effective use of the corresponding approved oncology therapeutic
product this risk may, for example, lead to inappropriate patient
management decisions made by a health care provider, such as, selecting
a suboptimal treatment for a patient, and failure for the patient to
realize benefit from a different therapy based on inaccurate benefit-
risk information related to the use of a corresponding oncology
therapeutic product.
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 nucleic acid-based test system in 2011. FDA believes that
oncology therapeutic nucleic acid-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 are necessary, in addition
to general controls, to 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
[[Page 53269]]
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 nucleic
acid-based test systems can provide significant benefits to health care
providers and patients.
In proposing to reclassify and establish special controls for
oncology therapeutic nucleic acid-based test systems, FDA has
considered and analyzed the following information: (1) data from 17
PMAs and 1 PMA panel-track supplement for oncology therapeutic nucleic
acid-based test systems available to FDA in accordance with section
520(h)(4) of the FD&C Act, (2) published peer-reviewed literature on
nucleic acid-based detection methods, including NAAT and sequencing
technologies, 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 nucleic acid-based test systems
which provide information related to the 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
nucleic acid-based test systems through review of PMA data dating back
to the initial approval of the first oncology therapeutic nucleic acid-
based test system in 2011, under product code OWD (P110020) (Ref. 2).
Subsequently, between August 17, 2011 and September 8, 2025, FDA
approved 35 PMAs and 403 supplements for oncology therapeutic nucleic
acid-based test systems under the product codes OWD, PJG, PQP, and SFL.
For the purpose of this reclassification, FDA was able to consider data
from the following 17 original PMAs and 1 panel-track supplement to an
original PMA in accordance with section 520(h)(4): cobas 4800 BRAF V600
Mutation Test (P110020), therascreen KRAS RGQ PCR Kit (P110027),
therascreen KRAS RGQ PCR Kit (P110030), THxID BRAF Kit (P120014), cobas
EGFR Mutation Test (P120019), therascreen EGFR RGQ PCR Kit (P120022),
BRACAnalysis CDx (P140020), cobas KRAS Mutation Test (P140023), cobas
EGFR Mutation Test v2 (P150044), cobas EGFR Mutation Test v2 (P150047),
FoundationFocus CDxBRCA Assay (P160018), FoundationFocus CDxBRCA
<INF>LOH</INF> (P160018/S001), Praxis Extended RAS Panel (P160038),
LeukoStrat CDx FLT3 Mutation Assay (P160040), Oncomine Dx Target Test
(P160045), Abbott RealTime IDH2 (P170005), FoundationOne CDx (P170019),
and Abbott RealTime IDH1 (P170041) (Ref. 2-5, and 7-20).\25\
---------------------------------------------------------------------------
\25\ 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 proposed special controls or to
otherwise inform this proposed reclassification.
---------------------------------------------------------------------------
As part of the Agency's analysis for the proposed reclassification
of oncology therapeutic nucleic acid-based test systems, FDA reviewed
and considered information provided within each of these applications,
including information available in the SSEDs and device labeling for
each application, which demonstrated a reasonable assurance of safety
and effectiveness of the devices. In developing the proposed special
controls, the Agency considered the analytical and clinical studies and
device performance data, all of which demonstrated appropriate
performance of the device and supported each approval. FDA believes the
proposed special controls can effectively mitigate the risks to health
identified in section V and, along with general controls, can provide a
reasonable assurance of the safety and effectiveness for oncology
therapeutic nucleic acid-based test systems. Additionally, FDA
identified the probable adverse effects or risks to health of the tests
based on information provided within the applications. As diagnostic
tests, oncology therapeutic nucleic acid-based test systems generally
do not pose additional safety hazards or direct adverse effects to the
patients being tested beyond those associated with routine procedures
typical for a diagnostic workup of the disease. The risks to health
identified within the applications include false test results (i.e.,
false negative or false positive test results), failure to correctly
interpret test results or incorrect test results interpretations, and
failure of the device to perform as intended or indicated. Based on
data collected in the clinical and non-clinical studies conducted, the
safety profile for the devices was generally deemed acceptable in
supporting the approvals of these devices.
While the oncology therapeutic nucleic acid-based test systems that
are the subject of the 17 PMAs and 1 PMA panel-track supplement have
unique test attributes in certain respects (e.g., the use of a specific
technology and/or the type of analyte(s) detected by the test system),
FDA has determined that these tests have sufficiently similar purposes,
design considerations, 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 18 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
three summaries are intended to provide examples that are
representative of the PMA information and data that was reviewed and
considered by FDA across the 18 applications in proposing to reclassify
oncology therapeutic nucleic acid-based test systems from class III
(premarket approval) into class II (special controls).
For example, FDA reviewed the original PMA data for the first FDA-
approved oncology therapeutic nucleic acid-based test system, which was
approved on August 17, 2011, through an original PMA (P110020) (product
code OWD) (Ref. 2), for a CDx test, cobas 4800 BRAF V600 Mutation Test,
intended for the qualitative detection of the BRAF V600E mutation in
DNA extracted from FFPE human melanoma tissues and to be used as an aid
in selecting melanoma patients whose tumors carry the BRAF V600E
mutation for treatment with vemurafenib. The Agency considered the
submitted studies and data provided in the approved submission, which
demonstrated reasonable assurance of safety and effectiveness of this
test when used in accordance with the indications for use. Such studies
and data include the results of the international, randomized, open-
label, controlled, multicenter, Phase III clinical study N025026
(BRIM3) for which the cobas 4800 BRAF V600 Mutation Test was used as a
CDx test for selecting patients for treatment with vemurafenib
(Zelboraf). Results from this clinical study demonstrated that patients
who received treatment with vemurafenib (Zelboraf) based on a BRAF
V600E positive test result as detected by the cobas 4800 BRAF V600
Mutation Test met the study's two co-primary efficacy endpoints, OS and
PFS as compared to dacarbazine. Therefore, the results of this clinical
study helped to demonstrate a reasonable assurance of the safety and
effectiveness of the cobas 4800 BRAF V600 Mutation Test for its
indicated use, as an aid in selecting melanoma patients whose tumors
carry the BRAF V600E mutation for treatment with vemurafenib. The
performance of the test was also supported by the analytical validation
studies. For example, reproducibility studies demonstrated very good
agreement to
[[Page 53270]]
support analytical performance of the test. The adverse effects of the
test are based on data collected in the BRIM3 clinical study. As a
diagnostic test, the cobas 4800 BRAF V600 Mutation Test involves
testing on FFPE human melanoma tissue sections, which are routinely
removed as part of the diagnosis of melanoma by pathologists. The test,
therefore, presents no additional safety hazard to the patient being
tested. Potential adverse effects of the cobas 4800 BRAF V600 Mutation
Test include failure of the device to perform as expected, failure to
correctly interpret test results, and/or false positive test results or
false negative test results which may lead to improper patient
management decisions in melanoma treatment.
Additionally, FDA considered the original PMA studies and data from
the Oncomine Dx Target Test PMA, which FDA approved on June 22, 2017
(P160045) (product code PQP) (Ref.17). The Oncomine Dx Target Test is a
qualitative test that uses targeted high throughput, parallel-
sequencing technology to detect single nucleotide variants (SNVs) and
deletions in 23 genes from DNA and fusions in ROS1 from RNA isolated
from FFPE tumor tissue samples from patients with non-small cell lung
cancer (NSCLC) using the Ion PGM Dx System. The test system is
indicated to aid in selecting NSCLC patients with V600E and EGFR (Ex.
19del or L858R variant) mutations in DNA, and ROS1 fusions in RNA for
the targeted therapies of Tafinlar (dabrafenib) in combination with
Mekinist (trametinib), Xalkori (crizotinib), and Iressa (gefitinib),
respectively, in accordance with the approved therapeutic product
labeling. The Agency considered the submitted studies and data in the
approved submission, which demonstrated reasonable assurance of safety
and effectiveness of the Oncomine Dx Target Test when used in
accordance with the indications for use. Such studies and data include
the retrospective analyses of patients enrolled in two clinical studies
(BRF113928 for BRAF V600E mutations and A8081001 for ROS1) and safety
and efficacy data obtained from these trials. The clinical outcomes,
based on objective response rate (ORR), observed for both clinical
studies were maintained based on the ORR estimated from the respective
bridging studies supporting the effectiveness of the Oncomine Dx Target
Test to select NSCLC patients whose tumors are positive for BRAF V600E
or ROS1 fusions for treatment with Tafinlar (dabrafenib) in combination
with Mekinist (trametinib), Xalkori (crizotinib), respectively. The
safety and effectiveness of the Oncomine Dx Target Test for the
selection of NSCLC patients with an EGFR (Ex. 19del or L858R variant)
mutation was demonstrated in a retrospective analysis of concordance
between the Oncomine Dx Target Test and the FDA-approved QIAGEN
therascreen EGFR RGQ PCR Kit. Results demonstrating a high concordance
between the Oncomine Dx Target Test and the QIAGEN therascreen EGFR RGQ
PCR Kit and comparable reproducibility performance observed between the
two tests supported the effectiveness of the Oncomine Dx Target Test to
identify NSCLC patients whose tumors are positive for the EGFR (Ex.
19del or L858R variant) mutations for treatment with Iressa
(gefitinib). Further, analytical performance studies were conducted
with the Oncomine Dx Target Test using DNA and RNA extracted from FFPE
tissue of NSCLC patients which demonstrated acceptable sensitivity for
the tested variants when used in accordance with the directions
provided. The risks of the test or potential adverse effects of the
test include failure of the device to perform as expected, 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 in NSCLC treatment. Therefore, the clinical and
analytical data in this application supported the reasonable assurance
of safety and effectiveness of the Oncomine Dx Target Test when used in
accordance with the approved indications for use.
As a final example, FDA considered PMA studies and data from the
FoundationFocus CDxBRCA <INF>LOH</INF> \26\ panel-track PMA supplement,
which FDA approved on April 6, 2018 expanding the indications for use
of this test (P160018/S001) (product code PQP) (Ref. 5) to include an
indication for use to provide information that while not essential to
the safe and effective use of a corresponding approved oncology
therapeutic product, provides information about known benefits and/or
risks related to the use of an approved oncology therapeutic product.
FoundationFocus CDxBRCA <INF>LOH</INF> was originally indicated for the
qualitative detection of BRCA1 and BRCA2 alterations in FFPE ovarian
tumor tissue to aid in identifying ovarian cancer patients with
deleterious tumor BRCA variants (tBRCA-positive) who may be eligible
for treatment with Rubraca (rucaparib), providing information that is
essential for the safe and effective use of Rubraca (rucaparib). The
panel-track PMA supplement expanded the indications for use to include
the qualitative detection of genomic LOH from FFPE ovarian tumor tissue
to determine HRD status (defined as tBRCA-positive and/or LOH high) in
ovarian cancer patients, and positive HRD status in such patients is
associated with improved PFS from Rubraca (rucaparib) maintenance
therapy. This new indication for use is to provide information about
known benefits related to the use of the approved oncology therapeutic
product, although the information provided is not essential to the safe
and effective use of the corresponding approved oncology therapeutic
product. In accordance with the six-year rule \27\ and to support this
proposed reclassification action, the Agency considered the submitted
studies and data in the approved submission, which demonstrated
reasonable assurance of safety and effectiveness of this test when used
in accordance with the indications for use. For example, the clinical
performance of the test for its new indication was established based on
results from ARIEL3, a Phase 3, global, randomized, double-blind
clinical study of Rubraca (rucaparib) maintenance therapy demonstrating
an improved PFS in patients selected by the FoundationFocus CDxBRCA
<INF>LOH</INF> and a clinical bridging study that included an analysis
of the concordance of the LOH results between the FoundationFocus
CDxBRCA LOH and the clinical trial assay (CTA) used in the therapeutic
product trial. The primary objective of the therapeutic product
clinical trial was to evaluate PFS by Response Evaluation Criteria in
Solid Tumors (RECIST) v1.1. The bridging study, which supports
extrapolating the clinical performance characteristics of the CTA to a
candidate device (in this case, the FoundationFocus CDxBRCA
<INF>LOH</INF>)
[[Page 53271]]
to support the clinical validity of the candidate device, includes
retrospective testing of clinical trial samples using the
FoundationFocus CDxBRCA <INF>LOH</INF>. To support that the
FoundationFocus CDxBRCA <INF>LOH</INF> is clinically meaningful and
provides information about known benefits and/or risks related to the
use of the approved oncology therapeutic product, the clinical trial
data were analyzed using a Cox Proportional Hazard model to demonstrate
that there is an interaction between the test results (HRD status) and
the corresponding therapeutic product in the intent-to-treat (ITT)
population. The Proportional Hazard model showed a statistically
significant improvement in PFS for patients randomized to Rubraca as
compared with placebo in all patients, including the biomarker positive
subgroups (i.e., HRD and tBRCA subgroups). Thus, results demonstrate
there is overall probable clinical benefit of the FoundationFocus
CDxBRCA <INF>LOH</INF> for its approved indication for use. However,
the approved oncology therapeutic product drug is intended for all
comers, irrespective of biomarker results, therefore, the information
provided is not essential to the safe and effective use of the
corresponding approved oncology therapeutic product. Further, the
performance of the FoundationFocus CDxBRCA <INF>LOH</INF> was also
supported by analytical validation studies, such as reproducibility and
repeatability studies, which demonstrated acceptable analytical
performance of the assay. The risks of the test are based on data
collected in the validation studies conducted to support the test
approval. The FoundationFocus CDxBRCA <INF>LOH</INF> involves testing
on FFPE ovarian cancer tumor tissue. The risks of the test or potential
adverse effects of the test include failure of the device to perform as
expected, failure to correctly interpret test results, and/or false
positive test results or false negative test results which could lead
to improper patient management decisions in ovarian cancer treatment.
Therefore, the clinical and analytical data in this panel-track PMA
supplement supported the reasonable assurance of safety and
effectiveness of this test when used in accordance with the indications
for use.
---------------------------------------------------------------------------
\26\ The original device was approved under the trade name
FoundationFocus CDxBRCA (P160018). The sponsor originally submitted
the panel-track PMA supplement application (P160018/S001) for the
same device with an expanded indication for use under the trade name
FoundationFocus CDxBRCA <INF>HRD</INF>. However, through the review
process, the sponsor decided to change the name to FoundationFocus
CDxBRCA <INF>LOH</INF>. For the purpose of providing example
summaries that are representative of the PMA information and data
that was reviewed and considered by FDA to support the proposed
reclassification action in accordance with the six-year rule (see
section 520(h)(4) of the FD&C Act), the name used throughout this
paragraph is FoundationFocus CDxBRCA <INF>LOH</INF>.
\27\ 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.
---------------------------------------------------------------------------
In addition to the original PMA data from the 17 available PMAs and
one PMA panel-track supplement, FDA further considered that nucleic
acid-based detection methods, including NAAT and sequencing, are well-
established technologies, for example, with NAAT, such as PCR, first
described in the 1980s (Ref. 23). These technologies have been commonly
used in both research and clinical settings for decades and their
general principles are well understood and widely published in the
literature at this time (Ref. 24). There have been significant
scientific developments aimed at addressing certain limitations for
NAAT and sequencing technologies and expanding the applications of
these technologies, such as the introduction of a thermostable DNA
polymerase in PCR and the emergence of high throughput or next
generation sequencing techniques (Ref. 25-26). These developments
further demonstrate the maturity of these technologies, and FDA
considered the breadth of knowledge available regarding NAAT and
sequencing technologies in proposing to reclassify oncology therapeutic
nucleic acid-based test systems from class III (premarket approval)
into class II (special controls). 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,
along with general controls, are necessary to provide a reasonable
assurance of the safety and effectiveness for these devices.
Finally, a search of FDA's publicly available MAUDE database
revealed 147 reported events for oncology therapeutic nucleic acid-
based test systems under product codes OWD, PJG, PQP, and SFL, a
significant majority of which did not cause patient harm per the
reports. A search of FDA's publicly available Medical Device Recalls
database revealed that there have been four class III recall, 23 class
II recalls, and no class I recalls involving oncology therapeutic
nucleic acid-based test systems. The lack of class I recalls, and
relatively few numbers of class II and class III recalls,\28\ coupled
with the relatively low number of reported events that caused patient
harm, indicate a generally good safety record for this device type (see
further discussion of the MDR and recall data in section II of this
proposed order).
---------------------------------------------------------------------------
\28\ As defined in 21 CFR 7.3(m), the numerical designation,
i.e., I, II, or III, assigned by the FDA to a particular product
recall indicates the relative degree of health hazard presented by
the product being recalled. Class I recalls are those classified as
the highest level of risk in which there is a reasonable probability
that the use of, or exposure to, a violative product will cause
serious adverse health consequences or death.
---------------------------------------------------------------------------
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
nucleic acid-based test systems from class III (premarket approval)
into class II (special controls) subject to 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 nucleic acid-based test systems.
Risks of false positive test results or false negative test
results, failure of the test system to perform as intended or
indicated, and failure to correctly interpret test results can be
mitigated by special controls, including certain design verification
and validation activities. For example, documentation of clinical
performance testing which must include clinical data demonstrating
acceptable performance of the device for its intended use based on data
generated using a dataset representative of the intended use
population. This may include, for example, data from use of the device
as the clinical trial enrollment assay in the therapeutic product
clinical trial or data from a method comparison study to an appropriate
FDA-authorized device. The analytical performance testing must include
data demonstrating appropriate analytical performance of the device
such as the precision, analytical accuracy, analytical sensitivity,
analytical specificity, and sample and reagent stability of the test
system. In addition, device design verification and validation
information must include the specification for risk mitigation elements
intended to mitigate risks associated with testing and results
interpretation including, controls, procedures, and user training
requirements.
The risks of false test results, failure to correctly interpret
test results, and failure of the device to perform as intended or
indicated can be further mitigated by special controls that require
specific information in the labeling for these test systems. For
example, a requirement to provide a device description that includes a
description of relevant limitations with regard to target/genomic
region(s) that cannot be targeted and/or detected by the test system,
as applicable. In addition, these risks can be further mitigated by
labeling special controls that require an appropriate, as
[[Page 53272]]
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 Nucleic Acid-Based Test Systems
------------------------------------------------------------------------
Identified risks to health Mitigation measures
------------------------------------------------------------------------
False positive test results Certain design verification and
or false negative test validation activities, including certain
results. analytical validation and clinical
validation data.
Certain labeling information, including
certain performance information.
Failure of the test system to Certain design verification and
perform as intended or validation activities, including certain
indicated. analytical validation and clinical
validation data.
Certain labeling information, including
certain performance information.
Failure to correctly Certain design verification and
interpret test results. validation activities, including certain
analytical validation and clinical
validation data.
Certain labeling information, including
certain performance information.
------------------------------------------------------------------------
If this proposed order is finalized, oncology therapeutic nucleic
acid-based test systems will be identified as prescription IVD devices.
Therefore, these devices would be subject to the prescription labeling
requirements for IVD products (see 21 CFR 809.10(a)(4) and (b)(5)(ii)).
If this proposed order is finalized, oncology therapeutic nucleic
acid-based test systems will be reclassified into class II (special
controls) and will be subject to premarket notification requirements
under section 510(k) of the FD&C Act. As discussed in this proposed
order, the intent is for the reclassification to be codified in the new
classification regulation 21 CFR 866.6075. If finalized, firms will be
required to comply with the particular mitigation measures set forth in
the special controls. Adherence to the special controls, in addition to
the general controls, is necessary to provide a reasonable assurance of
the safety and effectiveness of oncology therapeutic nucleic acid-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 proposal 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 Nucleic Acid-Based Test
Systems for Use with a Corresponding Approved Oncology Therapeutic
Product in the new 21 CFR 866.6075, under which these oncology
therapeutic nucleic acid-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 6, 2014
(available at <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/in-vitro-companion-diagnostic-devices">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/in-vitro-companion-diagnostic-devices</a>).
* 2. P110020 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=P110020.
* 3. P140020 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=P140020.
* 4. P160018 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=P160018.
* 5. P160018S001 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=P160018S001.
* 6. ``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>.
* 7. P110027 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=P110027.
* 8. P110030 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=P110030.
* 9. P120014 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=P120014.
[[Page 53273]]
* 10. P120019 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=P120019.
* 11. P120022 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=P120022.
* 12. P140023 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=P140023.
* 13. P150044 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=P150044.
* 14. P150047 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=P150047.
* 15. P160038 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=P160038.
* 16. P160040 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=P160040.
* 17. P160045 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=P160045.
* 18. P170005 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=P170005.
* 19. P170019 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=P170019.
* 20. P170041 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=P170041.
* 21. FDA, ``CDRH Announces Intent to Initiate the
Reclassification Process for Most High Risk IVDs,'' January 31,
2024. Available at <a href="https://www.fda.gov/medical-devices/medical-devices-news-and-events/cdrh-announces-intent-initiate-reclassification-process-most-high-risk-ivds">https://www.fda.gov/medical-devices/medical-devices-news-and-events/cdrh-announces-intent-initiate-reclassification-process-most-high-risk-ivds</a>.
22. Curtin, SC, Tejada-Vera, B, Bastian, Deaths: Leading Causes
for 2021. National Center for Health Statistics. Vital Health Stat
73(4). 2024.
23. Saiki RK, Scharf S, Faloona F, et al. Enzymatic
amplification of beta-globin genomic sequences and restriction site
analysis for diagnosis of sickle cell anemia. Science.
1985;230(4732):1350-1354. doi:10.1126/science.2999980.
24. Bej AK, Mahbubani MH, Atlas RM. Amplification of nucleic
acids by polymerase chain reaction (PCR) and other methods and their
applications. Crit Rev Biochem Mol Biol. 1991;26(3-4):301-334.
doi:10.3109/10409239109114071.
25. Saiki RK, Gelfand DH, Stoffel S, et al. Primer-directed
enzymatic amplification of DNA with a thermostable DNA polymerase.
Science. 1988;239(4839):487-491. doi:10.1126/science.2448875.
26. McCombie WR, McPherson JD, Mardis ER. Next-Generation
Sequencing Technologies. Cold Spring Harb Perspect Med.
2019;9(11):a036798. Published 2019 Nov 1. doi:10.1101/
cshperspect.a036798.
List of Subjects in 21 CFR Part 866
Biologics, Laboratories, Medical devices.
Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 866 be amended as follows:
PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES
0
1. The authority citation for 21 CFR part 866 continues to read as
follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.
0
2. Add Sec. 866.6075 to subpart G to read as follows:
Sec. 866.6075 Nucleic Acid-Based Test Systems for Use with a
Corresponding Approved Oncology Therapeutic Product.
(a) Identification. Nucleic acid-based test systems indicated for
use with a corresponding approved oncology therapeutic product are
identified as prescription in vitro diagnostic devices intended for the
detection of specific genetic variant(s) and/or other nucleic acid
biomarkers in human clinical specimens using nucleic acid amplification
(e.g., polymerase chain reaction) and/or sequencing technology (e.g.,
next generation sequencing) to provide information related to the use
of a corresponding approved oncology therapeutic product. These test
systems include devices that provide information that is essential for
the safe and effective use of a corresponding approved oncology
therapeutic product and devices that, while not essential to the safe
and effective use of the corresponding approved oncology therapeutic
product, provide information about known benefits and/or risks related
to the use of the corresponding approved oncology therapeutic product.
(b) Classification: Class II (special controls). The special
controls for this device are:
(1) Design verification and validation must include:
(i) A summary of the empirical evidence that establishes the
appropriate analytical quality metrics and thresholds for the test
system.
(ii) Device performance data demonstrating appropriate, as
determined by FDA, analytical and clinical performance of the device
for the intended use. This must include:
(A) Data demonstrating the precision, analytical accuracy,
analytical sensitivity, analytical specificity, and sample and reagent
stability of the test system. Analytical performance data must be
evaluated for each gene/variant, or alternatively, justification for an
alternative approach must be provided and determined by FDA to be
appropriate, such as the use of a representative set of genes and/or
variants.
(B) Data demonstrating all targeted region(s) that can be detected
by the test system and disclosure of any region(s) not targeted or
detected by the test system and/or with limited detection by the test
system, as applicable.
(C) Clinical data generated using clinical specimens representative
of the intended use population demonstrating appropriate, as determined
by FDA, clinical performance of the device for its intended use.
(D) Data demonstrating appropriate validation of the intended
specimen handling protocol and specimen preparation (e.g., nucleic acid
extraction and purification) as described in the labeling.
(iii) Specifications and data that appropriately demonstrate the
validity of the biomarker classification process, including any
bioinformatic pipeline. This information must include a description of
the classification process, including protocol(s) and criteria used for
classification and reporting, and detailed documentation of the basis
for biomarker interpretation with appropriate references.
(iv) Specification for risk mitigation elements intended to
mitigate risks associated with testing and results interpretation
including controls, procedures, and user training requirements, as
appropriate.
(2) Labeling must include the following:
(i) A device description which includes:
(A) The biomarker(s) detected by the test system;
(B) Relevant limitations with regard to target/genomic region(s)
that cannot be targeted or detected by the test system and/or with
limited detection by the test system, as applicable;
(C) A description of the analysis algorithms used for biomarker
detection and annotation, evaluation, and classification;
(D) A description of the quality metrics, thresholds, and filters
utilized at each step of the test system, as applicable.
(ii) An appropriate summary, as determined by FDA, of the
performance studies conducted and the results of those studies,
including those that relate to all design verification and validation
special controls.
(iii) For those test systems intended to provide information that
is essential for
[[Page 53274]]
the safe and effective use of a corresponding approved oncology
therapeutic product, language indicating that the test system is
indicated for use with a corresponding FDA-approved oncology
therapeutic product. Device labeling must be consistent with the
information set forth in the corresponding FDA-approved oncology
therapeutic product labeling.
(iv) For those test systems intended to provide information about
known benefits and/or risks related to the use of a corresponding FDA-
approved oncology therapeutic product but are not essential for the
safe and effective use of the corresponding approved oncology
therapeutic product, language summarizing the benefits and/or risks
related to the use of a corresponding FDA-approved oncology therapeutic
product that must be consistent with the information set forth in the
corresponding FDA-approved oncology therapeutic product labeling.
Lowell M. Zeta,
Acting Deputy Commissioner for Policy, Legislation, and International
Affairs.
[FR Doc. 2025-21071 Filed 11-24-25; 8:45 am]
BILLING CODE 4164-01-P
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</html>Indexed from Federal Register on November 25, 2025.
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