Rule2025-11793
Medical Devices; Hematology and Pathology Devices; Classification of the Fluorescence In Situ Hybridization-Based Detection of Chromosomal Abnormalities From Patients With Hematologic Malignancies
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Published
June 26, 2025
Effective
June 26, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, the Agency, or we) is classifying the fluorescence in situ hybridization-based detection of chromosomal abnormalities from patients with hematologic malignancies into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the fluorescence in situ hybridization-based detection of chromosomal abnormalities from patients with hematologic malignancies' classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens.
Full Text
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<title>Federal Register, Volume 90 Issue 121 (Thursday, June 26, 2025)</title>
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[Federal Register Volume 90, Number 121 (Thursday, June 26, 2025)]
[Rules and Regulations]
[Pages 27231-27234]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-11793]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 864
[Docket No. FDA-2025-N-1264]
Medical Devices; Hematology and Pathology Devices; Classification
of the Fluorescence In Situ Hybridization-Based Detection of
Chromosomal Abnormalities From Patients With Hematologic Malignancies
AGENCY: Food and Drug Administration, HHS.
ACTION: Final amendment; final order.
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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
classifying the fluorescence in situ hybridization-based detection of
chromosomal abnormalities from patients with hematologic malignancies
into class II (special controls). The special controls that apply to
the device type are identified in this order and will be part of the
codified language for the fluorescence in situ hybridization-based
detection of chromosomal abnormalities from patients with hematologic
malignancies' classification. We are taking this action because we have
determined that classifying the device into class II (special controls)
will provide a reasonable assurance of safety and effectiveness of the
device. We believe this action will also enhance patients' access to
beneficial innovative devices, in part by reducing regulatory burdens.
DATES: This order is effective June 26, 2025. The classification was
applicable on December 21, 2018.
FOR FURTHER INFORMATION CONTACT: Ryan Lubert, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 3414, Silver Spring, MD 20993-0002, 240-402-6357,
<a href="/cdn-cgi/l/email-protection#611318000f4f0d1403041315210705004f0909124f060e17"><span class="__cf_email__" data-cfemail="dba9a2bab5f5b7aeb9bea9af9bbdbfbaf5b3b3a8f5bcb4ad">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background
Upon request, FDA has classified the fluorescence in situ
hybridization-based detection of chromosomal abnormalities from
patients with hematologic malignancies as class II (special controls),
which we have determined will provide a reasonable assurance of safety
and effectiveness. In addition, we believe this action will enhance
patients' access to beneficial innovation, in part by reducing
regulatory burdens by placing the device into a lower device class than
the automatic class III assignment.
The automatic assignment of class III occurs by operation of law
and without any action by FDA, regardless of the level of risk posed by
the new device. Any device that was not in commercial distribution
before May 28, 1976, is automatically classified as, and remains
within, class III and requires premarket approval unless and until FDA
takes an action to classify or reclassify the device (see 21 U.S.C.
360c(f)(1)). We refer to these devices as ``postamendments devices''
because they were not in commercial distribution prior to the date of
enactment of the Medical Device Amendments of 1976, which amended the
Federal Food, Drug, and Cosmetic Act (FD&C Act).
FDA may take a variety of actions in appropriate circumstances to
classify or reclassify a device into class I or II. We may issue an
order finding a new device to be substantially equivalent under section
513(i) of the FD&C Act to a predicate device that does not require
premarket approval (21 U.S.C. 360c(i)). We determine whether a new
device is substantially equivalent to a predicate device by means of
the procedures for premarket notification under section 510(k) of the
FD&C Act (21 U.S.C. 360(k) and Part 807 (21 CFR part 807).
FDA may also classify a device through ``De Novo'' classification,
a common name for the process authorized under section 513(f)(2) of the
FD&C Act (see also part 860, subpart D (21 CFR part 860, subpart D)).
Section 207 of the Food and Drug Administration Modernization Act of
1997 (Pub. L. 105-115) established the first procedure for De Novo
classification. Section 607 of the Food and Drug Administration Safety
and Innovation Act (Pub. L. 112-144)
[[Page 27232]]
modified the De Novo application process by adding a second procedure.
A device sponsor may utilize either procedure for De Novo
classification.
Under the first procedure, the person submits a 510(k) for a device
that has not previously been classified. After receiving an order from
FDA classifying the device into class III under section 513(f)(1) of
the FD&C Act, the person then requests a classification under section
513(f)(2).
Under the second procedure, rather than first submitting a 510(k)
and then a request for classification, if the person determines that
there is no legally marketed device upon which to base a determination
of substantial equivalence, that person requests a classification under
section 513(f)(2) of the FD&C Act.
Under either procedure for De Novo classification, FDA is required
to classify the device by written order within 120 days. The
classification will be according to the criteria under section
513(a)(1) of the FD&C Act. Although the device was automatically placed
within class III, the De Novo classification is considered to be the
initial classification of the device.
We believe this De Novo classification will enhance patients'
access to beneficial innovation, in part by reducing regulatory
burdens. When FDA classifies a device into class I or II via the De
Novo process, the device can serve as a predicate for future devices of
that type, including for 510(k)s (see section 513(f)(2)(B)(i) of the
FD&C Act). As a result, other device sponsors do not have to submit a
De Novo request or premarket approval application to market a
substantially equivalent device (see section 513(i) of the FD&C Act,
defining ``substantial equivalence''). Instead, sponsors can use the
less burdensome 510(k) process, when necessary, to market their device.
II. De Novo Classification
On September 29, 2017, FDA received Cytocell, Ltd.'s request for De
Novo classification of the following devices: MLL (KMT2A) Breakapart
FISH Probe Kit; P53 (TP53) Deletion FISH Probe Kit; Del(20q) Deletion
FISH Probe Kit; CBF[beta] (CBFB)/MYH11 Translocation, Dual Fusion FISH
Probe Kit; Del(5q) Deletion FISH Probe Kit; Del(7q) Deletion FISH Probe
Kit; AML1/ETO (RUNX1/RUNX1T1) Translocation, Dual Fusion FISH Probe
Kit; and EVI1 (MECOM) Breakapart FISH Probe Kit. FDA reviewed the
request in order to classify the device under the criteria for
classification set forth in section 513(a)(1) of the FD&C Act.
We classify devices into class II if general controls by themselves
are insufficient to provide reasonable assurance of safety and
effectiveness, but there is sufficient information to establish special
controls that, in combination with the general controls, provide
reasonable assurance of the safety and effectiveness of the device for
its intended use (see 513(a)(1)(B) of the FD&C Act). After review of
the information submitted in the request, we determined that the device
can be classified into class II with the establishment of special
controls. FDA has determined that these special controls, in addition
to the general controls, will provide reasonable assurance of the
safety and effectiveness of the device.
Therefore, on December 21, 2018, FDA issued an order to the
requester classifying the device into class II. In this final order,
FDA is codifying the classification of the device by adding 21 CFR
864.1880.\1\ We have named the generic type of device ``fluorescence in
situ hybridization-based detection of chromosomal abnormalities from
patients with hematologic malignancies,'' and it is used to detect
chromosomal abnormalities in human specimens from patients with
hematologic malignancies. The test is indicated for the clinical
management of patients consistent with internationally accepted
guidelines (e.g., World Health Organization guidelines for
Classification of Tumours of Haematopoietic and Lymphoid Tissues) and
in conjunction with other clinical and clinicopathological criteria.
The results are to be interpreted by a pathologist or equivalent
professional.
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\1\ FDA notes that the ACTION caption for this final order is
styled as ``Final amendment; final order,'' rather than ``Final
order.'' Beginning in December 2019, this editorial change was made
to indicate that the document ``amends'' the Code of Federal
Regulations. The change was made in accordance with the Office of
Federal Register's (OFR) interpretations of the Federal Register Act
(44 U.S.C. chapter 15), its implementing regulations (1 CFR 5.9 and
parts 21 and 22), and the Document Drafting Handbook.
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FDA has identified the following risks to health associated
specifically with this type of device and the measures required to
mitigate these risks in table 1.
Table 1--Fluorescence In Situ Hybridization-Based Detection of
Chromosomal Abnormalities From Patients With Hematologic Malignancies
Risks and Mitigation Measures
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Identified risks to health Mitigation measures
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Incorrect test results................. Special controls (1) (21 CFR
864.1880(b)(1)), (2) (21 CFR
864.1880(b) (2)), (3) (21 CFR
864.1880(b)(3)), and (4) (21
CFR 864.1880(b) (4)).
Incorrect interpretation of test Special controls (1) (21 CFR
results. 864.1880(b)(1)), (2) (21 CFR
864.1880(b) (2)), (3) (21 CFR
864.1880(b)(3)), and (4) (21
CFR 864.1880(b) (4)).
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FDA has determined that special controls, in combination with the
general controls, address these risks to health and provide reasonable
assurance of safety and effectiveness. For a device to fall within this
classification, and thus avoid automatic classification in class III,
it would have to comply with the special controls named in this final
order. The necessary special controls appear in the regulation codified
by this final order. This device is subject to premarket notification
requirements under section 510(k) of the FD&C Act.
III. Analysis of Environmental Impact
The Agency has 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.
IV. Paperwork Reduction Act of 1995
This final order establishes special controls that refer to
previously approved collections of information found in other FDA
regulations and guidance. These collections of information are subject
to review by the Office of Management and Budget (OMB) under the
Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). The collections
of information in part 860, subpart D, regarding De Novo classification
have been approved under
[[Page 27233]]
OMB control number 0910-0844; the collections of information in 21 CFR
part 814, subparts A through E, regarding premarket approval have been
approved under OMB control number 0910-0231; the collections of
information in part 807, subpart E, regarding premarket notification
submissions have been approved under OMB control number 0910-0120; the
collections of information in 21 CFR part 820 regarding the quality
system regulation have been approved under OMB control number 0910-
0073; and the collections of information in 21 CFR parts 801 and 809
regarding labeling have been approved under OMB control number 0910-
0485.
List of Subjects in 21 CFR Part 864
Blood, Medical devices, Packaging and containers.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
864 is amended as follows:
PART 864--HEMATOLOGY AND PATHOLOGY DEVICES
0
1. The authority citation for part 864 continues to read as follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.
0
2. Add Sec. 864.1880 to subpart B to read as follows:
Sec. 864.1880 Fluorescence in situ hybridization (FISH)-based
detection of chromosomal abnormalities from patients with hematologic
malignancies.
(a) Identification. A fluorescence in situ hybridization (FISH)-
based detection of chromosomal abnormalities from patients with
hematologic malignancies is used to detect chromosomal abnormalities in
human specimens from patients with hematologic malignancies. The test
is indicated for the clinical management of patients consistent with
internationally accepted guidelines (e.g., World Health Organization
guidelines for Classification of Tumours of Haematopoietic and Lymphoid
Tissues) and in conjunction with other clinical and clinicopathological
criteria. The results are to be interpreted by a pathologist or
equivalent professional.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) Design verification and validation must include:
(i) A detailed description of all probes included in the kit;
(ii) Purpose of each probe;
(iii) Probe molecular specificity;
(iv) Probe specificity;
(v) Probe limits;
(vi) Probe sensitivity;
(vii) Specification of required ancillary reagents,
instrumentation, and equipment;
(viii) Specification of the specimen collection, processing,
storage and slide preparation methods;
(ix) Specification of the assay procedure;
(x) Specification of control elements that are incorporated into
the recommended testing procedures;
(xi) Specification of the criteria for test result interpretation
and reporting;
(xii) Documentation demonstrating analytical validation that
includes:
(A) Device analytical sensitivity data with a minimum of 25
specimens from karyotypically normal males.
(B) Device analytical specificity data with a minimum of five
specimens from karyotypically normal males.
(C) Description of how the clinical threshold was assigned and
verification of the assigned clinical threshold.
(D) Device precision/reproducibility data with a minimum of six
clinical specimens including two negative specimens, two positive
specimens near the clinical decision threshold (cut-off) and two
positive specimens. The data must include results obtained from three
sites (as applicable), with two operators at each site, with the assay
run for a minimum of 3-5 non-consecutive days and each specimen run in
duplicate for a minimum of 30 replicates.
(E) Between-reagent lot reproducibility using three reagent lots
and three clinical specimens representing negative, near cut-off/low
positive, and positive.
(F) Device stability data to include:
(1) Real-time stability,
(2) Freeze-thaw stability,
(3) Transport and temperature stability, as applicable,
(4) Post-hybridization signal stability, and
(5) Photostability of probe.
(xiii) Documentation demonstrating the clinical validity of the
device that includes:
(A) A summary of the prevalence and clinical thresholds reported in
three peer-reviewed published literature references for the intended
use population of the device and device performance data demonstrating
conformance with the published prevalence as reported in peer-reviewed
published literature references based on testing clinical specimens,
selected without bias (e.g., consecutively selected) from the intended
use population using the specific device seeking marketing clearance. A
minimum number of clinical specimens must be tested to ensure
sufficient positives are evaluated by the device, or alternatively, in
the absence of a sufficient number of positives, an additional
comparison of results obtained with the device to clinical truth (e.g.,
confirmed clinical diagnosis and/or G-banded karyotyping) with an
independent specimen set must be conducted.
(B) Documentation for peer-reviewed published literature references
must include the following elements:
(1) Whether the specific device was used in the literature
reference;
(2) Number and type of specimens;
(3) Target population studied;
(4) Upper reference limit; and
(5) Prevalence range estimated based on the number of positive
probe results.
(C) In the absence of clinical data obtained from paragraphs
(b)(1)(xiii)(A) and (B) of this section, clinical data obtained from a
method comparison to the predicate with positives and negative clinical
specimens.
(2) The intended use required on the label under Sec. 809.10(a)(4)
of this chapter and on the labeling required under Sec.
809.10(b)(5)(ii) of this chapter must include a statement that ``The
test is not intended for use as a stand-alone diagnostic, disease
screening, or as a companion diagnostic.''
(3) The labeling required under Sec. 809.10(b) of this chapter
must include information that demonstrates the performance
characteristics of the test, including a detailed summary of the
performance studies conducted and their results, as described in
paragraphs (b)(1)(iv) through (xiii) of this section. The labeling
required under Sec. 809.10(b) of this chapter must include the pre-
specified acceptance criteria for these performance studies,
justification for the pre-specified acceptance criteria, and whether
the pre-specified acceptance criteria were met.
(4) The labeling required under Sec. 809.10(b) of this chapter
must include the following limiting statements:
(i) ``Reporting and interpretation of FISH results should be
consistent with professional standards of practice and should take into
consideration other clinical and diagnostic information. This kit is
intended as an adjunct to other diagnostic laboratory tests and
therapeutic action should not be initiated on the basis of the FISH
result alone. Failure to adhere to the protocol may affect the
performance and lead to false results.''
(ii) ``Each lab is responsible for establishing their own cut-off
values. Each laboratory should test sufficiently
[[Page 27234]]
large number of samples to establish normal population distribution of
the signal levels and to assign a cut-off value. The product is for
professional use only and is intended to be interpreted by a qualified
pathologist or cytogeneticist.''
Dated: June 23, 2025.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-11793 Filed 6-25-25; 8:45 am]
BILLING CODE 4164-01-P
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