Rule2025-16032
Medical Devices; Immunology and Microbiology Devices; Classification of the Postnatal Chromosomal Copy Number Variation Detection System
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Published
August 21, 2025
Effective
August 21, 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 postnatal chromosomal copy number variation detection system 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 postnatal chromosomal copy number variation detection system's classification. We are taking this action because we have determined that classifying the device into class II 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 160 (Thursday, August 21, 2025)</title>
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[Federal Register Volume 90, Number 160 (Thursday, August 21, 2025)]
[Rules and Regulations]
[Pages 40713-40716]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-16032]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2025-N-2110]
Medical Devices; Immunology and Microbiology Devices;
Classification of the Postnatal Chromosomal Copy Number Variation
Detection System
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 postnatal chromosomal copy number variation detection
system 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 postnatal chromosomal copy number
variation detection system's classification. We are taking this action
because we have determined that classifying the device into class II
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 August 21, 2025. The classification was
applicable on January 17, 2014.
FOR FURTHER INFORMATION CONTACT: Scott McFarland, Center for Devices
and Radiological Health, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 66, Rm. 3572, Silver Spring, MD, 20993-0002, 301-
796-6217, <a href="/cdn-cgi/l/email-protection#7221111d06065c3f113413001e131c16321416135c1a1a015c151d04"><span class="__cf_email__" data-cfemail="d98abab6adadf794ba9fb8abb5b8b7bd99bfbdb8f7b1b1aaf7beb6af">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
[[Page 40714]]
I. Background
Upon request, FDA has classified the postnatal chromosomal copy
number variation detection system 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 (21 U.S.C. 360c(i)) to a predicate device that
does not require premarket approval. 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) 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 (PMA) 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
For this device, FDA issued an order on December 13, 2013, finding
the Affymetrix CytoScan Dx Assay not substantially equivalent to a
predicate not subject to PMA. Thus, the device remained in class III in
accordance with section 513(f)(1) of the FD&C Act when we issued the
order.
On December 23, 2013, FDA received Affymetrix, Inc.'s request for
De Novo classification of the Affymetrix CytoScan Dx Assay. 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 section 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 general controls, will provide reasonable assurance of the
safety and effectiveness of the device.
Therefore, on January 17, 2014, FDA issued an order to the
requestor classifying the device into class II. In this final order,
FDA is codifying the classification of the device by adding 21 CFR
866.5920.\1\ We have named the generic type of device postnatal
chromosomal copy number variation detection system, and it is
identified as a qualitative assay intended for the detection of copy
number variations (CNVs) in genomic DNA obtained from whole blood in
patients referred for chromosomal testing based on clinical
presentation. It is intended for the detection of CNVs associated with
developmental delay, intellectual disability, congenital anomalies, or
dysmorphic features. Assay results are intended to be used in
conjunction with other clinical and diagnostic findings, consistent
with professional standards of practice, including confirmation by
alternative methods, parental evaluation, clinical genetic evaluation,
and counseling, as appropriate. Interpretation of assay results is
intended to be performed by qualified healthcare professionals such as
clinical cytogeneticists or molecular geneticists. This device is not
intended to be used for standalone diagnostic purposes, pre-
implantation or prenatal testing or screening, population screening, or
for the detection of, or screening for, acquired or somatic genetic
aberrations.
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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.
[[Page 40715]]
Table 1--Postnatal Chromosomal Copy Number Variation Detection System
Risks and Mitigation Measures
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Identified risks to health Mitigation measures
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Inaccurate test results that provide false Special controls (1) and
positive and false negative results can (2).
lead to improper patient management.
Failure to correctly interpret test results Special controls (1)(iii)
can lead to false positive and false and (2).
negative results and accordingly improper
patient management.
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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 the 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 OMB control number 0910-0844; the collections
of information 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 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 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, 21 CFR part
866 is 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. 866.5920 to subpart F to read as follows:
Sec. 866.5920 Postnatal chromosomal copy number variation detection
system.
(a) Identification. A postnatal chromosomal copy number variation
detection system is a qualitative assay intended for the detection of
copy number variations (CNVs) in genomic DNA obtained from whole blood
in patients referred for chromosomal testing based on clinical
presentation. It is intended for the detection of CNVs associated with
developmental delay, intellectual disability, congenital anomalies, or
dysmorphic features. Assay results are intended to be used in
conjunction with other clinical and diagnostic findings, consistent
with professional standards of practice, including confirmation by
alternative methods, parental evaluation, clinical genetic evaluation,
and counseling, as appropriate. Interpretation of assay results is
intended to be performed by qualified healthcare professionals such as
clinical cytogeneticists or molecular geneticists. This device is not
intended to be used for standalone diagnostic purposes, pre-
implantation or prenatal testing or screening, population screening, or
for the detection of, or screening for, acquired or somatic genetic
aberrations.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) Design verification and validation must include the following
information:
(i) A detailed description of all components in the test system
that includes:
(A) A description of the assay components, array composition and
layout, all required reagents, instrumentation, and equipment,
including illustrations or photographs of non-standard equipment or
methods;
(B) A description of the design of the array in terms of
chromosomal coverage and probe density for different regions;
(C) An identification of the number of probes and size of the CNVs
reported at the lower range of the assay;
(D) Detailed documentation of the device software, including
standalone software applications and hardware-based devices that
incorporate software;
(E) Methodology and protocols for detecting copy number and
visualizing results;
(F) A description of the result outputs along with sample reports,
and a description of any links to external databases provided by the
device to the user or accessed by the device;
(G) Specifications for the methods to be used in specimen
collection, extraction (including DNA criteria for DNA quality and
quantity to perform the assay), and storage; and
(H) A description of appropriate internal and external controls
that are recommended or provided. The description must identify those
control elements that are incorporated into the testing procedure.
(ii) Information that demonstrates the performance characteristics
of the system, including:
(A) Device reproducibility data generated, at a minimum, using
three sites, with two operators at each site, for three non-consecutive
days using at least three instruments. A well-characterized panel of
samples that provide a wide range of CNVs (i.e., gains, losses,
adequate size coverage across the range of sizes claimed by the device,
adequate chromosomal coverage, challenging regions in the genome, CNVs
reported at the lower range of the assay, interstitial, subtelomeric,
and pericentromeric rearrangements, aneuploidy, unbalanced
translocations, mosaicism, and known syndromic regions) must be used.
The results must be itemized for all CNVs detected in each sample
across all replicates and summarized in a tabular format stratified by
size range
[[Page 40716]]
and range of probe numbers for gains and losses separately and
calculated for overall. The results must be analyzed using pairwise
replicate agreement, and summarized as overall pairwise replicate
agreement as well as pairwise replicate agreement conditional on
replicates having a positive copy number state call (gains or losses),
call rate, CNV size variation, and endpoint agreement;
(B) Device accuracy data using cell lines and clinical samples
representing a variety of CNVs and syndromes. In this analytical study,
accuracy must be determined for every CNV detected in a particular
sample. The accuracy data provided must include the copy number state
determination and endpoint accuracy. The accuracy samples must cover
different genomic variations across the genome (i.e., gains, losses,
adequate CNV size coverage across the range of sizes claimed by the
device, adequate chromosomal coverage, challenging regions in the
genome, CNVs reported at the lower range of the assay, interstitial,
subtelomeric, and pericentromeric rearrangements, aneuploidy,
unbalanced translocations, mosaicism, and known syndromic regions).
CNVs identified by the device must be compared to comparator method(s).
Agreement between the CNVs detected by the array and the comparator
must be summarized in a tabular format that includes the positive
percent agreement and false positive rate stratified by size range and
range of probe numbers for gains and losses separately and calculated
for overall;
(C) Assay performance data for CNVs reported at the lower range of
the assay for both gains and losses;
(D) Device analytical sensitivity data, including DNA input and
limit of detection for mosaicism, if applicable;
(E) Device analytical specificity data, including interference,
carryover, and cross-contamination data;
(F) Device stability data, including real-time stability under
various storage times, temperatures, and freeze-thaw conditions;
(G) Specimen matrix comparison data if more than one specimen type
or anticoagulant can be tested with the device;
(H) Data that demonstrates the clinical validity, including
diagnostic yield, of the device using a minimum of 800 retrospective
clinical samples that were collected prospectively and obtained from
three or more clinical laboratories, with results interpretation
equally divided between two or more qualified healthcare professionals
(e.g., cytogeneticists). Patients must be representative of the
intended use population and not limited to common syndromes. Diagnostic
yield data must be summarized in tabular format and stratified by the
comparison methodologies. Data must also be summarized comparing
interpretation of results, with description of reasons for variability
in calls between the device and the standard of care methods. Data to
support the accuracy of calls for known syndromes must be included; and
(I) Data that demonstrates device results when a minimum of 100
apparently healthy, phenotypically normal individuals are tested and
interpreted by one or more cytogeneticists blinded to the patient
status.
(iii) Identification of risk mitigation elements used by the
device, including a description of all additional procedures, methods,
and practices incorporated into the directions for use that mitigate
risks associated with testing.
(2) The labeling required under Sec. 809.10 of this chapter must
include:
(i) A warning statement that the device is not intended to be used
for standalone diagnostic purposes, pre-implantation or prenatal
testing or screening, population screening, or for the detection of, or
screening for, acquired or somatic genetic aberrations;
(ii) Limitations regarding the assay's performance with respect to
validated CNVs reported at the lower range of the assay, stratified by
size range and range of probe numbers for gains and losses separately;
and limitations regarding problematic (hypervariable) regions, loss of
heterozygosity, mosaicism, and inability to detect balanced
translocations, as appropriate;
(iii) A warning statement that interpretation of assay results is
intended to be performed by qualified healthcare professionals such as
clinical cytogeneticists or molecular geneticists; and,
(iv) A description of the performance studies performed in
accordance with paragraph (b)(1)(ii) of this section and a summary of
the results.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-16032 Filed 8-20-25; 8:45 am]
BILLING CODE 4164-01-P
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