Rule2025-09641
Medical Devices; Immunology and Microbiology Devices; Classification of the Inherited Nucleotide Repeat Disorder Deoxyribonucleic Acid Test
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
May 29, 2025
Effective
May 29, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, Agency, or we) is classifying the inherited nucleotide repeat disorder DNA test 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 inherited nucleotide repeat disorder DNA test's 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
<html>
<head>
<title>Federal Register, Volume 90 Issue 102 (Thursday, May 29, 2025)</title>
</head>
<body><pre>
[Federal Register Volume 90, Number 102 (Thursday, May 29, 2025)]
[Rules and Regulations]
[Pages 22629-22632]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-09641]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2025-N-1183]
Medical Devices; Immunology and Microbiology Devices;
Classification of the Inherited Nucleotide Repeat Disorder
Deoxyribonucleic Acid Test
AGENCY: Food and Drug Administration, HHS.
ACTION: Final amendment; final order.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is
classifying the inherited nucleotide repeat disorder DNA test 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 inherited nucleotide repeat disorder DNA
test's 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 May 29, 2025. The classification was
applicable on February 21, 2020.
FOR FURTHER INFORMATION CONTACT: Dina Jerebitski, Center for Devices
and Radiological Health, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 66, Rm. 3574, Silver Spring, MD 20993-0002, 301-
796-2411, <a href="/cdn-cgi/l/email-protection#57133e3936791d322532353e23243c3e17313336793f3f2479303821"><span class="__cf_email__" data-cfemail="4105282f206f0b243324232835322a28012725206f2929326f262e37">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background
Upon request, FDA has classified the inherited nucleotide repeat
disorder DNA test 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 (see 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
[[Page 22630]]
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 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 April 18, 2019, FDA received Asuragen, Inc.'s request for De
Novo classification of the AmplideX Fragile X Dx & Carrier Screen 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 21 U.S.C. 360c(a)(1)(B)). 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 February 21, 2020, 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
866.5970.\1\ We have named the generic type of device inherited
nucleotide repeat disorder DNA test, and it is identified as a
prescription in vitro diagnostic device that is intended to detect and
identify the number of nucleotide repeats in a gene using genomic DNA
isolated from post-natal patient specimens. It is solely intended as an
aid for carrier testing and as an aid for the diagnosis of inherited
nucleotide repeat-associated disorders. Assay results are solely
intended to be used in conjunction with other clinical and diagnostic
findings. These tests do not include those indicated for use for fetal
diagnostic testing or newborn screening.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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--Inherited Nucleotide Repeat Disorder DNA Test Risks and
Mitigation Measures
------------------------------------------------------------------------
Identified risks to health Mitigation measures
------------------------------------------------------------------------
Incorrect test results............... Certain design verification and
validation, and Certain labeling
information.
Incorrect interpretation of test Certain design verification and
results. validation, and Certain labeling
information.
------------------------------------------------------------------------
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 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 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 quality system regulation, have been approved under OMB
control number 0910-0073; and the collections of information in 21 CFR
[[Page 22631]]
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 part 866 continues to read as follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.
0
2. Add Sec. 866.5970 to subpart F to read as follows:
Sec. 866.5970 Inherited nucleotide repeat disorder DNA test.
(a) Identification. An inherited nucleotide repeat disorder DNA
test is a prescription in vitro diagnostic device that is intended to
detect and identify the number of nucleotide repeats in a gene using
genomic DNA isolated from post-natal patient specimens. It is solely
intended as an aid for carrier testing and as an aid for the diagnosis
of inherited nucleotide repeat-associated disorders. Assay results are
solely intended to be used in conjunction with other clinical and
diagnostic findings. These tests do not include those indicated for use
for fetal diagnostic testing or newborn screening.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) The intended use on the device's label required under Sec.
809.10(a)(2) of this chapter and device's labeling required under Sec.
809.10(b)(2) of this chapter must include a statement that assay
results are solely intended to be used in conjunction with other
clinical and diagnostic findings, consistent with professional
standards of practice, and that reflex testing, clinical genetic
evaluation, and genetic counseling should be offered as appropriate.
(2) The labeling required under Sec. 809.10(b) of this chapter
must include:
(i) A warning that mosaicism detected in one tissue may not reflect
mosaicism in other tissues and that the significance of mosaicism
should be interpreted with caution in conjunction with other laboratory
and clinical information (e.g., sex of patient, diagnostic testing or
carrier screening, patient symptoms) and should include appropriate
genetic counseling.
(ii) A prominent statement that this test is not indicated for use
for fetal diagnostic testing, newborn screening or for
stand[hyphen]alone diagnostic purposes.
(iii) Information that addresses how to interpret different result
outputs specific to the technology, such as (peaks) in the
electropherograms.
(3) Design verification and validation must include the following:
(i) Appropriate design features and control elements incorporated
into the testing procedure that mitigate the risk of incorrect clinical
results. These include controls as determined acceptable by FDA that:
(A) Enable the user to determine when the amplification may yield
incorrect results,
(B) Enable the user to determine when cross contamination may have
occurred;
(C) Software risk control measures that address device system
hazards;
(D) Provide software traceability that ensures all hazards are
adequately controlled and that all controls have been validated in the
final device design; and
(E) Ensure the instructions for use and test reports appropriately
inform the user about the limitations of the assay.
(ii) Validated and acceptable, as determined by FDA, criteria for
test result interpretation and reporting, including result outputs.
(iii) Acceptable, as determined by FDA, evidence demonstrating the
clinical validity of the device which supports each indicated
diagnostic use, including for each genotype and associated phenotype
used in providing a clinical determination for the target population.
(iv) Evidence demonstrating acceptable, as determined by FDA,
analytical device performance. Patient specimens must represent the
full spectrum of expected clinical results and be obtained through
unbiased collection. Specimens must be representative of all categories
of results and across the range of repeat sizes (e.g., categories and
repeat sizes for Fragile X syndrome are: normal 1-44 repeats;
intermediate 45-54 repeats; premutation 55-200 repeats, full mutation
greater than 200 repeats), across a range of allelic combinations, be
near decision points, and be from both male and female subjects. The
number of specimens tested must be sufficient to obtain unbiased
estimates of device performance. Analytical validation must include
data demonstrating acceptable, as determined by FDA:
(A) Agreement with a comparator method(s) determined to be
acceptable by FDA. This evidence must demonstrate the accuracy for
detecting the size of the nucleotide repeats and the diagnostic
categorical calls in DNA in the indicated specimen type(s) from
patients that are representative of the intended use population.
Accuracy must be assessed for both diagnostic and carrier subsets
independently.
(B) Device precision including repeatability and reproducibility,
using clinical samples. The study must evaluate all possible sources of
variability including, as appropriate, between-site and between
operator at a minimum of three sites of which two must be external with
a minimum of two operators per site, between-day on a minimum of 3 non-
consecutive days, between-run, within-run, between-lot in a minimum of
three lots, and between instrument on a minimum of three instruments.
Precision must be demonstrated per specimen and determine for both
categorical call and by the size of the repeat (i.e., the percentage of
replicates for which the allele fell within the target precision size
range). Precision data must be calculated and presented with and
without results determined to be invalid.
(C) Device performance at the limit of detection of each allele
across the range of sizes and as a function of the indicated DNA input
for the assay.
(D) Specificity of the reagents for their targets, absence of
cross-reactivity, evaluation of sources of interference relevant to the
specimen type, and a demonstration of the absence of cross
contamination.
(E) Performance of the pre-analytical methods, including DNA
extraction methods.
(F) Performance of the device across the range of indicated DNA
input concentrations for the assay.
(G) Specimen stability throughout indicated specimen storage
ranges, including under expected storage and transport conditions.
(v) Robust evidence demonstrating that the number and frequency of
incorrect results due to mosaicism are clinically acceptable, as
determined by FDA.
(vi) An appropriate traceability plan to minimize the risk of
incorrect results over time, including a description of the molecular
size standards and other reagents that may be required for result
interpretation, as applicable, that demonstrate the reliable
interpretation of the size of the fragments.
(vii) Acceptable, as determined by FDA, device stability protocols
and acceptance criteria, that are sufficient to ensure indicated
analytical and clinical performance throughout the indicated device
stability period. The protocols
[[Page 22632]]
and acceptance criteria must be adequate to demonstrate that there is
no degradation in signal intensity of full mutations when testing a
specimen at the latest indicated time point within the indicated device
stability that is comprised of the lowest indicated DNA input that can
be used.
Dated: May 22, 2025.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-09641 Filed 5-28-25; 8:45 am]
BILLING CODE 4164-01-P
</pre><script data-cfasync="false" src="/cdn-cgi/scripts/5c5dd728/cloudflare-static/email-decode.min.js"></script></body>
</html>Indexed from Federal Register on May 29, 2025.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.