Rule2025-08143
Medical Devices; Immunology and Microbiology Devices; Classification of the DNA-Based Test To Measure Minimal Residual Disease in Hematological Malignancies
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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 9, 2025
Effective
May 9, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, Agency, or we) is classifying the DNA-based test to measure minimal residual disease in hematological 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 DNA-based test to measure minimal residual disease in hematological 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 89 (Friday, May 9, 2025)</title>
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[Federal Register Volume 90, Number 89 (Friday, May 9, 2025)]
[Rules and Regulations]
[Pages 19638-19641]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-08143]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2025-N-0708]
Medical Devices; Immunology and Microbiology Devices;
Classification of the DNA-Based Test To Measure Minimal Residual
Disease in Hematological Malignancies
AGENCY: Food and Drug Administration, Department of Health and Human
Services (HHS).
ACTION: Final amendment; final order.
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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is
classifying the DNA-based test to measure minimal residual disease in
hematological 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 DNA-based test
to measure minimal residual disease in hematological 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 May 9, 2025. The classification was
applicable on September 28, 2018.
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#7a3e13141b54301f081f18130e0911133a1c1e1b54121209541d150c"><span class="__cf_email__" data-cfemail="91d5f8fff0bfdbf4e3f4f3f8e5e2faf8d1f7f5f0bff9f9e2bff6fee7">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background
Upon request, FDA has classified the DNA-based test to measure
minimal residual disease in hematological 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
[[Page 19639]]
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 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 September 29, 2017, FDA received Adaptive Biotechnologies
Corporation's request for De Novo classification of the clonoSEQ 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 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 September 28, 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
866.6100.\1\ We have named the generic type of device ``DNA-based test
to measure minimal residual disease in hematological malignancies,''
and it is identified as a prescription in vitro diagnostic device that
identifies and quantifies specific nucleic acid sequences within human
tissues to estimate the percentage of cells that harbor the specific
sequence(s). The test is intended to be used as an aid to measure
minimal residual disease to assess the change in burden of disease
during monitoring of treatment. The test is indicated for use by
qualified healthcare professionals in accordance with professional
guidelines for clinical decision-making, in conjunction with other
clinicopathological features.
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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
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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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--DNA-Based Test To Measure Minimal Residual Disease in
Hematological Malignancies Risks and Mitigation Measures
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Identified risks to health Mitigation measures
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Incorrect test results....... General controls and special controls (1)
(21 CFR 866.6100(b)(1)), (2) (21 CFR
866.6100(b)(2)), and (3) (21 CFR
866.6100(b)(3)).
Incorrect interpretation of General controls and special controls (1)
test results. (21 CFR 866.6100(b)(1)), (2) (21 CFR
866.6100(b)(2)), (3) (21 CFR
866.6100(b)(3)), and (4) (21 CFR
866.6100(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
[[Page 19640]]
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, subpart 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 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. 866.6100 to subpart G to read as follows:
Sec. 866.6100 DNA-based test to measure minimal residual disease in
hematological malignancies.
(a) Identification. A DNA-based test to measure minimal residual
disease in hematological malignancies is a prescription in vitro
diagnostic device that identifies and quantifies specific nucleic acid
sequences within human tissues to estimate the percentage of cells that
harbor the specific sequence(s). The test is intended to be used as an
aid to measure minimal residual disease to assess the change in burden
of disease during monitoring of treatment. The test is indicated for
use by qualified healthcare professionals in accordance with
professional guidelines for clinical decision-making, in conjunction
with other clinicopathological features.
(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 the device, including:
(A) A detailed description of all test components, reagents,
instrumentation, and software, including software applications and any
hardware-based devices that incorporate software.
(B) A detailed description of all genomic regions that are detected
and quantified by the assay.
(C) A detailed description of the methodology and protocols for
each step of the test, including description of the quality metrics,
thresholds, and filters at each step of the test that are implemented
for final result reporting and a description of the metrics for run-
failures, specimen-failures, and invalids, as appropriate.
(D) Detailed specifications and procedures for sample collection,
processing, and storage.
(E) A description of the internal and external controls that are
recommended or provided. The description must identify those control
elements that are incorporated into the testing procedure. If
appropriate, this description must include a description of the
controls and control procedures used during the sequencing and data
analysis.
(ii) Identification of risk mitigation elements used by the device,
including a detailed description of all additional procedures, methods,
and practices incorporated into the instructions for use that mitigate
risks associated with use of the device.
(iii) As part of the risk management activities, an appropriate end
user device training program must be offered as an effort to mitigate
the risk of failure from user error, as appropriate.
(iv) Description of analytical and clinical studies, including:
(A) Device performance data that demonstrates the ability to
measure minimal residual disease in the claimed specimen type(s) from
patients that are representative of the intended use population. Data
can be obtained via:
(1) A method comparison study comparing the device to a predicate
device with clinical data for the specified hematological neoplastic
indication using the specified specimen type(s); or
(2) A clinical study demonstrating clinical validity using well
characterized clinical specimens from patients with known clinical
outcomes using a study design deemed acceptable by FDA.
(B) Device precision (repeatability and reproducibility) data using
clinical samples covering the range of minimal residual disease
frequencies reported by the test and covering the stated range of DNA
inputs that are indicated as allowable for use with the test. Results
shall be reported as the standard deviation and/or percentage
coefficient of variation with the 95 percent confidence interval for
each level tested. The study must evaluate all sources of variability,
including, as appropriate, between-site and between operator (minimum
of three sites of which two must be external with a minimum of two
operators per site), between-day (minimum of 3 days), between-run,
within-run, between-lot (minimum of three lots), between instrument
(minimum of three instruments), and total variation.
(C) Device linearity data generated from samples covering the
device measuring range using a dilution panel created from clinical
samples.
(D) Device accuracy by comparison to flow cytometry across the
measuring interval or to the predicate method across the measuring
interval.
(E) Device analytic sensitivity data, including limit of blank,
limit of detection, and limit of quantitation, using a dilution panel
created from clinical samples.
(F) Analytical specificity data, including interference and cross-
contamination, and index cross-contamination, as appropriate.
(G) Validation of pre-analytical methods, including DNA extraction
methods and cell enrichment methods, as appropriate.
(H) Device stability data, including real-time stability of
reagents under various storage times and temperatures.
(I) Specimen and prepared sample stability data established for
each specimen matrix in the anticoagulant
[[Page 19641]]
combinations and storage/use conditions that will be indicated,
including specimen transport, as appropriate.
(2) The intended use for the labeling required under Sec.
809.10(a)(4) of this chapter and for the labeling required under Sec.
809.10(b)(5)(ii) of this chapter, as applicable, must include:
(i) The clinical hematopoietic malignancy for which the assay was
designed and validated (e.g., multiple myeloma or B-cell acute
lymphoblastic leukemia);
(ii) Specimen type (e.g., bone marrow);
(iii) The specific DNA regions that are being identified and
quantified (e.g., rearranged IgH (VDJ), IgH (DJ), IgK, and IgL receptor
gene sequences); and
(iv) A statement that the results are indicated to be interpreted
by qualified healthcare professionals in accordance with professional
guidelines for clinical decision-making in conjunction with other
clinicopathological features.
(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)(A) through (I) of this section.
(4) The device output, including any test report, must include the
estimated minimal residual disease (MRD) frequency and an appropriate
range of the uncertainty of that frequency based on the amount of DNA
that was evaluated by the test and the number of specific nucleic acid
sequences that were detected (e.g., ``MRD = 1.2 x 10<SUP>-5</SUP>
[Range = 0.8 x 10<SUP>-6</SUP> to 2.0 x 10<SUP>-5</SUP>]'').
Dated: May 5, 2025.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-08143 Filed 5-8-25; 8:45 am]
BILLING CODE 4164-01-P
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</html>Indexed from Federal Register on May 9, 2025.
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