[Federal Register Volume 89, Number 180 (Tuesday, September 17, 2024)]
[Rules and Regulations]
[Pages 75953-75955]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-21086]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2024-N-4084]


Medical Devices; Immunology and Microbiology Devices; 
Classification of the Quantitative Viral Nucleic Acid Test for 
Transplant Patient Management

AGENCY: Food and Drug Administration, HHS.

ACTION: Final amendment; final order.

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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is 
classifying the quantitative viral nucleic acid test for transplant 
patient management 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 quantitative viral 
nucleic acid test for transplant patient management'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.

DATES: This order is effective September 17, 2024. The classification 
was applicable on July 30, 2020.

FOR FURTHER INFORMATION CONTACT: Silke Schlottmann, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, Rm. 3258, Silver Spring, MD 20993-0002, 301-
796-9551, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Upon request, FDA has classified the quantitative viral nucleic 
acid test for transplant patient management as class II (special 
controls), which we have determined will provide a reasonable assurance 
of safety and effectiveness.
    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 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.
    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 
510(k) process, when necessary, to market their device.

II. De Novo Classification

    On March 2, 2020, FDA received Roche Molecular Systems, Inc.'s 
request for De Novo classification of the cobas EBV. 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 July 30, 2020, FDA issued an order to the requester 
classifying the device into class II. In

[[Page 75954]]

this final order, FDA is codifying the classification of the device by 
adding 21 CFR 866.3183.\1\ We have named the generic type of device 
quantitative viral nucleic acid test for transplant patient management, 
and it is identified as a device intended for prescription use in the 
detection of viral pathogens by measurement of viral deoxyribonucleic 
acid (DNA) or ribonucleic acid (RNA) using specified specimen 
processing, amplification, and detection instrumentation. The test is 
intended for use as an aid in the management of transplant patients 
with active viral infection or at risk for developing viral infections. 
The test results are intended to be interpreted by qualified healthcare 
professionals in conjunction with other relevant clinical and 
laboratory findings.
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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--Quantitative Viral Nucleic Acid Test for Transplant Patient
                Management Risks and Mitigation Measures
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  Identified risks to health              Mitigation measures
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Risk of false results........  Certain warnings, limitations, results
                                interpretation information, and
                                explanation of procedures in labeling;
                                and
                               Certain device descriptions and
                                specifications, analytical studies,
                                clinical studies, and risk analysis in
                                design verification and validation.
Failure to correctly           Certain warnings, limitations, results
 interpret test results.        interpretation information, and
                                explanation of procedures in labeling.
Failure to correctly operate   Certain warnings, limitations, results
 the device.                    interpretation information, and
                                explanation of procedures in labeling.
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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 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 
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.  866.3183 to subpart D to read as follows:


Sec.  866.3183  Quantitative viral nucleic acid test for transplant 
patient management.

    (a) Identification. A quantitative viral nucleic acid test for 
transplant patient management is identified as a device intended for 
prescription use in the detection of viral pathogens by measurement of 
viral DNA or RNA using specified specimen processing, amplification, 
and detection instrumentation. The test is intended for use as an aid 
in the management of transplant patients with active viral infection or 
at risk for developing viral infections. The test results are intended 
to be interpreted by qualified healthcare professionals in conjunction 
with other relevant clinical and laboratory findings.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) The labeling required under Sec.  809.10(b) of this chapter 
must include:
    (i) A prominent statement that the device is not intended for use 
as a donor screening test for the presence of viral nucleic acid in 
blood or blood products.
    (ii) Limitations which must be updated to reflect current clinical 
practice. These limitations must include, but are not limited to, 
statements that indicate:
    (A) Test results are to be interpreted by qualified licensed 
healthcare professionals in conjunction with clinical signs and 
symptoms and other relevant laboratory results; and
    (B) Negative test results do not preclude viral infection or tissue 
invasive viral disease and that test results must not be the sole basis 
for patient management decisions.

[[Page 75955]]

    (iii) A detailed explanation of the interpretation of results and 
acceptance criteria must be provided and include specific warnings 
regarding the potential for variability in viral load measurement when 
samples are measured by different devices. Warnings must include the 
following statement, where applicable: ``Due to the potential for 
variability in [analyte] measurements across different [analyte] 
assays, it is recommended that the same device be used for the 
quantitation of [analyte] when managing individual patients.''
    (iv) A detailed explanation of the principles of operation and 
procedures for assay performance.
    (2) Design verification and validation must include the following:
    (i) Detailed documentation of the device description, including all 
parts that make up the device, ancillary reagents required for use with 
the assay but not provided, an explanation of the methodology, design 
of the primer/probe sequences, rationale for the selected gene target, 
and specifications for amplicon size, guanine-cytosine content, and 
degree of nucleic acid sequence conservation. The design and nature of 
all primary, secondary and tertiary quantitation standards used for 
calibration must also be described.
    (ii) A detailed description of the impact of any software, 
including software applications and hardware-based devices that 
incorporate software, on the device's functions;
    (iii) Documentation and characterization (e.g., determination of 
the identity, supplier, purity, and stability) of all critical reagents 
and protocols for maintaining product integrity throughout its labeled 
shelf-life.
    (iv) Stability data for reagents provided with the device and 
indicated specimen types, in addition to the basis for the stability 
acceptance criteria at all time points chosen across the spectrum of 
the device's indicated life cycle, which must include a time point at 
the end of shelf life.
    (v) All stability protocols, including acceptance criteria.
    (vi) Final lot release criteria along with documentation of an 
appropriate justification that lots released at the extremes of the 
specifications will meet the claimed analytical and clinical 
performance characteristics as well as the stability claims.
    (vii) Risk analysis and documentation demonstrating how risk 
control measures are implemented to address device system hazards, such 
as Failure Mode Effects Analysis and/or Hazard Analysis. This 
documentation must include a detailed description of a protocol 
(including all procedures and methods) for the continuous monitoring, 
identification, and handling of genetic mutations and/or novel viral 
stains (e.g., regular review of published literature and annual in 
silico analysis of target sequences to detect possible primer or probe 
mismatches). All results of this protocol, including any findings, must 
be documented.
    (viii) Analytical performance testing that includes:
    (A) Detailed documentation of the following analytical performance 
studies: limit of detection, upper and lower limits of quantitation, 
inclusivity, precision, reproducibility, interference, cross 
reactivity, carry-over, quality control, specimen stability studies, 
and additional studies as applicable to specimen type and intended use 
for the device;
    (B) Identification of the viral strains selected for use in 
analytical studies, which must be representative of clinically relevant 
circulating strains;
    (C) Inclusivity study results obtained with a variety of viral 
genotypes as applicable to the specific assay target and supplemented 
by in silico analysis;
    (D) Reproducibility studies that include the testing of three 
independent production lots;
    (E) Documentation of calibration to a reference standard that FDA 
has determined is appropriate for the quantification of viral DNA or 
RNA (e.g., a recognized consensus standard); and
    (F) Documentation of traceability performed each time a new lot of 
the standardized reference material to which the device is traceable is 
released, or when the field transitions to a new standardized reference 
material.
    (ix) Clinical performance testing that includes:
    (A) Detailed documentation from either a method comparison study 
with a comparator that FDA has determined is appropriate, or results 
from a prospective clinical study demonstrating clinical validity of 
the device;
    (B) Data from patient samples, with an acceptable number of the 
virus-positive samples containing an analyte concentration near the 
lower limit of quantitation and any clinically relevant decision 
points. If an acceptable number of virus-positive samples containing an 
analyte concentration near the lower limit of quantitation and any 
clinically relevant decision cannot be obtained, contrived samples may 
be used to supplement sample numbers when appropriate, as determined by 
FDA;
    (C) The method comparison study must include predefined maximum 
acceptable differences between the test and comparator method across 
all primary outcome measures in the clinical study protocol; and
    (D) The final release test results for each lot used in the 
clinical study.

    Dated: September 12, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-21086 Filed 9-16-24; 8:45 am]
BILLING CODE 4164-01-P