[Federal Register Volume 89, Number 159 (Friday, August 16, 2024)]
[Rules and Regulations]
[Pages 66552-66556]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-18266]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2024-N-3655]


Medical Devices; Immunology and Microbiology Devices; 
Classification of the Device To Detect and Identify Nucleic Acid 
Targets Including SARS-CoV-2 in Respiratory Specimens

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 device to detect and identify nucleic acid targets in 
respiratory specimens from microbial agents that cause the SARS-CoV-2 
respiratory infection and other microbial agents when in a multi-target 
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 device to detect and identify nucleic acid 
targets in respiratory specimens from microbial agents that cause the 
SARS-CoV-2 respiratory infection and other microbial agents when in a 
multi-target 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.

DATES: This order is effective August 16, 2024. The classification was 
applicable on March 17, 2021.

FOR FURTHER INFORMATION CONTACT: Uwe Scherf, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, Rm. 3110, Silver Spring, MD 20993-0002, 301-796-5456, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Upon request, FDA has classified the device to detect and identify 
nucleic acid targets in respiratory specimens from microbial agents 
that cause the SARS-CoV-2 respiratory infection and other microbial 
agents when in a multi-target 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 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).

[[Page 66553]]

    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. 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) of the FD&C Act.
    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 
less-burdensome 510(k) process, when necessary, to market their device.

II. De Novo Classification

    On May 19, 2020, FDA received Biofire Diagnostics, LLC's request 
for De Novo classification of the BioFire Respiratory Panel 2.1 (RP2.1) 
device. 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 March 17, 2021, 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 
866.3981.\1\ We have named the generic type of device as device to 
detect and identify nucleic acid targets in respiratory specimens from 
microbial agents that cause the SARS-CoV-2 respiratory infection and 
other microbial agents when in a multi-target test, and it is 
identified as an in vitro diagnostic device intended for the detection 
and identification of SARS-CoV-2 and other microbial agents when in a 
multi-target test in human clinical respiratory specimens from patients 
suspected of respiratory infection who are at risk for exposure or who 
may have been exposed to these agents. The device is intended to aid in 
the diagnosis of respiratory infection in conjunction with other 
clinical, epidemiologic, and laboratory data or other risk factors.
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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.'' In December 2019, FDA began adding the term ``Final 
amendment'' to the ``ACTION'' caption for these documents, typically 
styled ``Final order,'' to indicate an amendment to the Code of 
Federal Regulations. This editorial 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--Device To Detect and Identify Nucleic Acid Targets in
  Respiratory Specimens From Microbial Agents That Cause the SARS-CoV-2
 Respiratory Infection and Other Microbial Agents When in a Multi-Target
                   Test Risks and Mitigation Measures
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         Identified risks                    Mitigation measures
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Risk of an inaccurate test result   Certain labeling information,
 (false positive or false negative   including limitations, warnings,
 result) leading to improper         device descriptions, explanation of
 patient management.                 procedures, and performance
                                     information identified in special
                                     controls (1), (3), (5), and (6);
                                    Use of certain specimen collection
                                     devices identified in special
                                     control (2);
                                    Certain design verification and
                                     validation, documentation of
                                     certain analytical studies and
                                     clinical studies, risk analysis
                                     strategies, and device descriptions
                                     identified in special control (4);
                                     and Testing of characterized viral
                                     samples and labeling information
                                     identified in special control (7).
Misinterpretation of test results   Certain labeling information,
 leading to misdiagnosis and         including limitations, warnings,
 associated risk of false test       device descriptions, explanation of
 results.                            procedures, results interpretation
                                     information, and performance
                                     information identified in special
                                     controls (1), (3), and (5);
                                    Certain design verification and
                                     validation, documentation of
                                     certain analytical studies and
                                     clinical studies, risk analysis
                                     strategies, and device descriptions
                                     identified in special control (4).

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Failure to correctly operate the    Certain labeling information,
 device leading to inaccurate test   including limitations, warnings,
 results.                            device descriptions, explanation of
                                     procedures, and performance
                                     information identified in special
                                     controls (1), (3), (5), and (6);
                                    Use of certain specimen collection
                                     devices identified in special
                                     control (2); and
                                    Certain design verification and
                                     validation, documentation of
                                     certain analytical studies and
                                     clinical studies, risk analysis
                                     strategies, and device descriptions
                                     identified in special control (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. In order 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 21 CFR 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 801and 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.  866.3981 to read as follows:


Sec.  866.3981  Device to detect and identify nucleic acid targets in 
respiratory specimens from microbial agents that cause the SARS-CoV-2 
respiratory infection and other microbial agents when in a multi-target 
test.

    (a) Identification. A device to detect and identify nucleic acid 
targets in respiratory specimens from microbial agents that cause the 
SARS-CoV-2 respiratory infection and other microbial agents when in a 
multi-target test is an in vitro diagnostic device intended for the 
detection and identification of SARS-CoV-2 and other microbial agents 
when in a multi-target test in human clinical respiratory specimens 
from patients suspected of respiratory infection who are at risk for 
exposure or who may have been exposed to these agents. The device is 
intended to aid in the diagnosis of respiratory infection in 
conjunction with other clinical, epidemiologic, and laboratory data or 
other risk factors.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) The intended use in the labeling required under Sec.  809.10 of 
this chapter must include a description of the following: Analytes and 
targets the device detects and identifies, the specimen types tested, 
the results provided to the user, the clinical indications for which 
the test is to be used, the specific intended population(s), the 
intended use locations including testing location(s) where the device 
is to be used (if applicable), and other conditions of use as 
appropriate.
    (2) Any sample collection device used must be FDA-cleared, -
approved, or -classified as 510(k) exempt (standalone or as part of a 
test system) for the collection of specimen types claimed by this 
device; alternatively, the sample collection device must be cleared in 
a premarket submission as a part of this device.
    (3) The labeling required under Sec.  809.10(b) of this chapter 
must include:
    (i) A detailed device description, including reagents, instruments, 
ancillary materials, all control elements, and a detailed explanation 
of the methodology, including all pre-analytical methods for processing 
of specimens;
    (ii) Detailed descriptions of the performance characteristics of 
the device for each specimen type claimed in the intended use based on 
analytical studies including the following, as applicable: Limit of 
Detection, inclusivity, cross-reactivity, interfering substances, 
competitive inhibition, carryover/cross contamination, specimen 
stability, precision, reproducibility, and clinical studies;
    (iii) Detailed descriptions of the test procedure(s), the 
interpretation of test results for clinical specimens, and acceptance 
criteria for any quality control testing;
    (iv) A warning statement that viral culture should not be attempted 
in cases of positive results for SARS-CoV-2 and/or any similar 
microbial agents unless a facility with an appropriate level of 
laboratory biosafety (e.g., BSL 3 and BSL 3+, etc.) is available to 
receive and culture specimens; and
    (v) A prominent statement that device performance has not been 
established for specimens collected from individuals not identified in 
the intended use population (e.g., when applicable, that device 
performance has not been established in individuals

[[Page 66555]]

without signs or symptoms of respiratory infection).
    (vi) Limiting statements that indicate that:
    (A) A negative test result does not preclude the possibility of 
infection;
    (B) The test results should be interpreted in conjunction with 
other clinical and laboratory data available to the clinician;
    (C) There is a risk of incorrect results due to the presence of 
nucleic acid sequence variants in the targeted pathogens;
    (D) That positive and negative predictive values are highly 
dependent on prevalence;
    (E) Accurate results are dependent on adequate specimen collection, 
transport, storage, and processing. Failure to observe proper 
procedures in any one of these steps can lead to incorrect results; and
    (F) When applicable (e.g., recommended by the Centers for Disease 
Control and Prevention, by current well-accepted clinical guidelines, 
or by published peer-reviewed literature), that the clinical 
performance may be affected by testing a specific clinical 
subpopulation or for a specific claimed specimen type.
    (4) Design verification and validation must include:
    (i) Detailed documentation, including performance results, from a 
clinical study that includes prospective (sequential) samples for each 
claimed specimen type and, as appropriate, additional characterized 
clinical samples. The clinical study must be performed on a study 
population consistent with the intended use population and compare the 
device performance to results obtained using a comparator that FDA has 
determined is appropriate. Detailed documentation must include the 
clinical study protocol (including a predefined statistical analysis 
plan), study report, testing results, and results of all statistical 
analyses.
    (ii) Risk analysis and documentation demonstrating how risk control 
measures are implemented to address device system hazards, such as 
Failure Modes 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 
respiratory pathogen isolates or strains (e.g., regular review of 
published literature and periodic in silico analysis of target 
sequences to detect possible mismatches). All results of this protocol, 
including any findings, must be documented and must include any 
additional data analysis that is requested by FDA in response to any 
performance concerns identified under this section or identified by FDA 
during routine evaluation. Additionally, if requested by FDA, these 
evaluations must be submitted to FDA for FDA review within 48 hours of 
the request. Results that are reasonably interpreted to support the 
conclusion that novel respiratory pathogen strains or isolates impact 
the stated expected performance of the device must be sent to FDA 
immediately.
    (iii) A detailed description of the identity, phylogenetic 
relationship, and other recognized characterization of the respiratory 
pathogen(s) that the device is designed to detect. In addition, 
detailed documentation describing how to interpret the device results 
and other measures that might be needed for a laboratory diagnosis of 
respiratory infection.
    (iv) A detailed device description, including device components, 
ancillary reagents required but not provided, and a detailed 
explanation of the methodology, including molecular target(s) for each 
analyte, design of target detection reagents, rationale for target 
selection, limiting factors of the device (e.g., saturation level of 
hybridization and maximum amplification and detection cycle number, 
etc.), internal and external controls, and computational path from 
collected raw data to reported result (e.g., how collected raw signals 
are converted into a reported signal and result), as applicable.
    (v) A detailed description of device software, including software 
applications and hardware-based devices that incorporate software. The 
detailed description must include documentation of verification, 
validation, and hazard analysis and risk assessment activities, 
including an assessment of the impact of threats and vulnerabilities on 
device functionality and end users/patients as part of cybersecurity 
review.
    (vi) For devices intended for the detection and identification of 
microbial agents for which an FDA recommended reference panel is 
available, design verification and validation must include the 
performance results of an analytical study testing the FDA recommended 
reference panel of characterized samples. Detailed documentation must 
be kept of that study and its results, including the study protocol, 
study report for the proposed intended use, testing results, and 
results of all statistical analyses.
    (vii) For devices with an intended use that includes detection of 
Influenza A and Influenza B viruses and/or detection and 
differentiation between the Influenza A virus subtypes in human 
clinical specimens, the design verification and validation must include 
a detailed description of the identity, phylogenetic relationship, or 
other recognized characterization of the Influenza A and B viruses that 
the device is designed to detect, a description of how the device 
results might be used in a diagnostic algorithm and other measures that 
might be needed for a laboratory identification of Influenza A or B 
virus and of specific Influenza A virus subtypes, and a description of 
the clinical and epidemiological parameters that are relevant to a 
patient case diagnosis of Influenza A or B and of specific Influenza A 
virus subtypes. An evaluation of the device compared to a currently 
appropriate and FDA accepted comparator method. Detailed documentation 
must be kept of that study and its results, including the study 
protocol, study report for the proposed intended use, testing results, 
and results of all statistical analyses.
    (5) When applicable, performance results of the analytical study 
testing the FDA recommended reference panel described in paragraph 
(b)(4)(vi) of this section must be included in the device's labeling 
under Sec.  809.10(b) of this chapter.
    (6) For devices with an intended use that includes detection of 
Influenza A and Influenza B viruses and/or detection and 
differentiation between the Influenza A virus subtypes in human 
clinical specimens in addition to detection of SARS-CoV-2 and similar 
microbial agents, the required labeling under Sec.  809.10(b) of this 
chapter must include the following:
    (i) Where applicable, a limiting statement that performance 
characteristics for Influenza A were established when Influenza A/H3 
and A/H1-2009 (or other pertinent Influenza A subtypes) were the 
predominant Influenza A viruses in circulation.
    (ii) Where applicable, a warning statement that reads if infection 
with a novel Influenza A virus is suspected based on current clinical 
and epidemiological screening criteria recommended by public health 
authorities, specimens should be collected with appropriate infection 
control precautions for novel virulent influenza viruses and sent to 
State or local health departments for testing. Viral culture should not 
be attempted in these cases unless a BSL 3+ facility is

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available to receive and culture specimens.
    (iii) Where the device results interpretation involves combining 
the outputs of several targets to get the final results, such as a 
device that both detects Influenza A and differentiates all known 
Influenza A subtypes that are currently circulating, the device's 
labeling must include a clear interpretation instruction for all valid 
and invalid output combinations, and recommendations for any required 
followup actions or retesting in the case of an unusual or unexpected 
device result.
    (iv) A limiting statement that if a specimen yields a positive 
result for Influenza A, but produces negative test results for all 
specific influenza A subtypes intended to be differentiated (i.e., H1-
2009 and H3), this result requires notification of appropriate local, 
State, or Federal public health authorities to determine necessary 
measures for verification and to further determine whether the specimen 
represents a novel strain of Influenza A.
    (7) If one of the actions listed at section 564(b)(1)(A) through 
(D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to 
an influenza viral strain, or if the Secretary of Health and Human 
Services determines, under section 319(a) of the Public Health Service 
Act, that a disease or disorder presents a public health emergency, or 
that a public health emergency otherwise exists, with respect to an 
influenza viral strain:
    (i) Within 30 days from the date that FDA notifies manufacturers 
that characterized viral samples are available for test evaluation, the 
manufacturer must have testing performed on the device with those 
influenza viral samples in accordance with a standardized protocol 
considered and determined by FDA to be acceptable and appropriate.
    (ii) Within 60 days from the date that FDA notifies manufacturers 
that characterized influenza viral samples are available for test 
evaluation and continuing until 3 years from that date, the results of 
the influenza emergency analytical reactivity testing, including the 
detailed information for the virus tested as described in the 
certificate of authentication, must be included as part of the device's 
labeling in a tabular format, either by:
    (A) Placing the results directly in the device's labeling required 
under Sec.  809.10(b) of this chapter that accompanies the device in a 
separate section of the labeling where analytical reactivity testing 
data can be found, but separate from the annual analytical reactivity 
testing results; or
    (B) In a section of the device's label or in other labeling that 
accompanies the device, prominently providing a hyperlink to the 
manufacturer's public website where the analytical reactivity testing 
data can be found. The manufacturer's website, as well as the primary 
part of the manufacturer's website that discusses the device, must 
provide a prominently placed hyperlink to the website containing this 
information and must allow unrestricted viewing access.

    Dated: August 12, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-18266 Filed 8-15-24; 8:45 am]
BILLING CODE 4164-01-P