Rule2024-18266
Medical Devices; Immunology and Microbiology Devices; Classification of the Device To Detect and Identify Nucleic Acid Targets Including SARS-CoV-2 in Respiratory Specimens
Primary source
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Published
August 16, 2024
Effective
August 16, 2024
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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.
Full Text
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<title>Federal Register, Volume 89 Issue 159 (Friday, August 16, 2024)</title>
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[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 [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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,
<a href="/cdn-cgi/l/email-protection#055072602b56666d607763456361642b6d6d762b626a73"><span class="__cf_email__" data-cfemail="95c0e2f0bbc6f6fdf0e7f3d5f3f1f4bbfdfde6bbf2fae3">[email protected]</span></a>.
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).
[[Page 66554]]
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
[[Page 66556]]
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
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