
[Federal Register Volume 84, Number 50 (Thursday, March 14, 2019)]
[Rules and Regulations]
[Pages 9226-9228]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-04719]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2019-N-0360]


Medical Devices; Immunology and Microbiology Devices; 
Classification of the Device To Detect and Identify Microorganisms and 
Associated Resistance Marker Nucleic Acids Directly in Respiratory 
Specimens

AGENCY: Food and Drug Administration, HHS.

ACTION: Final order.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or we) is classifying 
the device to detect and identify microorganisms and associated 
resistance marker nucleic acids directly in respiratory specimens 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 microorganisms 
and associated resistance marker nucleic acids directly in respiratory 
specimens 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 March 14, 2019. The classification was 
applicable on April 3, 2018.

FOR FURTHER INFORMATION CONTACT: Dina Jerebitski, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, Rm. 4450, Silver Spring, MD 20993-0002, 301-
796-4221, Dina.Jerebitski@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background

    Upon request, FDA has classified the device to detect and identify 
microorganisms and associated resistance marker nucleic acids directly 
in respiratory specimens as class II (special controls), which we have 
determined will provide a reasonable assurance of safety and 
effectiveness. In addition, we believe this action will enhance 
patients' access to beneficial innovation, in part by reducing 
regulatory burdens by placing the device into a lower device class than 
the automatic class III assignment.
    The automatic assignment of class III occurs by operation of law 
and without any action by FDA, regardless of the level of risk posed by 
the new device. Any device that was not in commercial distribution 
before May 28, 1976, is automatically classified as, and remains 
within, class III and requires premarket approval unless and until FDA 
takes an action to classify or reclassify the device (see 21 U.S.C. 
360c(f)(1)). We refer to these devices as ``postamendments devices'' 
because they were not in commercial distribution prior to the date of 
enactment of the Medical Device Amendments of 1976, which amended the 
Federal Food, Drug, and Cosmetic Act (FD&C Act).
    FDA may take a variety of actions in appropriate circumstances to 
classify or reclassify a device into class I or II. We may issue an 
order finding a new device to be substantially equivalent under section 
513(i) of the FD&C Act to a predicate device that does not require 
premarket approval (see 21 U.S.C. 360c(i)). We determine whether a new 
device is substantially equivalent to a predicate by means of the 
procedures for premarket notification under section 510(k) (21 U.S.C. 
360(k)) of the FD&C

[[Page 9227]]

Act and Part 807 (21 CFR part 807) respectively.
    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 established the first procedure for De Novo classification 
(Pub. L. 105-115). Section 607 of the Food and Drug Administration 
Safety and Innovation Act modified the De Novo application process by 
adding a second procedure (Pub. L. 112-144). 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 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 21 U.S.C. 360c(f)(2)(B)(i)). As a 
result, other device sponsors do not have to submit a De Novo request 
or premarket approval application in order to market a substantially 
equivalent device (see 21 U.S.C. 360c(i), defining ``substantial 
equivalence''). Instead, sponsors can use the 510(k) process, when 
necessary, to market their device.

II. De Novo Classification

    On September 11, 2017, Curetis GmbH submitted a request for De Novo 
classification of the Unyvero LRT Application. 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 April 3, 2018, FDA issued an order to the requester 
classifying the device into class II. FDA is codifying the 
classification of the device by adding 21 CFR 866.3985. We have named 
the generic type of device ``device to detect and identify 
microorganisms and associated resistance marker nucleic acids directly 
in respiratory specimens,'' and it is identified as an in vitro 
diagnostic device intended for the detection and identification of 
microorganisms and associated resistance markers in respiratory 
specimens collected from patients with signs or symptoms of respiratory 
infection. The device is intended to aid in the diagnosis of 
respiratory infection in conjunction with clinical signs and symptoms 
and other laboratory findings. These devices do not provide 
confirmation of antibiotic susceptibility since mechanisms of 
resistance may exist other than those detected by the device.
    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 Microorganisms and Associated
 Resistance Marker Nucleic Acids Directly in Respiratory Specimens Risks
                         and Mitigation Measures
------------------------------------------------------------------------
       Identified risks                   Mitigation measures
------------------------------------------------------------------------
Incorrect identification or    General Controls and Special Controls (1)
 lack of identification of a    (21 CFR 866.3985(b)(1)), (2) (21 CFR
 pathogenic microorganism by    866.3985(b)(2)), (3) (21 CFR
 the device can lead to         866.3985(b)(3)), and (4) (21 CFR
 improper patient management.   866.3985(b)(4)).
Failure to correctly           General Controls and Special Controls (1)
 interpret test results.        (21 CFR 866.3985(b)(1)), (2)(iii) (21
                                CFR 866.3985(b)(2)(iii)), (2)(iv) (21
                                CFR 866.3985(b)(2)(iv)), (2)(v) (21 CFR
                                866.3985(b)(2)(v)), (2)(vi) (21 CFR
                                866.3985(b)(2)(vi)), (2)(vii) (21 CFR
                                866.3985(b)(2)(vii)), (2)(viii) (21 CFR
                                866.3985(b)(2)(viii)), and (3) (21 CFR
                                866.3985(b)(3)).
Failure to correctly operate   General Controls and Special Controls (1)
 the instrument.                (21 CFR 866.3985(b)(1)), (2)(i) (21 CFR
                                866.3985(b)(2)(i)), (4)(ii) (21 CFR
                                866.3985(b)(4)(ii)), (4)(iii) (21 CFR
                                866.3985(b)(4)(iii)), and (4)(iv) (21
                                CFR 866.3985(b)(4)(iv)).
------------------------------------------------------------------------

    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).

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

[[Page 9228]]

(OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). 
The collections of information in the guidance document ``De Novo 
Classification Process (Evaluation of Automatic Class III 
Designation)'' have been approved under OMB control number 0910-0844; 
the collections of information in 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 
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.  866.3985 to subpart D to read as follows:


Sec.  866.3985  Device to detect and identify microorganisms and 
associated resistance marker nucleic acids directly in respiratory 
specimens.

    (a) Identification. A device to detect and identify microorganisms 
and associated resistance marker nucleic acids directly from 
respiratory specimens is an in vitro diagnostic device intended for the 
detection and identification of microorganisms and associated 
resistance markers in respiratory specimens collected from patients 
with signs or symptoms of respiratory infection. The device is intended 
to aid in the diagnosis of respiratory infection in conjunction with 
clinical signs and symptoms and other laboratory findings. These 
devices do not provide confirmation of antibiotic susceptibility since 
mechanisms of resistance may exist other than those detected by the 
device.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) The intended use for the 21 CFR 809.10 labeling must include a 
detailed description of what the device detects, the type of results 
provided to the user, the clinical indications appropriate for test 
use, and the specific population(s) for which the device is intended.
    (2) The 21 CFR 809.10(b) labeling must include:
    (i) A detailed device description, including all device components, 
control elements incorporated into the test procedure, instrument 
requirements, ancillary reagents required but not provided, and a 
detailed explanation of the methodology, including all pre-analytical 
methods for processing of specimens.
    (ii) Performance characteristics from analytical studies, 
including, but not limited to, limit of detection, inclusivity, 
reproducibility, cross reactivity, interfering substances, competitive 
inhibition, carryover/cross contamination, specimen stability, and 
linearity, as applicable.
    (iii) A limiting statement that the device is intended to be used 
in conjunction with clinical history, signs and symptoms, and results 
of other diagnostic tests, including culture and antimicrobial 
susceptibility testing.
    (iv) A detailed explanation of the interpretation of test results 
for clinical specimens and acceptance criteria for any quality control 
testing.
    (v) A limiting statement that negative results for microorganisms 
do not preclude the possibility of infection, and should not be used as 
the sole basis for diagnosis, treatment, or other patient management 
decisions.
    (vi) If applicable, a limiting statement that detected 
microorganisms may not be the cause of lower respiratory tract 
infection and may be indicative of colonizing or normal respiratory 
flora.
    (vii) If applicable, a limiting statement that detection of 
resistance markers cannot be definitively linked to specific 
microorganisms and that the source of a detected resistance marker may 
be an organism not detected by the assay, including colonizing flora.
    (viii) If applicable, a limiting statement that detection of 
antibiotic resistance markers may not correlate with phenotypic gene 
expression.
    (3) The 21 CFR 809.10(b) labeling and any test report generated by 
the device must include a limiting statement that negative results for 
resistance markers do not indicate susceptibility of detected 
microorganisms.
    (4) Design verification and validation must include:
    (i) Performance characteristics from clinical studies that include 
prospective (sequential) samples and, if appropriate, additional 
characterized samples. The study must be performed on a study 
population consistent with the intended use population and compare the 
device performance to results obtained from an FDA accepted reference 
method and/or FDA accepted comparator method, as appropriate. Results 
from the clinical studies must include the clinical study protocol 
(including predefined statistical analysis plan, if applicable), 
clinical study report, and results of all statistical analyses.
    (ii) A detailed device description including the following:
    (A) Thorough description of the assay methodology including, but 
not limited to, primer/probe sequences, primer/probe design, and 
rationale for target sequence selection, as applicable.
    (B) Algorithm used to generate a final result from raw data (e.g., 
how raw signals are converted into a reported result).
    (iii) A detailed description of device software, including, but not 
limited to, validation activities and outcomes.
    (iv) 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.

    Dated: March 8, 2019.
Lowell J. Schiller,
Acting Associate Commissioner for Policy.
[FR Doc. 2019-04719 Filed 3-13-19; 8:45 am]
BILLING CODE 4164-01-P


