[Federal Register Volume 82, Number 208 (Monday, October 30, 2017)]
[Rules and Regulations]
[Pages 50075-50077]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-23489]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2017-N-5870]


Medical Devices; Immunology and Microbiology Devices; 
Classification of the Aquaporin-4 Autoantibody Immunological Test 
System

AGENCY: Food and Drug Administration, HHS.

ACTION: Final order.

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SUMMARY: The Food and Drug Administration (FDA or we) is classifying 
the Aquaporin-4 autoantibody immunological test system 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 Aquaporin-4 autoantibody immunological test system'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, in part by reducing regulatory burdens.

DATES: This order is effective October 30, 2017. The classification was 
applicable on April 25, 2016.

FOR FURTHER INFORMATION CONTACT: Steven Tjoe, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, Rm. 4550, Silver Spring, MD 20993-0002, 301-796-5866, 
[email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    Upon request, FDA has classified the Aquaporin-4 autoantibody 
immunological test system 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 (the 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 (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 by means of the procedures 
for premarket notification under section 510(k) of the FD&C Act and 
part 807 (21 U.S.C. 360(k) and 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 placed 
within class III, the De Novo classification is considered to be the 
initial classification of the device.
    We believe this De Novo classification will enhance patients' 
access to beneficial innovation, in part by reducing regulatory 
burdens. When FDA classifies a device into class I or II via the De 
Novo process, the device can serve as a predicate for future devices of 
that type, including for 510(k)s (see 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 less-burdensome 510(k) 
process, when necessary, to market their device.

II. De Novo Classification

    On July 2, 2015, KRONUS, Inc. submitted a request for De Novo 
classification of the KRONUS Aquaporin-4 Autoantibody (AQP4Ab) ELISA 
Assay. FDA reviewed the request in order to classify the device under 
the criteria for classification set forth in section 513(a)(1) of the 
FD&C Act. We classify devices into class II if general controls by 
themselves are insufficient to provide reasonable assurance of safety 
and effectiveness, but there is sufficient information to establish 
special controls that, in combination with the general controls, 
provide reasonable assurance of the safety and effectiveness of the 
device for its intended use (see 21 U.S.C. 360c(a)(1)(B)). After review 
of the information submitted in the request, we determined that the 
device can be classified into class II with the establishment of 
special controls. FDA has determined that these special controls, in 
addition to general controls, will provide reasonable assurance of the 
safety and effectiveness of the device.
    Therefore, on April 25, 2016, FDA issued an order to the requestor 
classifying the device into class II. FDA is codifying the 
classification of the device by adding 21 CFR 866.5665. We have named 
the generic type of device Aquaporin-4 autoantibody immunological test 
system, and it is identified as a device that consists of reagents used 
to measure by immunochemical techniques autoantibodies in human serum 
samples that react with Aquaporin-4 (AQP4Ab). The measurements aid in 
the diagnosis of neuromyelitis optica and neuromyelitis optica spectrum 
disorders, in conjunction with other clinical, laboratory, and 
radiological (e.g., magnetic resonance imaging) findings.
    FDA has identified the following risks to health associated 
specifically with this type of device and the measures

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required to mitigate these risks in table 1.

  Table 1--Aquaporin-4 Autoantibody Immunological Test System Risks and
                           Mitigation Measures
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                                            Mitigation measures/21 CFR
            Identified risks                         section
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Inaccurate test results that provide     Special controls (1), (2), and
 false positive or false negative         (3) (21 CFR 866.5665(b)(1); 21
 results can lead to improper patient     CFR 866.5665(b)(2); and 21 CFR
 management.                              866.5665(b)(3)).
Failure to correctly interpret test      Special controls (1)(iii), (2),
 results can lead to false positive or    and (3) (21 CFR
 false negative results.                  866.5665(b)(1)(iii); 21 CFR
                                          866.5665(b)(2); and 21 CFR
                                          866.5665(b)(3)).
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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. 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. 3501-3520). 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 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.  866.5665 to subpart F to read as follows:


Sec.  866.5665   Aquaporin-4 autoantibody immunological test system.

    (a) Identification. An Aquaporin-4 autoantibody immunological test 
system is a device that consists of reagents used to measure by 
immunochemical techniques autoantibodies in human serum samples that 
react with Aquaporin-4 (AQP4Ab). The measurements aid in the diagnosis 
of neuromyelitis optica (NMO) and neuromyelitis optica spectrum 
disorders (NMOSD) in conjunction with other clinical, laboratory, and 
radiological (e.g., magnetic resonance imaging) findings.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) Premarket notification submissions must include the following 
information:
    (i) A detailed device description including:
    (A) A detailed description of all components including all required 
ancillary reagents in the test;
    (B) If applicable, a detailed description of instrumentation and 
equipment, including illustrations or photographs of non-standard 
equipment or manuals;
    (C) If applicable, detailed documentation of the device software, 
including, but not limited to, standalone software applications and 
hardware-based devices that incorporate software;
    (D) A detailed description of appropriate internal and external 
quality controls that are recommended or provided. The description must 
identify those control elements that are incorporated into the 
specified testing procedures;
    (E) Detailed specifications for sample collection, processing, and 
storage;
    (F) A detailed description of methodology and assay procedure;
    (G) A description of how the assay cutoff (the medical decision 
point between positive and negative) was established and validated as 
well as supporting data; and
    (H) Detailed specification of the criteria for test results 
interpretation and reporting.
    (ii) Detailed information demonstrating the performance 
characteristics of the device, including:
    (A) Device precision/reproducibility data generated from within-
run, between-run, between-day, between-lot, between-site, and total 
precision for multiple nonconsecutive days, as applicable. A well 
characterized panel of patient samples or pools from the indicated 
population that covers the device measuring range must be used.
    (B) Device linearity data generated from samples covering the 
device measuring range, if applicable.
    (C) Information on traceability to a reference material and 
description of value assignment of calibrators and controls, if 
applicable.
    (D) Device analytical sensitivity data, including limit of blank, 
limit of detection, and limit of quantitation, if applicable.
    (E) Device analytical specificity data, including interference by 
endogenous and exogenous substances, as well as cross-reactivity with 
samples derived from patients with other autoimmune diseases or 
conditions.
    (F) Device instrument carryover data, when applicable.
    (G) Device stability data, including real-time stability under 
various storage times and temperatures.
    (H) Specimen stability data, including stability under various 
storage times, temperatures, freeze-thaw, and transport conditions, 
where appropriate.
    (I) Method comparison data generated by comparison of the results 
obtained with the device to those obtained with a legally marketed 
predicate device with similar indications of use. A well-characterized 
panel of patient samples from the indicated population covering the 
device measuring range must be used.

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    (J) Specimen matrix comparison data, if more than one specimen type 
or anticoagulant can be tested with the device. Samples used for 
comparison must be from well-characterized patient samples covering the 
device measuring range.
    (K) Clinical performance must be established by comparing data 
generated by testing samples from the indicated population and the 
differential diagnosis or non-target disease groups with the device to 
the clinical diagnostic standard.
    (1) The diagnosis of NMO and NMOSD must be based on clinical 
findings, laboratory tests (e.g., serological tests), and radiological 
tests (e.g., magnetic resonance imaging).
    (2) The differential diagnosis or non-target disease group must 
include the applicable diseases or conditions, including but not be 
limited to the following: Multiple sclerosis, stroke, Lyme disease, 
shingles, syphilis, human immunodeficiency virus, hepatitis B, 
tuberculosis, Srgen's syndrome, systemic lupus erythematous, systemic 
vasculitis, sarcoidosis, Graves' disease, Hashimoto's disease, Type I 
diabetes, rheumatoid arthritis, Addison's disease, and myasthenia 
gravis.
    (3) Diagnosis of diseases or conditions for the differential or 
non-target disease groups must be based on established diagnostic 
criteria and clinical evaluation.
    (4) For all samples, the diagnostic clinical criteria and the 
demographic information must be collected and provided.
    (5) The clinical validation results must demonstrate clinical 
sensitivity and clinical specificity for the test values based on the 
presence or absence of NMO and NMOSD.
    (6) The data must be summarized in tabular format comparing the 
interpretation of results to the disease status.
    (L) Expected/reference values generated by testing an adequate 
number of samples from apparently healthy normal individuals.
    (iii) Identification of risk mitigation elements used by the 
device, including description of all additional procedures, methods, 
and practices incorporated into the directions for use that mitigate 
risks associated with testing.
    (2) The device's 21 CFR 809.10(b) compliant labeling must include 
warnings relevant to the device including:
    (i) A warning statement that reads ``The device is for use by 
laboratory professionals in a clinical laboratory setting''; and
    (ii) A warning statement that reads ``The device is not to be used 
as a stand-alone device but as an adjunct to other clinical 
information. A diagnosis of Neuromyelitis Optica (NMO) and 
Neuromyelitis Optica Spectrum Disorders (NMOSD) should not be made on a 
single test result. The clinical symptoms, results from physical 
examination, laboratory tests (e.g., serological tests), and 
radiological tests (e.g. Magnetic Resonance Imaging), when appropriate, 
should always be taken into account when considering the diagnosis of 
NMO and NMOSD.''
    (3) The device's 21 CFR 809.10(b) compliant labeling must include a 
detailed description of the protocol and performance studies performed 
in accordance with paragraph (b)(1)(ii) of this section and a summary 
of the results.

    Dated: October 24, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning, Legislation, and Analysis.
[FR Doc. 2017-23489 Filed 10-27-17; 8:45 am]
 BILLING CODE 4164-01-P