[Federal Register Volume 82, Number 204 (Tuesday, October 24, 2017)]
[Rules and Regulations]
[Pages 49102-49104]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-22995]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2017-N-5651]


Medical Devices; Immunology and Microbiology Devices; 
Classification of the Zinc Transporter 8 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 zinc transporter 8 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 zinc transporter 8 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 24, 2017. The classification was 
applicable on August 20, 2014.

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 zinc transporter 8 
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 (21 U.S.C. 360c(a)(1)). 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 (PMA) 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

    For this device, FDA issued an order on May 21, 2014, finding the 
KRONUS Zinc Transporter 8 Autoantibody (ZnT8Ab) ELISA Assay not 
substantially equivalent to a predicate not subject to PMA. Thus, the 
device remained in class III in accordance with section 513(f)(1) of 
the FD&C Act when we issued the order.
    On June 16, 2014, KRONUS Market Development Associates, Inc., 
submitted a request for De Novo classification of the KRONUS Zinc 
Transporter 8 Autoantibody (ZnT8Ab) 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.

[[Page 49103]]

    Therefore, on August 20, 2014, 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 866.5670. We have named 
the generic type of device zinc transporter 8 autoantibody 
immunological test system, and it is identified as a device that 
consists of reagents used to measure, by immunochemical techniques, the 
autoantibodies in human serum samples that react with Zinc Transporter 
8 (ZnT8). The measurements aid in the diagnosis of Type 1 diabetes 
mellitus (autoimmune mediated diabetes) in conjunction with other 
clinical and laboratory findings.
    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--Zinc Transporter 8 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 866.5670(b)(1), 21
 results can lead to improper patient     CFR 866.5670(b)(2), and 21 CFR
 management.                              866.5670(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.                  866.5670(b)(1)(iii), 21 CFR
                                          866.5670(b)(2), and 21 CFR
                                          866.5670(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).

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 21 CFR 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.  866.5670 to subpart F to read as follows:


Sec.  866.5670  Zinc transporter 8 autoantibody immunological test 
system.

    (a) Identification. A zinc transporter 8 autoantibody immunological 
test system is a device that consists of reagents used to measure, by 
immunochemical techniques, the autoantibodies in human serum samples 
that react with Zinc Transporter 8 (ZnT8). The measurements aid in the 
diagnosis of Type 1 diabetes mellitus (autoimmune mediated diabetes) in 
conjunction with other clinical and laboratory 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 description of the device that includes:
    (A) A detailed description of all components in the test system, 
including a description of the assay components in the kit and all 
required ancillary reagents;
    (B) A detailed description of instrumentation and equipment, and 
illustrations or photographs of non-standard equipment or methods if 
applicable;
    (C) Detailed documentation of the device software, including, but 
not limited to, standalone software applications and hardware-based 
devices that incorporate software where applicable;
    (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 
recommended testing procedures;
    (E) Detailed specifications for sample collection, processing, and 
storage;
    (F) A detailed description of methodology and assay procedure; and
    (G) Detailed specification of the criteria for test results 
interpretation and reporting.
    (ii) Information that demonstrates the performance characteristics 
of the device, including:
    (A) Device precision/reproducibility data generated from within-
run, between-run, between-day, between-lot, between-operator, between-
instruments, between-site, and total precision for multiple 
nonconsecutive days as applicable. A well characterized panel of 
patient samples or pools from the intended use population that covers 
the device measuring range must be used;
    (B) Device linearity data generated from patient samples covering 
the assay 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;

[[Page 49104]]

    (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 indication of use. Patient samples from 
the intended use population covering the device measuring range must be 
used;
    (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 patient samples covering the device measuring 
range;
    (K) A description of how the assay cut-off (the medical decision 
point between positive and negative) was established and validated as 
well as supporting data;
    (L) Clinical performance must be established by comparing data 
generated by testing samples from the intended use population and the 
differential diagnosis groups with the device to the clinical 
diagnostic standard. The diagnosis of Type 1 diabetes mellitus must be 
based on clinical history, physical examination, and laboratory tests, 
such as one or more pancreatic or insulin autoantibody test. Because 
the intended use population for Type 1 diabetes mellitus includes 
subjects less than 18 years old, samples from representative numbers of 
these subjects must be included. Representative numbers of samples from 
all age strata must also be included. The differential diagnosis groups 
must include, but not be limited to the following: Type 2 diabetes 
mellitus; metabolic syndrome; latent autoimmune diabetes in adults; 
other autoimmune diseases such as celiac disease (without a concomitant 
diagnosis of Type 1 diabetes mellitus), systemic lupus erythematosus, 
rheumatoid arthritis, and Hashimoto's thyroiditis; infection; renal 
disease; and testicular cancer. Diseases for the differential groups 
must be based on established diagnostic criteria and clinical 
evaluation. For all samples, the diagnostic clinical criteria and the 
demographic information must be collected and provided. The clinical 
validation results must demonstrate clinical sensitivity and clinical 
specificity for the test values based on the presence or absence of 
Type 1 diabetes mellitus. The data must be summarized in tabular format 
comparing the interpretation of results to the disease status; and
    (M) 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) Your 21 CFR 809.10(a) compliant label and 21 CFR 809.10(b) 
compliant labeling must include warnings relevant to the assay 
including:
    (i) A warning statement that reads, ``The device is for use by 
laboratory professionals in a clinical laboratory setting'';
    (ii) A warning statement that reads, ``The test is not a stand-
alone test but an adjunct to other clinical information. A diagnosis of 
Type 1 diabetes mellitus should not be made on a single test result. 
The clinical symptoms, results on physical examination, and laboratory 
tests (e.g., serological tests), when appropriate, should always be 
taken into account when considering the diagnosis of Type 1 diabetes 
mellitus and Type 2 diabetes mellitus'';
    (iii) A warning statement that reads, ``Absence of Zinc T8 
autoantibody does not rule out a diagnosis of Type 1 diabetes 
mellitus''; and
    (iv) A warning statement that reads, ``The assay has not been 
demonstrated to be effective for monitoring the stage of disease or its 
response to treatment.''
    (3) Your 21 CFR 809.10(b) compliant labeling must include a 
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 18, 2017.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2017-22995 Filed 10-23-17; 8:45 am]
BILLING CODE 4164-01-P


