Federal Register / Vol. 82, No. 208 / Monday, October 30, 2017 / Rules and Regulations 50075 

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. 

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, 

steven.tjoe@fda.hhs.gov. 

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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50076 Federal Register / Vol. 82, No. 208 / Monday, October 30, 2017 / Rules and Regulations 

required to mitigate these risks in 

table 1. 

TABLE 1—AQUAPORIN-4 AUTOANTIBODY IMMUNOLOGICAL TEST SYSTEM RISKS AND MITIGATION MEASURES

Identified risks Mitigation measures/21 CFR section 

Inaccurate test results that provide false positive or false negative results can lead to improper patient management.Special controls (1), (2), and (3) (21 CFR 866.5665(b)(1); 21 CFR 

866.5665(b)(2); and 21 CFR 866.5665(b)(3)). 

Failure to correctly interpret test results can lead to false positive or 

false negative results.

Special controls (1)(iii), (2), and (3) (21 CFR 866.5665(b)(1)(iii); 21 

CFR 866.5665(b)(2); and 21 CFR 866.5665(b)(3)). 

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 

■ 1. The authority citation for part 866 

continues to read as follows: 

Authority: 21 U.S.C. 351, 360, 360c, 360e, 

360j, 360l, 371. 

■ 2. Add § 866.5665 to subpart F to read 

as follows: 

§ 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 hardwarebased 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 wellcharacterized panel of patient samples 

from the indicated population covering 

the device measuring range must be 

used. 


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Federal Register / Vol. 82, No. 208 / Monday, October 30, 2017 / Rules and Regulations 50077 

(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 nontarget 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 standalone 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 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 866 

[Docket No. FDA–2017–N–5924] 

Medical Devices; Immunology and 

Microbiology Devices; Classification of 

the Newborn Screening Test for Severe 

Combined Immunodeficiency Disorder 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final order. 

SUMMARY: The Food and Drug 

Administration (FDA or we) is 

classifying the newborn screening test 

for severe combined immunodeficiency 

disorder (SCID) 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 newborn 

screening test for SCID’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 December 15, 2014. 

FOR FURTHER INFORMATION CONTACT: 

Caryl Giuliano, Center for Devices and 

Radiological Health, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 66, Rm. 5664, Silver Spring, 

MD 20993–0002, 301–796–2478, 

caryl.giuliano@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background 

Upon request, FDA has classified the 

newborn screening test for SCID 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. 


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