232 Federal Register / Vol. 83, No. 2 / Wednesday, January 3, 2018 / Rules and Regulations 

instructions, and specifies that action as RC: 

This AD requires using a method approved 

in accordance with the procedures specified 

in paragraph (j) of this AD. 

(i) Credit for Previous Actions 

This paragraph provides credit for the 

actions specified in paragraph (g) of this AD, 

if those actions were performed before the 

effective date of this AD using Boeing Alert 

Service Bulletin 757–53A0100, dated 

November 14, 2016. 

(j) Alternative Methods of Compliance 

(AMOCs) 

(1) The Manager, Los Angeles ACO Branch, 

FAA, has the authority to approve AMOCs 

for this AD, if requested using the procedures 

found in 14 CFR 39.19. In accordance with 

14 CFR 39.19, send your request to your 

principal inspector or local Flight Standards 

District Office, as appropriate. If sending 

information directly to the manager of the 

certification office, send it to the attention of 

the person identified in paragraph (k)(1) of 

this AD. Information may be emailed to 9- 

ANM-LAACO-AMOC-Requests@faa.gov. 

(2) Before using any approved AMOC, 

notify your appropriate principal inspector, 

or lacking a principal inspector, the manager 

of the local flight standards district office/ 

certificate holding district office. 

(3) An AMOC that provides an acceptable 

level of safety may be used for any repair, 

modification, or alteration required by this 

AD if it is approved by the Boeing 

Commercial Airplanes Organization 

Designation Authorization (ODA) that has 

been authorized by the Manager, Los Angeles 

ACO Branch, to make those findings. To be 

approved, the repair method, modification 

deviation, or alteration deviation must meet 

the certification basis of the airplane, and the 

approval must specifically refer to this AD. 

(4) Except as required by paragraph (h)(2) 

of this AD: For service information that 

contains steps that are labeled as RC, the 

provisions of paragraphs (j)(4)(i) and (j)(4)(ii) 

of this AD apply. 

(i) The steps labeled as RC, including 

substeps under an RC step and any figures 

identified in an RC step, must be done to 

comply with the AD. If a step or substep is 

labeled ‘‘RC Exempt,’’ then the RC 

requirement is removed from that step or 

substep. An AMOC is required for any 

deviations to RC steps, including substeps 

and identified figures. 

(ii) Steps not labeled as RC may be 

deviated from using accepted methods in 

accordance with the operator’s maintenance 

or inspection program without obtaining 

approval of an AMOC, provided the RC steps, 

including substeps and identified figures, can 

still be done as specified, and the airplane 

can be put back in an airworthy condition. 

(k) Related Information 

(1) For more information about this AD, 

contact Muoi Vuong, Aerospace Engineer, 

Airframe Section, FAA, Los Angeles ACO 

Branch, 3960 Paramount Boulevard, 

Lakewood, CA 90712–4137; phone: 562–627– 

5205; fax: 562–627–5210; email: 

muoi.vuong@faa.gov. 

(2) Service information identified in this 

AD that is not incorporated by reference is 

available at the addresses specified in 

paragraphs (l)(3) and (l)(4) of this AD. 

(l) Material Incorporated by Reference 

(1) The Director of the Federal Register 

approved the incorporation by reference 

(IBR) of the service information listed in this 

paragraph under 5 U.S.C. 552(a) and 1 CFR 

part 51. 

(2) You must use this service information 

as applicable to do the actions required by 

this AD, unless the AD specifies otherwise. 

(i) Boeing Alert Service Bulletin 757– 

53A0100, Revision 1, dated September 14, 

2017. 

(ii) Reserved. 

(3) For service information identified in 

this AD, contact Boeing Commercial 

Airplanes, Attention: Contractual & Data 

Services (C&DS), 2600 Westminster Blvd., 

MC 110–SK57, Seal Beach, CA 90740; 

telephone 562–797–1717; internet https://

www.myboeingfleet.com. 

(4) You may view this service information 

at the FAA, Transport Standards Branch, 

1601 Lind Avenue SW, Renton, WA. For 

information on the availability of this 

material at the FAA, call 425–227–1221. 

(5) You may view this service information 

that is incorporated by reference at the 

National Archives and Records 

Administration (NARA). For information on 

the availability of this material at NARA, call 

202–741–6030, or go to: http://

www.archives.gov/federal-register/cfr/ibrlocations.html. 

Issued in Renton, Washington, on 

December 14, 2017. 

Jeffrey E. Duven, 

Director, System Oversight Division, Aircraft 

Certification Service. 

[FR Doc. 2017–28148 Filed 1–2–18; 8:45 am] 

BILLING CODE 4910–13–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 864 

[Docket No. FDA–2017–N–6599] 

Medical Devices; Hematology and 

Pathology Devices; Classification of a 

Cervical Intraepithelial Neoplasia Test 

System 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final order. 

SUMMARY: The Food and Drug 

Administration (FDA or we) is 

classifying the cervical intraepithelial 

neoplasia (CIN) 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 CIN 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 January 3, 

2018. The classification was applicable 

on March 4, 2017. 

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 

cervical intraepithelial neoplasia (CIN) 

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 (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 


jstallworth on DSKBBY8HB2PROD with RULES
Federal Register / Vol. 83, No. 2 / Wednesday, January 3, 2018 / Rules and Regulations 233 

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 shall 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 May 23, 2016, Ventana Medical 

Systems, Inc., submitted a request for De 

Novo classification of the CINtec 

Histology. 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 4, 2017, 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 864.1865. We 

have named the generic type of device 

the cervical intraepithelial neoplasia 

(CIN) test system, and it is identified as 

a device used to detect a biomarker 

associated with CIN in human tissues. 

The device is indicated as an adjunct 

test and not to be used as a stand-alone 

device. The test results must be 

interpreted in the context of the 

patient’s clinical history including, but 

not limited to, prior and current cervical 

biopsy results, Papanicolaou (Pap) test 

results, human papillomavirus (HPV) 

test results, and morphology on 

hematoxylin and eosin (H&E) stained 

sections. This device is not intended to 

detect the presence of HPV. 

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—CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN) TEST SYSTEM RISKS TO HEALTH AND REQUIRED MITIGATIONS

Identified risks Required mitigations/21 CFR section 

Inaccurate test results, such as false positive or false negative results General controls and special controls (1) and (2) (21 CFR 

864.1865(b)(1); 21 CFR 864.1865(b)(2)). 

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

false negative results.

General controls and special controls (1) and (2) (21 CFR 

864.1865(b)(1); 21 CFR 864.1865(b)(2)). 

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. 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 

21 CFR parts 801 and 809, regarding 

labeling, have been approved under 

OMB control number 0910–0485; 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 814, 

subparts A through E, regarding 

premarket approval, have been 

approved under OMB control number 

0910–0231; and 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. 

List of Subjects in 21 CFR Part 864 

Blood, Medical devices, Packaging 

and containers. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 


jstallworth on DSKBBY8HB2PROD with RULES
234 Federal Register / Vol. 83, No. 2 / Wednesday, January 3, 2018 / Rules and Regulations 

of Food and Drugs, 21 CFR part 864 is 

amended as follows: 

PART 864—HEMATOLOGY AND 

PATHOLOGY DEVICES 

■ 1. The authority citation for part 864 

continues to read as follows: 

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

360j, 360l, 371. 

■ 2. Add § 864.1865 to subpart B to read 

as follows: 

§ 864.1865 Cervical intraepithelial 

neoplasia (CIN) test system. 

(a) Identification. A cervical 

intraepithelial neoplasia (CIN) test 

system is a device used to detect a 

biomarker associated with CIN in 

human tissues. The device is indicated 

as an adjunct test and not to be used as 

a stand-alone device. The test results 

must be interpreted in the context of the 

patient’s clinical history including, but 

not limited to, prior and current cervical 

biopsy results, Papanicolaou (Pap) test 

results, human papillomavirus (HPV) 

test results, and morphology on 

hematoxylin and eosin (H&E) stained 

sections. This device is not intended to 

detect the presence of HPV. 

(b) Classification. Class II (special 

controls). The special controls for this 

device are: 

(1) Premarket notification 

submissions must include the following 

information: 

(i) The indications for use must 

specify the biomarker that is intended to 

be identified and its adjunct use (e.g., 

adjunct to examination of H&E stained 

slides) to improve consistency in the 

diagnosis of CIN. 

(ii) Summary of professional society 

recommendations, as applicable. 

(iii) A detailed device description 

including: 

(A) A detailed description of all test 

components, including all provided 

reagents and required, but not provided, 

ancillary reagents. 

(B) 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 positive and negative 

controls that are recommended or 

provided. 

(E) Detailed specifications for sample 

collection, processing, and storage. 

(F) A detailed description of 

methodology and assay procedure. 

(G) A description of the assay cutoff 

(the medical decision point between 

positive and negative) or other relevant 

criteria that distinguishes positive and 

negative results, including the rationale 

for the chosen cutoff or other relevant 

criteria and results supporting 

validation of the cutoff. 

(H) Detailed specification of the 

criteria for test results interpretation and 

reporting. 

(iv) Detailed information 

demonstrating the performance 

characteristics of the device, including: 

(A) Analytical specificity studies such 

as, but not limited to, antibody 

characterization (e.g., Western Blot, 

peptide inhibition analysis), studies 

conducted on panels of normal tissues 

and neoplastic tissues, interference by 

endogenous and exogenous substances 

as well as cross-reactivity, as applicable. 

(B) Device analytical sensitivity data 

generated by testing an adequate 

number of samples from individuals 

with the target condition including limit 

of blank, limit of detection, and limit of 

quantification, as applicable. 

(C) Device precision/reproducibility 

data to evaluate within-run, betweenrun, between-day, between-lot, betweensite, between-reader, within-reader and 

total precision, as applicable, using a 

panel of samples covering the device 

measuring range and/or the relevant 

disease categories (e.g. No CIN, CIN1, 

CIN2, CIN3, cervical cancer) and testing 

in replicates across multiple, 

nonconsecutive days. 

(D) Device robustness/guardbanding 

studies to assess the tolerance ranges for 

various critical test and specimen 

parameters. 

(E) Device stability data, including 

real-time stability and shipping stability 

under various storage times, 

temperatures, and freeze-thaw 

conditions. 

(F) Data from a clinical study 

demonstrating clinical validity using 

well-characterized prospectively or 

retrospectively obtained clinical 

specimens, as appropriate, 

representative of the intended use 

population. The study must evaluate the 

consistency of the diagnosis of CIN, for 

example, by comparing the levels of 

agreements of diagnoses rendered by 

community pathologists to those 

rendered by a panel of expert 

pathologists. Agreement for each CIN 

diagnostic category (e.g., No CIN, CIN1, 

CIN2, CIN3, cancer) and for alternate 

diagnostic categories (e.g., No CIN, low 

grade squamous intraepithelial lesion 

(LSIL)-histology, high grade squamous 

intraepithelial lesion (HSIL)-histology, 

cancer) between reference diagnosis by 

expert pathologist and community 

pathologist must be evaluated, as 

applicable. In addition, agreements for 

CIN binary categories as ≥CIN2 (i.e., 

CIN2 or CIN3 or cancer) and ≤CIN1 (i.e., 

No CIN or CIN1) between reference 

diagnosis by expert pathologist with 

H&E staining and community 

pathologist with H&E staining and 

agreements for alternate CIN binary 

categories as ≥HSIL-histology (i.e., HSILhistology or cancer) and ≤LSIL-histology 

(i.e., No CIN or LSIL-histology) between 

reference diagnosis by an expert 

pathologist with H&E + [biomarker 

specified in paragraph (b)(1)(i) of this 

section] and a community pathologist 

with H&E + [biomarker specified in 

paragraph (b)(1)(i) of this section] must 

be evaluated and compared, as 

applicable. 

(G) The staining performance of the 

device as determined by the community 

pathologists during review of the study 

slides must be evaluated. The staining 

performance criteria assessed must 

include overall staining acceptability, 

background staining acceptability, and 

morphology acceptability, as applicable. 

(H) Appropriate training requirements 

for users, including interpretation 

manual, as applicable. 

(I) Identification of risk mitigation 

elements used by the device, including 

a description of all additional 

procedures, methods, and practices 

incorporated into the instructions for 

use that mitigate risks associated with 

testing. 

(2) The device’s 21 CFR 809.10(b) 

compliant labeling must include a 

detailed description of the protocol, 

including the information described in 

paragraph (b)(1)(ii) of this section, as 

applicable, and a detailed description of 

the performance studies performed and 

the summary of the results, including 

those that relate to paragraph (b)(1)(ii) of 

this section, as applicable. 

Dated: December 27, 2017. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2017–28342 Filed 1–2–18; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF STATE 

22 CFR Parts 35, 103, 127, and 138 

[Public Notice 10236] 

RIN 1400–AE50 

Department of State 2018 Civil 

Monetary Penalties Inflationary 

Adjustment 

AGENCY: Department of State. 

ACTION: Final rule. 


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