[Federal Register Volume 83, Number 2 (Wednesday, January 3, 2018)]
[Rules and Regulations]
[Pages 232-234]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-28342]


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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.

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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, 
[email protected].

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

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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
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                                           Required mitigations/21 CFR
            Identified risks                         section
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Inaccurate test results, such as false   General controls and special
 positive or false negative results.      controls (1) and (2) (21 CFR
                                          864.1865(b)(1); 21 CFR
                                          864.1865(b)(2)).
Failure to correctly interpret test      General controls and special
 results can lead to false positive or    controls (1) and (2) (21 CFR
 false negative results.                  864.1865(b)(1); 21 CFR
                                          864.1865(b)(2)).
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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. 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

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of Food and Drugs, 21 CFR part 864 is amended as follows:

PART 864--HEMATOLOGY AND PATHOLOGY DEVICES

0
1. The authority citation for part 864 continues to read as follows:

    Authority:  21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.

0
2. Add Sec.  864.1865 to subpart B to read as follows:


Sec.  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, stand-alone 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, 
between-run, between-day, between-lot, between-site, 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., HSIL-histology 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