Document ID: FDA-2018-N-0399-0001
Agency: fda
Document Type: Rule
Title: Medical Devices; Hematology and Pathology Devices; Classification 
of Lynch Syndrome Test Systems
Posted Date: 2018-02-27T05:00Z

[Federal Register Volume 83, Number 39 (Tuesday, February 27, 2018)]
[Rules and Regulations]
[Pages 8355-8357]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-03924]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 864

[Docket No. FDA 2018-N-0339]

Medical Devices; Hematology and Pathology Devices; Classification 
of Lynch Syndrome Test Systems

AGENCY: Food and Drug Administration, HHS.

ACTION: Final order.

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SUMMARY: The Food and Drug Administration (FDA or we) is classifying 
Lynch syndrome test systems 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 Lynch syndrome 
test systems' 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 February 27, 2018. The classification 
was applicable on October 27, 2017.

FOR FURTHER INFORMATION CONTACT: Scott McFarland, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, Rm. 4676, Silver Spring,

[[Page 8356]]

MD 20993-0002, 301-796-5866, [email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    Upon request, FDA has classified Lynch syndrome test systems 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 to a predicate device that does not require 
premarket approval (see 21 U.S.C. 360c(i)). 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 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 31, 2017, Ventana Medical Systems, Inc. submitted a request 
for De Novo classification of the Ventana MMR IHC Panel. 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 October 27, 2017, FDA issued an order to the 
requester classifying the device into class II. FDA is codifying the 
classification of the device by adding 21 CFR 864.1866. We have named 
the generic type of device Lynch syndrome test systems, and it is 
identified as in vitro diagnostic tests for use with tumor tissue to 
identify previously diagnosed cancer patients at risk for having Lynch 
syndrome.
    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--Lynch Syndrome Test Systems Risks and Mitigation Measures
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          Identified risk                    Mitigation measures
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False positive test result........  General controls; Special controls
                                     (1) and (2) (21 CFR 864.1866(b)(1)
                                     and (2)).
False negative test result........  General controls; Special control
                                     (1) and (2) (21 CFR 864.1866(b)(1)
                                     and(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).

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

[[Page 8357]]

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 and guidance. 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 the guidance document ``De Novo Classification 
Process (Evaluation of Automatic Class III Designation)'' have been 
approved under OMB control number 0910-0844; the collections of 
information in part 814, subparts A through E, regarding premarket 
approval, have been approved under OMB control number 0910-0231; the 
collections of information in part 807, subpart E, regarding premarket 
notification submissions, have been approved under OMB control number 
0910-0120; 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 864

    Blood, Medical devices, Packaging and containers.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner 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.  864.1866 to subpart B to read as follows:

Sec.  864.1866  Lynch syndrome test systems.

    (a) Identification. Lynch syndrome test systems are in vitro 
diagnostic tests for use with tumor tissue to identify previously 
diagnosed cancer patients at risk for having Lynch syndrome.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) Premarket notification submissions must include the following 
information, as appropriate:
    (i) A detailed description of all test components, including all 
provided reagents, and required but not provided, ancillary reagents.
    (ii) A detailed description of instrumentation and equipment, 
including illustrations or photographs of non-standard equipment or 
manuals.
    (iii) Detailed documentation of the device software, including, but 
not limited to, standalone software applications and hardware-based 
devices that incorporate software.
    (iv) A detailed description of quality controls including 
appropriate positive and negative controls that are recommended or 
provided.
    (v) Detailed specifications for sample collection, processing, and 
storage.
    (vi) A detailed description of methodology and assay procedure.
    (vii) A description of the assay cut-off (i.e., the medical 
decision point between positive and negative results) or other relevant 
criteria that distinguishes positive and negative results, or ordinal 
classes of marker expression, including the rationale for the chosen 
cut-off or other relevant criteria and results supporting validation of 
the cut-off.
    (viii) Detailed specification of the criteria for test result 
interpretation and reporting.
    (ix) Detailed information demonstrating the performance 
characteristics of the device, including:
    (A) Data from an appropriate study demonstrating clinical accuracy 
using well-characterized clinical specimens representative of the 
intended use population (i.e., concordance to Deoxyribonucleic Acid 
(DNA) sequencing results of the Lynch syndrome associated genes or 
method comparison to the predicate device using samples with known 
alterations in genes representative of Lynch syndrome). Pre-specified 
acceptance criteria must be provided and followed.
    (B) Appropriate device reproducibility data investigating all 
sources of variance (e.g., for distributed tests, data generated using 
a minimum of three sites, of which at least two sites must be external 
sites). Each site must perform testing over a minimum of 5 
nonconsecutive days evaluating a sample panel that spans the claimed 
measuring range, and includes the clinical threshold. Pre-specified 
acceptance criteria must be provided and followed.
    (C) Data demonstrating reader reproducibility, both within-reader 
and between-reader, assessed by three readers over 3 nonconsecutive 
days at each site, including a 2 week washout period between reads, as 
appropriate.
    (D) Device precision data using clinical samples spanning the 
measuring range and controls to evaluate the within-lot, between-lot, 
within-run, between run, and total variation.
    (E) Analytical specificity studies including as appropriate, 
western blots, peptide inhibition, testing in normal tissues and 
neoplastic tissues, interference by endogenous and exogenous 
substances, and cross-reactivity and cross contamination testing.
    (F) Device analytical sensitivity data generated by testing an 
adequate number of samples from individuals with the target condition 
such that prevalence of the biomarker in the target population is 
established.
    (G) Device stability data, including real-time stability and in-use 
stability, and stability evaluating various storage times, 
temperatures, and freeze-thaw conditions, as appropriate.
    (H) The staining performance criteria assessed must include overall 
staining acceptability, background staining acceptability, and 
morphology acceptability, as appropriate.
    (I) Appropriate training requirements for users, including 
interpretation manual, as applicable.
    (J) 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 Sec.  809.10(b) of this chapter compliant labeling 
must include a detailed description of the protocol, including the 
information described in paragraphs (b)(1)(i) through (viii) of this 
section, as appropriate, and a detailed description of the performance 
studies performed and the summary of the results, including those that 
relate to paragraph (b)(1)(ix) of this section, as appropriate.

    Dated: February 21, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-03924 Filed 2-26-18; 8:45 am]
BILLING CODE 4164-01-P