[Federal Register Volume 83, Number 121 (Friday, June 22, 2018)]
[Rules and Regulations]
[Pages 28994-28996]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-13406]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2018-N-1929]


Medical Devices; Immunology and Microbiology Devices; 
Classification of the Next Generation Sequencing Based Tumor Profiling 
Test

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 next generation sequencing based tumor profiling test 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 next generation sequencing based tumor profiling test'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 June 22, 2018. The classification was 
applicable on November 15, 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, MD, 20993-0002, 301-
796-6217, [email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    Upon request, FDA has classified the next generation sequencing 
based tumor profiling test 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) & 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 (21 U.S.C. 360c(f)(2)). 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 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 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

    On September 25, 2017, Memorial Sloan-Kettering Cancer Center 
Department of Pathology submitted a request for De Novo classification 
of the MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer 
Targets). 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 November 15, 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 866.6080. We have named 
the generic type of device next generation sequencing (NGS) based tumor 
profiling test, and it is identified as a qualitative in vitro 
diagnostic test intended for NGS analysis of tissue

[[Page 28995]]

specimens from malignant solid neoplasms to detect somatic mutations in 
a broad panel of targeted genes to aid in the management of previously 
diagnosed cancer patients by qualified health care professionals.
    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--Next Generation Sequencing Based Tumor Profiling Test Risks and
                           Mitigation Measures
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            Identified risk                    Mitigation measures
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Incorrect performance of the test        General controls and Special
 leading to false positives, false        control (1) (21 CFR
 negatives.                               866.6080(b)(1)).
Incorrect interpretation of test         General controls; Special
 results.                                 control (1)(21 CFR
                                          866.6080(b)(1)(iii)(E)); and
                                          Special control (2) (21 CFR
                                          866.6080(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. 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 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 collection of 
information in part 814, subparts A through E, regarding premarket 
approval, have been approved under OMB control number 0910-0231; the 
collection 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 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.  866.6080 to subpart G to read as follows:


Sec.  866.6080  Next generation sequencing based tumor profiling test.

    (a) Identification. A next generation sequencing (NGS) based tumor 
profiling test is a qualitative in vitro diagnostic test intended for 
NGS analysis of tissue specimens from malignant solid neoplasms to 
detect somatic mutations in a broad panel of targeted genes to aid in 
the management of previously diagnosed cancer patients by qualified 
health care professionals.
    (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 all somatic mutations that are 
intended to be detected by the test and that are adequately supported 
in accordance with paragraph (b)(1)(v) of this section and reported in 
the test results in accordance with paragraph (b)(2)(iv) of this 
section, including:
    (A) A listing of mutations that are cancer mutations with evidence 
of clinical significance.
    (B) As appropriate, a listing of mutations that are cancer 
mutations with potential clinical significance.
    (ii) The indications for use must specify the following:
    (A) The test is indicated for previously diagnosed cancer patients.
    (B) The intended specimen type(s) and matrix (e.g., formalin-fixed, 
paraffin-embedded tumor tissue).
    (C) The mutation types (e.g., single nucleotide variant, insertion, 
deletion, copy number variation or gene rearrangement) for which 
validation data has been provided.
    (D) The name of the testing facility or facilities, as applicable.
    (iii) A detailed device description including the following:
    (A) A description of the test in terms of genomic coverage, as 
follows:
    (1) Tabulated summary of all mutations reported, grouped according 
to gene and target region within each gene, along with the specific 
cDNA and amino acid positions for each mutation.
    (2) A description of any within-gene targeted regions that cannot 
be reported and the data behind such conclusion.
    (B) Specifications for specimen requirements including any specimen 
collection devices and preservatives, specimen volume, minimum tumor 
content, specimen handling, DNA extraction, and criteria for DNA 
quality and quantity metrics that are prerequisite to performing the 
assay.
    (C) A detailed description of all test components, reagents, 
instrumentation, and software required. Detailed documentation of the 
device software including but not limited to, software applications and 
hardware-based devices that incorporate software.
    (D) A detailed description of the methodology and protocols for 
each step of the test, including description of the quality metrics, 
thresholds, and filters at each step of the test that are implemented 
for final result reporting and a description of the metrics for run-
failures, specimen-failures, invalids, as applicable.
    (E) A list of links provided by the device to the user or accessed 
by the device for internal or external information (e.g., decision 
rules or databases) supporting clinical significance of test results 
for the panel

[[Page 28996]]

or its elements in accordance with paragraphs (b)(1)(v) and (b)(2)(vi) 
of this section.
    (F) A description of internal and external controls that are 
recommended or provided and control procedures. The description must 
identify those control elements that are incorporated into the testing 
procedure.
    (iv) Information demonstrating analytical validity of the device 
according to analytical performance characteristics, evaluated either 
specifically for each gene/mutation or, when clinically and practically 
justified, using a representative approach based on other mutations of 
the same type, including:
    (A) Data that adequately supports the intended specimen type (e.g., 
formalin-fixed, paraffin-embedded tumor tissue), specimen handling 
protocol, and nucleic acid purification for specific tumor types or for 
a pan-tumor claim.
    (B) A summary of the empirical evidence obtained to demonstrate how 
the analytical quality metrics and thresholds were optimized.
    (C) Device precision data using clinical samples to adequately 
evaluate intra-run, inter-run, and total variability. The samples must 
cover all mutation types tested (both positive and negative samples) 
and include samples near the limit of detection of the device. 
Precision must be assessed by agreement within replicates on the assay 
final result for each representative mutation, as applicable, and also 
supported by sequencing quality metrics for targeted regions across the 
panel.
    (D) Description of the protocols and/or data adequately 
demonstrating the interchangeability of reagent lots and multiplexing 
barcodes.
    (E) A description of the nucleic acid assay input concentration 
range and the evidence to adequately support the range.
    (F) A description of the data adequately supporting the limit of 
detection of the device.
    (G) A description of the data to adequately support device accuracy 
using clinical specimens representing the intended specimen type and 
range of tumor types, as applicable.
    (1) Clinical specimens tested to support device accuracy must 
adequately represent the list of cancer mutations with evidence of 
clinical significance to be detected by the device.
    (2) For mutations that are designated as cancer mutations with 
evidence of clinical significance and that are based on evidence 
established in the intended specimen type (e.g., tumor tissues) but for 
a different analyte type (e.g., protein, RNA) and/or a measurement 
(e.g., incorporating a score or copy number) and/or with an alternative 
technology (e.g., IHC, RT-qPCR, FISH), evidence of accuracy must 
include clinically adequate concordance between results for the 
mutation and the medically established biomarker test (e.g., evidence 
generated from an appropriately sized method comparison study using 
clinical specimens from the target population).
    (3) For qualitative DNA mutations not described in paragraph 
(b)(1)(iv)(G)(2) of this section, accuracy studies must include both 
mutation-positive and wild-type results.
    (H) Adequate device stability information.
    (v) Information that adequately supports the clinical significance 
of the panel must include:
    (A) Criteria established on what types and levels of evidence will 
clinically validate a mutation as a cancer mutation with evidence of 
clinical significance versus a cancer mutation with potential clinical 
significance.
    (B) For representative mutations of those designated as cancer 
mutations with evidence of clinical significance, a description of the 
clinical evidence associated with such mutations, such as clinical 
evidence presented in professional guidelines, as appropriate, with 
method comparison performance data as described in paragraph 
(b)(1)(iv)(G) of this section.
    (C) For all other mutations designated as cancer mutations with 
potential clinical significance, a description of the rationale for 
reporting.
    (2) The 21 CFR 809.10 compliant labeling and any product 
information and test report generated, must include the following, as 
applicable:
    (i) The intended use statement must specify the following:
    (A) The test is indicated for previously diagnosed cancer patients.
    (B) The intended specimen type(s) and matrix (e.g., formalin-fixed, 
paraffin-embedded tumor tissue).
    (C) The mutation types (e.g., single nucleotide variant, insertion, 
deletion, copy number variation or gene rearrangement) for which 
validation data has been provided.
    (D) The name of the testing facility or facilities, as applicable.
    (ii) A description of the device and summary of the results of the 
performance studies performed in accordance with paragraphs 
(b)(1)(iii), (b)(1)(iv), and (b)(1)(v) of this section.
    (iii) A description of applicable test limitations, including, for 
device specific mutations validated with method comparison data to a 
medically established test in the same intended specimen type, 
appropriate description of the level of evidence and/or the differences 
between next generation sequencing results and results from the 
medically established test (e.g., as described in professional 
guidelines).
    (iv) A listing of all somatic mutations that are intended to be 
detected by the device and that are reported in the test results under 
the following two categories or equivalent designations, as 
appropriate: ``cancer mutations panel with evidence of clinical 
significance'' or ``cancer mutations panel with potential clinical 
significance.''
    (v) For mutations reported under the category of ``cancer mutations 
panel with potential clinical significance,'' a limiting statement that 
states ``For the mutations listed in [cancer mutations panel with 
potential clinical significance or equivalent designation], the 
clinical significance has not been demonstrated [with adequate clinical 
evidence (e.g., by professional guidelines) in accordance with 
paragraph (b)(1)(v) of this section] or with this test.''
    (vi) For mutations under the category of ``cancer mutations panel 
with evidence of clinical significance,'' or equivalent designation, 
link(s) for physicians to access internal or external information 
concerning decision rules or conclusions about the level of evidence 
for clinical significance that is associated with the marker in 
accordance with paragraph (b)(1)(v) of this section.

    Dated: June 18, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-13406 Filed 6-21-18; 8:45 am]
 BILLING CODE 4164-01-P