28994 Federal Register / Vol. 83, No. 121 / Friday, June 22, 2018 / Rules and Regulations 

(g) Sunset provision. The provisions 

of this section will no longer be effective 

on August 2, 2019, unless we terminate 

them earlier or extend them beyond that 

date by notice of a final rule in the 

Federal Register. 

[FR Doc. 2018–13359 Filed 6–21–18; 8:45 am] 

BILLING CODE 4191–02–P 

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. 

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, 

Scott.McFarland@fda.hhs.gov. 

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 


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Federal Register / Vol. 83, No. 121 / Friday, June 22, 2018 / Rules and Regulations 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

Identified risk Mitigation measures 

Incorrect performance of the test leading to false positives, false negatives.General controls and Special control (1) (21 CFR 866.6080(b)(1)). 

Incorrect interpretation of test results ....................................................... General controls; Special control (1)(21 CFR 866.6080(b)(1)(iii)(E)); 

and Special control (2) (21 CFR 866.6080(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. 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 

■ 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 § 866.6080 to subpart G to read 

as follows: 

§ 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 runfailures, 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 


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28996 Federal Register / Vol. 83, No. 121 / Friday, June 22, 2018 / Rules and Regulations 

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., formalinfixed, 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 

DEPARTMENT OF THE INTERIOR 

Office of Surface Mining Reclamation 

and Enforcement 

30 CFR Part 901 

[SATS No. AL–080–FOR; Docket ID: OSM– 

2016–0011; S1D1S SS08011000 SX064A000 

189S180110; S2D2S SS08011000 

SX064A000 18XS501520] 

Alabama Abandoned Mine Land 

Reclamation Plan 

AGENCY: Office of Surface Mining 

Reclamation and Enforcement, Interior. 

ACTION: Final rule; approval of 

amendment. 

SUMMARY: We, the Office of Surface 

Mining Reclamation and Enforcement 


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