Medical Devices; Immunology and Microbiology Devices; Classification of the Next Generation Sequencing Based Tumor Profiling Test, 28994-28996 [2018-13406]
Download as PDF
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.
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:
SUMMARY:
daltland on DSKBBV9HB2PROD with RULES
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
VerDate Sep<11>2014
16:09 Jun 21, 2018
Jkt 244001
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.
PO 00000
Frm 00018
Fmt 4700
Sfmt 4700
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
E:\FR\FM\22JNR1.SGM
22JNR1
Federal Register / Vol. 83, No. 121 / Friday, June 22, 2018 / Rules and Regulations
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
28995
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.
Incorrect interpretation of test results .......................................................
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.
daltland on DSKBBV9HB2PROD with RULES
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.
VerDate Sep<11>2014
16:09 Jun 21, 2018
Jkt 244001
General controls and Special control (1) (21 CFR 866.6080(b)(1)).
General controls; Special control (1)(21 CFR 866.6080(b)(1)(iii)(E));
and Special control (2) (21 CFR 866.6080(b)(2)).
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:
PO 00000
Frm 00019
Fmt 4700
Sfmt 4700
(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
E:\FR\FM\22JNR1.SGM
22JNR1
daltland on DSKBBV9HB2PROD with RULES
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,
VerDate Sep<11>2014
16:09 Jun 21, 2018
Jkt 244001
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
PO 00000
Frm 00020
Fmt 4700
Sfmt 4700
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
Office of Surface Mining
Reclamation and Enforcement, Interior.
ACTION: Final rule; approval of
amendment.
AGENCY:
We, the Office of Surface
Mining Reclamation and Enforcement
SUMMARY:
E:\FR\FM\22JNR1.SGM
22JNR1
Agencies
[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]
=======================================================================
-----------------------------------------------------------------------
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, [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
------------------------------------------------------------------------
Identified risk Mitigation measures
------------------------------------------------------------------------
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)).
------------------------------------------------------------------------
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