Medical Devices; Immunology and Microbiology Devices; Classification of the Newborn Screening Test for Severe Combined Immunodeficiency Disorder, 50077-50080 [2017-23496]
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Federal Register / Vol. 82, No. 208 / Monday, October 30, 2017 / Rules and Regulations
(J) Specimen matrix comparison data,
if more than one specimen type or
anticoagulant can be tested with the
device. Samples used for comparison
must be from well-characterized patient
samples covering the device measuring
range.
(K) Clinical performance must be
established by comparing data generated
by testing samples from the indicated
population and the differential
diagnosis or non-target disease groups
with the device to the clinical
diagnostic standard.
(1) The diagnosis of NMO and
NMOSD must be based on clinical
findings, laboratory tests (e.g.,
serological tests), and radiological tests
(e.g., magnetic resonance imaging).
(2) The differential diagnosis or nontarget disease group must include the
applicable diseases or conditions,
including but not be limited to the
following: Multiple sclerosis, stroke,
Lyme disease, shingles, syphilis, human
immunodeficiency virus, hepatitis B,
tuberculosis, Srgen’s syndrome,
systemic lupus erythematous, systemic
vasculitis, sarcoidosis, Graves’ disease,
Hashimoto’s disease, Type I diabetes,
rheumatoid arthritis, Addison’s disease,
and myasthenia gravis.
(3) Diagnosis of diseases or conditions
for the differential or non-target disease
groups must be based on established
diagnostic criteria and clinical
evaluation.
(4) For all samples, the diagnostic
clinical criteria and the demographic
information must be collected and
provided.
(5) The clinical validation results
must demonstrate clinical sensitivity
and clinical specificity for the test
values based on the presence or absence
of NMO and NMOSD.
(6) The data must be summarized in
tabular format comparing the
interpretation of results to the disease
status.
(L) Expected/reference values
generated by testing an adequate
number of samples from apparently
healthy normal individuals.
(iii) Identification of risk mitigation
elements used by the device, including
description of all additional procedures,
methods, and practices incorporated
into the directions for use that mitigate
risks associated with testing.
(2) The device’s 21 CFR 809.10(b)
compliant labeling must include
warnings relevant to the device
including:
(i) A warning statement that reads
‘‘The device is for use by laboratory
professionals in a clinical laboratory
setting’’; and
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(ii) A warning statement that reads
‘‘The device is not to be used as a standalone device but as an adjunct to other
clinical information. A diagnosis of
Neuromyelitis Optica (NMO) and
Neuromyelitis Optica Spectrum
Disorders (NMOSD) should not be made
on a single test result. The clinical
symptoms, results from physical
examination, laboratory tests (e.g.,
serological tests), and radiological tests
(e.g. Magnetic Resonance Imaging),
when appropriate, should always be
taken into account when considering
the diagnosis of NMO and NMOSD.’’
(3) The device’s 21 CFR 809.10(b)
compliant labeling must include a
detailed description of the protocol and
performance studies performed in
accordance with paragraph (b)(1)(ii) of
this section and a summary of the
results.
Dated: October 24, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning,
Legislation, and Analysis.
[FR Doc. 2017–23489 Filed 10–27–17; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA–2017–N–5924]
Medical Devices; Immunology and
Microbiology Devices; Classification of
the Newborn Screening Test for Severe
Combined Immunodeficiency Disorder
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Final order.
The Food and Drug
Administration (FDA or we) is
classifying the newborn screening test
for severe combined immunodeficiency
disorder (SCID) 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 newborn
screening test for SCID’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 October
30, 2017. The classification was
applicable on December 15, 2014.
SUMMARY:
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50077
FOR FURTHER INFORMATION CONTACT:
Caryl Giuliano, Center for Devices and
Radiological Health, Food and Drug
Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 5664, Silver Spring,
MD 20993–0002, 301–796–2478,
caryl.giuliano@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
Upon request, FDA has classified the
newborn screening test for SCID 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 (the FD&C Act).
FDA may take a variety of actions in
appropriate circumstances to classify or
reclassify a device into class I or II. We
may issue an order finding a new device
to be substantially equivalent under
section 513(i) of the FD&C Act (21
U.S.C. 360c(i)) to a predicate device that
does not require premarket approval.
We determine whether a new device is
substantially equivalent to a predicate
by means of the procedures for
premarket notification under section
510(k) of the FD&C Act and part 807 (21
U.S.C. 360(k) and 21 CFR part 807,
respectively).
FDA may also classify a device
through ‘‘De Novo’’ classification, a
common name for the process
authorized under section 513(f)(2) of the
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.
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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
placed within class III, the De Novo
classification is considered to be the
initial classification of the device.
We believe this De Novo classification
will enhance patients’ access to
beneficial innovation, in part by
reducing regulatory burdens. When FDA
classifies a device into class I or II via
the De Novo process, the device can
serve as a predicate for future devices of
that type, including for 510(k)s (see 21
U.S.C. 360c(f)(2)(B)(i)). As a result, other
device sponsors do not have to submit
a De Novo request or premarket
approval application (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 October 14, 2014, Wallac Oy, a
subsidiary of PerkinElmer, Inc.,
submitted a request for De Novo
classification of the EnLite Neonatal
TREC Kit. 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 general controls,
will provide reasonable assurance of the
safety and effectiveness of the device.
Therefore, on December 15, 2014,
FDA issued an order to the requestor
classifying the device into class II. FDA
is codifying the classification of the
device by adding 21 CFR 866.5930. We
have named the generic type of device
newborn screening test for SCID, and it
is identified as a prescription device
intended to measure T-cell receptor
excision circle (TREC) DNA obtained
from dried blood spot specimens on
filter paper using a polymerase chain
reaction based test as an aid in
screening newborns for SCID.
Presumptive positive results must be
followed up by diagnostic confirmatory
testing. This test is not intended for use
as a diagnostic test, or for screening of
SCID-like syndromes, such as DiGeorge
syndrome or Omenn syndrome. It is also
not intended to screen for less acute
SCID syndromes, such as leaky SCID or
variant SCID.
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—NEWBORN SCREENING TEST FOR SCID RISKS AND MITIGATION MEASURES
Identified risks
Mitigation measures/21 CFR section
False negative results due to device or user error ..................................
Special controls (1) and (2) (21 CFR 866.5930(b)(1) and 21 CFR
866.5930(b)(2)).
Special controls (1) and (2) (21 CFR 866.5930(b)(1) and 21 CFR
866.5930(b)(2)).
False positive results due to device or user error ...................................
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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) of the
FD&C Act.
III. Analysis of Environmental Impact
The Agency has determined under 21
CFR 25.34(b) that this action is of a type
that does not individually or
cumulatively have a significant effect on
the human environment. Therefore,
neither an environmental assessment
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nor an environmental impact statement
is required.
IV. Paperwork Reduction Act of 1995
This final order establishes special
controls that refer to previously
approved collections of information
found in other FDA regulations. These
collections of information are subject to
review by the Office of Management and
Budget (OMB) under the Paperwork
Reduction Act of 1995 (44 U.S.C. 3501–
3520). The collections of information in
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
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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.
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2. Add § 866.5930 to subpart F to read
as follows:
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§ 866.5930 Newborn screening test for
severe combined immunodeficiency
disorder (SCID).
(a) Identification. A newborn
screening test for SCID is a prescription
device intended to measure T-cell
receptor excision circle (TREC) DNA
obtained from dried blood spot
specimens on filter paper using a
polymerase chain reaction based test as
an aid in screening newborns for SCID.
Presumptive positive results must be
followed up by diagnostic confirmatory
testing. This test is not intended for use
as a diagnostic test, or for screening of
SCID-like syndromes, such as DiGeorge
syndrome or Omenn syndrome. It is also
not intended to screen for less acute
SCID syndromes, such as leaky SCID or
variant SCID.
(b) Classification. Class II (special
controls). The special controls for this
device are:
(1) Premarket notification
submissions must include the following
information:
(i) The intended use must indicate:
(A) The test is not intended for
diagnostic use, or for screening of SCIDlike syndromes, such as DiGeorge
syndrome or Omenn syndrome; and
(B) The test is not intended to screen
for less acute SCID syndromes, such as
leaky SCID or variant SCID.
(ii) A detailed description of all
components in the test that includes:
(A) A detailed description of the test
components, all required reagents,
instrumentation and equipment,
including illustrations or photographs of
nonstandard equipment or methods;
(B) Detailed documentation of the
device software including, but not
limited to, standalone software
applications and hardware-based
devices that incorporate software;
(C) Specifications for the filter paper,
which must be appropriately labeled for
in vitro diagnostic use, to be used in
specimen collection and how it will be
used in specimen collection validation.
These specifications must include:
descriptive characteristics of the filter
paper, instructions on how a lab should
choose the appropriate filter paper,
chemical properties of the filter paper,
interference concerns associated with
the chemicals in the filter paper,
absorption properties of the filter paper,
punch size, absorption capacity, testing
for homogeneity of punches, diameter of
the circle for the dried blood spot
aliquot, absorption time, physical
composition, and number and size of
punches to be tested;
(D) Methodology and protocols for
detection of T-cell receptor excision
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circles and methods for determination
of results. The cutoff must be selected
before conducting clinical and
analytical studies;
(E) A description of the result outputs
along with sample reports. Sample
reports must include the scale used in
reporting of results (e.g., TREC copies/
mL) and the range of values that will be
reported out; and
(F) A description of appropriate
internal and external controls that are
recommended or provided. The
description must identify those control
elements that are incorporated into the
testing procedure.
(iii) Information that demonstrates the
performance characteristics of the test,
including:
(A) Data that demonstrates the clinical
validity of the device, using well
characterized prospectively or
retrospectively obtained clinical
specimens representative of the
intended use population. A minimum of
10 to 15 confirmed positive specimens
must be obtained from more than 1 site,
including relevant annotation, and, at 1
year or beyond, a SCID diagnosis by
flow cytometry or clinically meaningful
information regarding the status of the
subject must be obtained. Additional
specimens should have been obtained
that are characterized by other disorders
that can be found by screening
specimens that have low or absent TREC
(e.g., other T-cell lymphopenic
disorders) to supplement the range of
results. The clinical validation study
must have a pre-specified clinical
decision point (i.e., cutoff to distinguish
positive and negative results). Results
must be summarized in tabular format
comparing interpretation of results to
the reference method. Point estimates
together with two-sided 95 percent
confidence intervals must be provided
for the positive percent agreement,
negative percent agreement, and overall
percent agreement. Data must include
the retest rate, the false positive rate
before retest, the final false positive rate,
and the false negative rate;
(B) Device reproducibility data
generated, using a minimum of three
sites of which at least two must be
external sites, with two operators at
each site. Each site must conduct a
minimum of five runs per operator over
five nonconsecutive days evaluating a
minimum of six different relevant TREC
concentrations that span and are well
distributed over the measuring range
and include the clinical cutoff.
Specimens must include cord blood and
cord blood diluted with ABO matched
adult blood specimens. Identical
specimens from the same sample panel
must be tested at each site. Each
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50079
specimen must be run in triplicate and
include controls run in triplicate.
Results must be reported as the standard
deviation and percentage coefficient of
variation for each level tested. Results
must also be displayed as a
dichotomous variable around the cutoff.
Total variation must be partitioned into
the sum of within-lab and between-lab
variations with pre-specified acceptance
criteria and 95 percent confidence
intervals for all data. Pre-specified
acceptance criteria must be provided
and followed;
(C) Device precision data using
clinical samples to evaluate the withinlot, between-lot, within-run, between
run, and total variation. A range of
TREC levels of the specimen must
include samples within the measuring
range, samples above and below the
measuring range, as well as with
samples very near above and below the
cutoff value. At least three replicates of
each specimen must be tested with
controls and calibrator(s) according to
the device instructions for use. The
precision study must use well
characterized samples using different
lots, instruments, and operators. Results
must be summarized in tabular format.
Pre-specified acceptance criteria must
be provided and followed;
(D) Linearity of the test must be
demonstrated using a dilution panel
from clinical samples. The range of
dilution samples must include samples
within the measuring range, samples
above and below the measuring range,
as well as with samples very near above
and below the cutoff value. Results of
the regression analysis must be
summarized in tabular format and fitted
into a linear regression model with the
individual measurement results against
the dilution factors. Pre-specified
acceptance criteria must be provided
and followed;
(E) Device analytic sensitivity data,
including limit of blank, limit of
detection, and limit of quantification;
(F) Device specificity data, including
interference, carryover, crosscontamination, and in silico analysis of
potential off-target genomic sequences;
(G) Device stability data, including
real-time stability of samples under
various storage times, temperatures, and
freeze-thaw conditions. A separate
shipping stability study must be
performed;
(H) Lot-to-lot reproducibility study of
each filter paper that will be validated
with the test. The lot-to-lot study must
include a minimum of three lots of each
blood spot card that will be validated
with the test and be conducted over five
nonconsecutive days. The sample panel
must consist of specimens with a range
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of TREC levels and include samples
within the measuring range, samples
above and below the measuring range,
and samples very near above and below
the cutoff value. Multiple punches must
be obtained from each card for
demonstration of homogeneity of the
analyte across the dried blood spot.
Comparability of the test performance
for each filter paper must be
demonstrated. Stability and storage of
TREC DNA on each blood spot card
must be demonstrated. Results of the
lot-to-lot study must be summarized
providing the mean, standard deviation,
and percentage coefficient of variation
in a tabular format. Data must be
calculated for within-run, between-run,
within-lot, and between-lot. Data
demonstrating the concordance between
results across different filter papers
must be provided. Study acceptance
criteria must be provided and followed;
and
(I) If applicable, a thermocycler
reproducibility study must be
performed using thermocyclers from
three independent thermocyler
manufacturers. The sample panel must
consist of specimens with a range of
TREC levels and must include samples
within the measuring range, samples
above and below the measuring range,
and samples very near above and below
the cutoff value. The study must be
done using three filter paper lots and
conducted over five nonconsecutive
days. Results of the thermocycler
reproducibility study must be
summarized providing the mean,
standard deviation, and percentage
coefficient of variance in a tabular
format. Data must be calculated for the
within-run, between-run, within-lot,
between-lot, and between thermocycler
manufacturer study results. Study
acceptance criteria must be provided
and followed.
(iv) Identification of risk mitigation
elements used by your device, including
a description of all additional
procedures, methods, and practices
incorporated into the directions for use
that mitigate risks associated with
testing.
(2) Your § 809.10 compliant labeling
must include:
(i) A warning statement that reads
‘‘This test is not intended for diagnostic
use, preimplantation or prenatal testing,
or for screening of SCID-like syndromes,
such as DiGeorge syndrome or Omenn
syndrome. It is also not intended to
screen for less acute SCID syndromes,
such as leaky SCID or variant SCID.’’;
(ii) A warning statement that reads
‘‘Test results are intended to be used in
conjunction with other clinical and
diagnostic findings, consistent with
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professional standards of practice,
including confirmation by alternative
methods and clinical evaluation, as
appropriate.’’;
(iii) A description of the performance
studies listed in paragraph (b)(1)(iii) and
a summary of the results; and
(iv) A description of the filter paper
specifications required for the test.
Dated: October 24, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning,
Legislation, and Analysis.
[FR Doc. 2017–23496 Filed 10–27–17; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Part 876
[Docket No. FDA–2017–N–1609]
Medical Devices; GastroenterologyUrology Devices; Classification of the
Oral Removable Palatal Space
Occupying Device for Weight
Management and/or Weight Loss
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Final order; correction.
The Food and Drug
Administration (FDA) is correcting a
final order entitled ‘‘Medical Devices;
Gastroenterology-Urology Devices;
Classification of the Oral Removable
Palatal Space Occupying Device for
Weight Management and/or Weight
Loss’’ that appeared in the Federal
Register of July 28, 2017. The final order
was published with an incorrect
statement in the preamble about
whether FDA planned to exempt the
device from premarket notification
requirements. This document corrects
that error.
DATES: Effective October 30, 2017
FOR FURTHER INFORMATION CONTACT:
Mark Antonino, Center for Devices and
Radiological Health, Food and Drug
Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. G208, Silver Spring,
MD 20993–0002, 240–402–9980,
mark.antonino@fda.hhs.gov.
SUPPLEMENTARY INFORMATION: In the
Federal Register of July 28, 2017 (82 FR
35067), FDA published the final order
‘‘Medical Devices; GastroenterologyUrology Devices; Classification of the
Oral Removable Palatal Space
Occupying Device for Weight
Management and/or Weight Loss.’’ The
final order published with an incorrect
statement in the preamble about
SUMMARY:
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whether FDA planned to exempt the
device from premarket notification
requirements under section 510(k) of the
FD&C Act.
In the Federal Register of July 28,
2017, (82 FR 35067), the following
correction is made: On page 35069, in
the first column, the first paragraph is
corrected as follows:
‘‘Section 510(m) of the FD&C Act
provides that FDA may exempt a class
II device from the premarket notification
requirements under section 510(k), if
FDA determines that premarket
notification is not necessary to provide
reasonable assurance of the safety and
effectiveness of the device. For this type
of device, FDA has determined that
premarket notification is necessary to
provide reasonable assurance of the
safety and effectiveness of the device.
Therefore, this device type is not
exempt from premarket notification
requirements. Persons who intend to
market this type of device must submit
to FDA a premarket notification, prior to
marketing the device, which contains
information about the oral removable
palatal space occupying device for
weight management and/or weight loss
they intend to market.’’
Dated: October 24, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning,
Legislation, and Analysis.
[FR Doc. 2017–23490 Filed 10–27–17; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Part 882
[Docket No. FDA–2017–N–5934]
Medical Devices; Neurological
Devices; Classification of the NonElectroencephalogram Physiological
Signal Based Seizure Monitoring
System
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Final order.
The Food and Drug
Administration (FDA or we) is
classifying the nonelectroencephalogram (non-EEG)
physiological signal based seizure
monitoring system into class II (special
controls). The special controls that
apply to the device type are identified
in this order and will be part of the
codified language for the non-EEG
physiological signal based seizure
monitoring system’s classification. We
SUMMARY:
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]]>Agencies
[Federal Register Volume 82, Number 208 (Monday, October 30, 2017)]
[Rules and Regulations]
[Pages 50077-50080]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-23496]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2017-N-5924]
Medical Devices; Immunology and Microbiology Devices;
Classification of the Newborn Screening Test for Severe Combined
Immunodeficiency Disorder
AGENCY: Food and Drug Administration, HHS.
ACTION: Final order.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA or we) is classifying
the newborn screening test for severe combined immunodeficiency
disorder (SCID) 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 newborn screening test for SCID'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 October 30, 2017. The classification was
applicable on December 15, 2014.
FOR FURTHER INFORMATION CONTACT: Caryl Giuliano, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 5664, Silver Spring, MD 20993-0002, 301-796-2478,
[email protected].
SUPPLEMENTARY INFORMATION:
I. Background
Upon request, FDA has classified the newborn screening test for
SCID 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 (the FD&C Act).
FDA may take a variety of actions in appropriate circumstances to
classify or reclassify a device into class I or II. We may issue an
order finding a new device to be substantially equivalent under section
513(i) of the FD&C Act (21 U.S.C. 360c(i)) to a predicate device that
does not require premarket approval. We determine whether a new device
is substantially equivalent to a predicate by means of the procedures
for premarket notification under section 510(k) of the FD&C Act and
part 807 (21 U.S.C. 360(k) and 21 CFR part 807, respectively).
FDA may also classify a device through ``De Novo'' classification,
a common name for the process authorized under section 513(f)(2) of the
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.
[[Page 50078]]
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 placed
within class III, the De Novo classification is considered to be the
initial classification of the device.
We believe this De Novo classification will enhance patients'
access to beneficial innovation, in part by reducing regulatory
burdens. When FDA classifies a device into class I or II via the De
Novo process, the device can serve as a predicate for future devices of
that type, including for 510(k)s (see 21 U.S.C. 360c(f)(2)(B)(i)). As a
result, other device sponsors do not have to submit a De Novo request
or premarket approval application (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 October 14, 2014, Wallac Oy, a subsidiary of PerkinElmer, Inc.,
submitted a request for De Novo classification of the EnLite Neonatal
TREC Kit. 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 general controls, will provide reasonable assurance of the
safety and effectiveness of the device.
Therefore, on December 15, 2014, FDA issued an order to the
requestor classifying the device into class II. FDA is codifying the
classification of the device by adding 21 CFR 866.5930. We have named
the generic type of device newborn screening test for SCID, and it is
identified as a prescription device intended to measure T-cell receptor
excision circle (TREC) DNA obtained from dried blood spot specimens on
filter paper using a polymerase chain reaction based test as an aid in
screening newborns for SCID. Presumptive positive results must be
followed up by diagnostic confirmatory testing. This test is not
intended for use as a diagnostic test, or for screening of SCID-like
syndromes, such as DiGeorge syndrome or Omenn syndrome. It is also not
intended to screen for less acute SCID syndromes, such as leaky SCID or
variant SCID.
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--Newborn Screening Test for SCID Risks and Mitigation Measures
------------------------------------------------------------------------
Mitigation measures/21 CFR
Identified risks section
------------------------------------------------------------------------
False negative results due to device or Special controls (1) and (2)
user error. (21 CFR 866.5930(b)(1) and 21
CFR 866.5930(b)(2)).
False positive results due to device or Special controls (1) and (2)
user error. (21 CFR 866.5930(b)(1) and 21
CFR 866.5930(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) of the FD&C Act.
III. Analysis of Environmental Impact
The Agency has determined under 21 CFR 25.34(b) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
IV. Paperwork Reduction Act of 1995
This final order establishes special controls that refer to
previously approved collections of information found in other FDA
regulations. These collections of information are subject to review by
the Office of Management and Budget (OMB) under the Paperwork Reduction
Act of 1995 (44 U.S.C. 3501-3520). The collections of information in
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 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.
[[Page 50079]]
0
2. Add Sec. 866.5930 to subpart F to read as follows:
Sec. 866.5930 Newborn screening test for severe combined
immunodeficiency disorder (SCID).
(a) Identification. A newborn screening test for SCID is a
prescription device intended to measure T-cell receptor excision circle
(TREC) DNA obtained from dried blood spot specimens on filter paper
using a polymerase chain reaction based test as an aid in screening
newborns for SCID. Presumptive positive results must be followed up by
diagnostic confirmatory testing. This test is not intended for use as a
diagnostic test, or for screening of SCID-like syndromes, such as
DiGeorge syndrome or Omenn syndrome. It is also not intended to screen
for less acute SCID syndromes, such as leaky SCID or variant SCID.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) Premarket notification submissions must include the following
information:
(i) The intended use must indicate:
(A) The test is not intended for diagnostic use, or for screening
of SCID-like syndromes, such as DiGeorge syndrome or Omenn syndrome;
and
(B) The test is not intended to screen for less acute SCID
syndromes, such as leaky SCID or variant SCID.
(ii) A detailed description of all components in the test that
includes:
(A) A detailed description of the test components, all required
reagents, instrumentation and equipment, including illustrations or
photographs of nonstandard equipment or methods;
(B) Detailed documentation of the device software including, but
not limited to, standalone software applications and hardware-based
devices that incorporate software;
(C) Specifications for the filter paper, which must be
appropriately labeled for in vitro diagnostic use, to be used in
specimen collection and how it will be used in specimen collection
validation. These specifications must include: descriptive
characteristics of the filter paper, instructions on how a lab should
choose the appropriate filter paper, chemical properties of the filter
paper, interference concerns associated with the chemicals in the
filter paper, absorption properties of the filter paper, punch size,
absorption capacity, testing for homogeneity of punches, diameter of
the circle for the dried blood spot aliquot, absorption time, physical
composition, and number and size of punches to be tested;
(D) Methodology and protocols for detection of T-cell receptor
excision circles and methods for determination of results. The cutoff
must be selected before conducting clinical and analytical studies;
(E) A description of the result outputs along with sample reports.
Sample reports must include the scale used in reporting of results
(e.g., TREC copies/[mu]L) and the range of values that will be reported
out; and
(F) A description of appropriate internal and external controls
that are recommended or provided. The description must identify those
control elements that are incorporated into the testing procedure.
(iii) Information that demonstrates the performance characteristics
of the test, including:
(A) Data that demonstrates the clinical validity of the device,
using well characterized prospectively or retrospectively obtained
clinical specimens representative of the intended use population. A
minimum of 10 to 15 confirmed positive specimens must be obtained from
more than 1 site, including relevant annotation, and, at 1 year or
beyond, a SCID diagnosis by flow cytometry or clinically meaningful
information regarding the status of the subject must be obtained.
Additional specimens should have been obtained that are characterized
by other disorders that can be found by screening specimens that have
low or absent TREC (e.g., other T-cell lymphopenic disorders) to
supplement the range of results. The clinical validation study must
have a pre-specified clinical decision point (i.e., cutoff to
distinguish positive and negative results). Results must be summarized
in tabular format comparing interpretation of results to the reference
method. Point estimates together with two-sided 95 percent confidence
intervals must be provided for the positive percent agreement, negative
percent agreement, and overall percent agreement. Data must include the
retest rate, the false positive rate before retest, the final false
positive rate, and the false negative rate;
(B) Device reproducibility data generated, using a minimum of three
sites of which at least two must be external sites, with two operators
at each site. Each site must conduct a minimum of five runs per
operator over five nonconsecutive days evaluating a minimum of six
different relevant TREC concentrations that span and are well
distributed over the measuring range and include the clinical cutoff.
Specimens must include cord blood and cord blood diluted with ABO
matched adult blood specimens. Identical specimens from the same sample
panel must be tested at each site. Each specimen must be run in
triplicate and include controls run in triplicate. Results must be
reported as the standard deviation and percentage coefficient of
variation for each level tested. Results must also be displayed as a
dichotomous variable around the cutoff. Total variation must be
partitioned into the sum of within-lab and between-lab variations with
pre-specified acceptance criteria and 95 percent confidence intervals
for all data. Pre-specified acceptance criteria must be provided and
followed;
(C) Device precision data using clinical samples to evaluate the
within-lot, between-lot, within-run, between run, and total variation.
A range of TREC levels of the specimen must include samples within the
measuring range, samples above and below the measuring range, as well
as with samples very near above and below the cutoff value. At least
three replicates of each specimen must be tested with controls and
calibrator(s) according to the device instructions for use. The
precision study must use well characterized samples using different
lots, instruments, and operators. Results must be summarized in tabular
format. Pre-specified acceptance criteria must be provided and
followed;
(D) Linearity of the test must be demonstrated using a dilution
panel from clinical samples. The range of dilution samples must include
samples within the measuring range, samples above and below the
measuring range, as well as with samples very near above and below the
cutoff value. Results of the regression analysis must be summarized in
tabular format and fitted into a linear regression model with the
individual measurement results against the dilution factors. Pre-
specified acceptance criteria must be provided and followed;
(E) Device analytic sensitivity data, including limit of blank,
limit of detection, and limit of quantification;
(F) Device specificity data, including interference, carryover,
cross-contamination, and in silico analysis of potential off-target
genomic sequences;
(G) Device stability data, including real-time stability of samples
under various storage times, temperatures, and freeze-thaw conditions.
A separate shipping stability study must be performed;
(H) Lot-to-lot reproducibility study of each filter paper that will
be validated with the test. The lot-to-lot study must include a minimum
of three lots of each blood spot card that will be validated with the
test and be conducted over five nonconsecutive days. The sample panel
must consist of specimens with a range
[[Page 50080]]
of TREC levels and include samples within the measuring range, samples
above and below the measuring range, and samples very near above and
below the cutoff value. Multiple punches must be obtained from each
card for demonstration of homogeneity of the analyte across the dried
blood spot. Comparability of the test performance for each filter paper
must be demonstrated. Stability and storage of TREC DNA on each blood
spot card must be demonstrated. Results of the lot-to-lot study must be
summarized providing the mean, standard deviation, and percentage
coefficient of variation in a tabular format. Data must be calculated
for within-run, between-run, within-lot, and between-lot. Data
demonstrating the concordance between results across different filter
papers must be provided. Study acceptance criteria must be provided and
followed; and
(I) If applicable, a thermocycler reproducibility study must be
performed using thermocyclers from three independent thermocyler
manufacturers. The sample panel must consist of specimens with a range
of TREC levels and must include samples within the measuring range,
samples above and below the measuring range, and samples very near
above and below the cutoff value. The study must be done using three
filter paper lots and conducted over five nonconsecutive days. Results
of the thermocycler reproducibility study must be summarized providing
the mean, standard deviation, and percentage coefficient of variance in
a tabular format. Data must be calculated for the within-run, between-
run, within-lot, between-lot, and between thermocycler manufacturer
study results. Study acceptance criteria must be provided and followed.
(iv) Identification of risk mitigation elements used by your
device, including a description of all additional procedures, methods,
and practices incorporated into the directions for use that mitigate
risks associated with testing.
(2) Your Sec. 809.10 compliant labeling must include:
(i) A warning statement that reads ``This test is not intended for
diagnostic use, preimplantation or prenatal testing, or for screening
of SCID-like syndromes, such as DiGeorge syndrome or Omenn syndrome. It
is also not intended to screen for less acute SCID syndromes, such as
leaky SCID or variant SCID.'';
(ii) A warning statement that reads ``Test results are intended to
be used in conjunction with other clinical and diagnostic findings,
consistent with professional standards of practice, including
confirmation by alternative methods and clinical evaluation, as
appropriate.'';
(iii) A description of the performance studies listed in paragraph
(b)(1)(iii) and a summary of the results; and
(iv) A description of the filter paper specifications required for
the test.
Dated: October 24, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning, Legislation, and Analysis.
[FR Doc. 2017-23496 Filed 10-27-17; 8:45 am]
BILLING CODE 4164-01-P
