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[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]

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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.

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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
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                                            Mitigation measures/21 CFR
            Identified risks                         section
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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)).
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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 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
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