[Federal Register Volume 89, Number 176 (Wednesday, September 11, 2024)]
[Rules and Regulations]
[Pages 73565-73568]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-20550]
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Rules and Regulations
Federal Register
________________________________________________________________________
This section of the FEDERAL REGISTER contains regulatory documents
having general applicability and legal effect, most of which are keyed
to and codified in the Code of Federal Regulations, which is published
under 50 titles pursuant to 44 U.S.C. 1510.
The Code of Federal Regulations is sold by the Superintendent of Documents.
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Federal Register / Vol. 89, No. 176 / Wednesday, September 11, 2024 /
Rules and Regulations
[[Page 73565]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2024-N-4018]
Medical Devices; Immunology and Microbiology Devices;
Classification of the Whole Exome Sequencing Constituent Device
AGENCY: Food and Drug Administration, HHS.
ACTION: Final amendment; final order.
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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is
classifying the whole exome sequencing constituent device 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 whole exome sequencing constituent device'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.
DATES: This order is effective September 11, 2024. The classification
was applicable on December 23, 2020.
FOR FURTHER INFORMATION CONTACT: Zivana Tezak, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 3424, Silver Spring, MD 20993-0002, 301-796-6206,
[email protected].
SUPPLEMENTARY INFORMATION:
I. Background
Upon request, FDA has classified the whole exome sequencing
constituent device as class II (special controls), which we have
determined will provide a reasonable assurance of safety and
effectiveness.
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 (see 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 device by means of
the procedures for premarket notification under section 510(k) of the
FD&C Act (21 U.S.C. 360(k)) and part 807 (21 CFR part 807).
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 (see also part 860, subpart D (21 CFR part 860, subpart D)).
Section 207 of the Food and Drug Administration Modernization Act of
1997 (Pub. L. 105-115) established the first procedure for De Novo
classification. Section 607 of the Food and Drug Administration Safety
and Innovation Act (Pub. L. 112-144) modified the De Novo application
process by adding a second procedure. 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. Although the device was automatically placed
within class III, the De Novo classification is considered to be the
initial classification of the device.
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 section 513(f)(2)(B)(i) of the FD&C
Act). As a result, other device sponsors do not have to submit a De
Novo request or premarket approval application to market a
substantially equivalent device (see section 513(i) of the FD&C Act,
defining ``substantial equivalence''). Instead, sponsors can use the
510(k) process, when necessary, to market their device.
II. De Novo Classification
On August 2, 2019, FDA received Helix OpCo, LLC's request for De
Novo classification of the Helix Learning Platform. 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 December 23, 2020, FDA issued an order to the
requester classifying the device into class II. In this final order,
FDA is codifying the classification of the device by adding 21
[[Page 73566]]
CFR 866.6000.\1\ We have named the generic type of device whole exome
sequencing constituent device, and it is identified as a device for
germline whole exome sequencing of genomic deoxyribonucleic acid (DNA)
isolated from human specimens. The DNA sequence generated by this
device is intended as input for clinical germline DNA assays that have
FDA marketing authorization and are intended for use with this device.
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\1\ FDA notes that the ``ACTION'' caption for this final order
is styled as ``Final amendment; final order,'' rather than ``Final
order.'' Beginning in December 2019, this editorial change was made
to indicate that the document ``amends'' the Code of Federal
Regulations. The change was made in accordance with the Office of
Federal Register's (OFR) interpretations of the Federal Register Act
(44 U.S.C. chapter 15), its implementing regulations (1 CFR 5.9 and
parts 21 and 22), and the Document Drafting Handbook.
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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--Whole Exome Sequencing Constituent Device Risks and Mitigation
Measures
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Identified risks to health Mitigation measures
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Inaccurate test results and Certain design verification and
failure to provide results. validation, including certain
analytical studies and clinical
studies; and Certain labeling
information, including certain
performance information and device
limitations.
Incorrect application or Certain design verification and
interpretation of results. validation, including certain
clinical studies; and Certain
labeling information, including
certain performance information and
device limitations.
User error and improper use of the Certain design verification and
device. validation, including certain
analytical studies and clinical
studies; and Certain labeling
information, including certain
performance information and device
limitations.
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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. 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 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. 3501-3521). The collections
of information in part 860, subpart D, regarding De Novo classification
have been approved under OMB control number 0910-0844; the collections
of information in 21 CFR 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; the collections of information in 21 CFR part
820, regarding quality system regulation, have been approved under OMB
control number 0910-0073; 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. 866.6000 to subpart G to read as follows:
Sec. 866.6000 Whole exome sequencing constituent device.
(a) Identification. A whole exome sequencing constituent device is
for germline whole exome sequencing of genomic deoxyribonucleic acid
(DNA) isolated from human specimens. The DNA sequence generated by this
device is intended as input for clinical germline DNA assays that have
FDA marketing authorization and are intended for use with this device.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) The intended use on the device's label and labeling required
under Sec. 809.10 of this chapter must include:
(i) The indicated variant types for which acceptable, as determined
by FDA, validation data has been provided. Distinct variant types are
considered as single nucleotide variant, insertion, deletion, tandem
repeats, copy number variants, or gene rearrangements, and validated
for specific sizes and lengths, as applicable.
(ii) The indicated specimen type(s) for which acceptable, as
determined by FDA, validation data has been provided.
(2) The labeling required under Sec. 809.10(b) of this chapter
must include:
(i) The identification of, or the specifications for, the
collection device or devices to be used for sample collection, as
applicable.
(ii) A description of the reportable range, which is the region of
the genome for which the assay is intended to provide results, as well
as a description of the targeted regions of the genome that have
enhanced coverage. This must include a description of any genomic
regions that are excluded from the reportable region due to
unacceptable risk of erroneous results, or for other reasons. A
description of the clinically relevant genes excluded from the
reportable range must also be included, if applicable.
(iii) A description of the design features and control elements,
including the quality metrics and thresholds which are used for
reporting the analytical range (the genomic DNA in the reportable range
that passed the quality metrics in the run required for reporting to
the user) that are incorporated into the testing procedure, that
mitigate the risk of incorrect clinical results. The following metrics
[[Page 73567]]
are considered applicable in the generation of high confidence data and
the established thresholds for these metrics for reporting must be
described and be determined to be acceptable by FDA: cluster density
and percent of cluster pass quality filter, percent of bases meeting
the minimum base quality score, average coverage of reads, percent of
reads mapped on target, percent of reportable region with coverage
meeting the minimum requirement, percent of unassigned read indices,
percent of reads for non-human DNA, allele fraction, and strand bias.
Any alternate metrics used must be described and an acceptable, as
determined by FDA, rationale for applicability must be provided.
(iv) A representative sample of the device output report(s)
provided to users, which must include any relevant limitations of the
device, as determined applicable by FDA.
(3) Design verification and validation must include:
(i) A detailed description of the impact of any software, including
software applications and hardware-based devices that incorporate
software, on the device's function.
(ii) Acceptable data, as determined by FDA, demonstrating how the
key quality metrics and quality metric thresholds in the list in
paragraph (b)(2)(iii) of this section for reporting were established
and optimized for accuracy using appropriate DNA standards with
established reference genomic sequence. Data must include, as
applicable, base quality score, allele fraction for heterozygosity and
coverage, and other applicable metrics.
(iii) Data demonstrating acceptable, as determined by FDA,
analytical device performance using patient specimens representing the
full spectrum of expected variant types reported across the genome and
in genomic regions that are difficult to sequence. The number of
specimens tested must be sufficient to obtain estimates of device
performance that are representative of the device performance that can
be expected for the reportable region and clinically relevant subsets
of the reportable region, as applicable. For each study, data must
include a summary of the key quality metric data; the number and
percentage of true positives (TP), false positives (FP), and false
negatives (FN); number and percentage of no-calls; positive percent
agreement (PPA); negative percent agreement (NPA); positive predictive
value (PPV); technical positive percent value (TPPV); and non-reference
concordance (NRC). These data must be provided per sample and
stratified by variant type. The variant data must also be further
stratified by size and zygosity (homozygous common allele,
heterozygous, homozygous rare allele). Data demonstrating the accuracy
assay based on guanine and cytosine (GC) content, pseudogenes, and
proximity to short tandem repeats must also be presented. The data must
be presented for the entire exome and also for clinically relevant
subsets of the reportable region. For each study, the number of run
failures and repeat/requeued specimens must be summarized.
(iv) Documentation of acceptance criteria that are applied to
analytical and clinical validation studies, which must be justified
based on the estimated risk of erroneous results on clinically
significant genes and variants and must be clinically acceptable, as
determined by FDA. The acceptance criteria must be pre-specified prior
to clinical and analytical validation studies, and all validation
testing results must be documented with respect to those acceptance
criteria.
(v) Analytical validation must be demonstrated by conducting
studies that provide:
(A) Data demonstrating acceptable, as determined by FDA, accuracy
based on agreement with an acceptable, as determined by FDA, comparator
method(s) that has been validated to have high accuracy and
reproducibility. Accuracy of the test shall be evaluated with reference
standards and clinical specimens for each indicated specimen type of a
number determined acceptable by FDA, collected and processed in a
manner consistent with the test's instructions for use.
(B) Data demonstrating acceptable, as determined by FDA, precision
from a precision study using clinical samples to adequately evaluate
intra-run, inter-run, and total variability across operator,
instrument, lot, day, and site, as applicable. The samples must include
the indicated range of DNA input. Precision, including repeatability
and reproducibility, must be assessed by agreement between replicates,
and also supported by sequencing quality metrics for targeted regions
across the panel. Precision must be demonstrated per specimen and in
aggregate. Precision data must be calculated and presented with and
without no calls/invalid results.
(C) Data demonstrating acceptable, as determined by FDA, accuracy
in the presence of clinically relevant levels of potential interfering
substances that are present in the specimen type and intended use
population, including, for example, endogenous substances, exogenous
substances, and microbes, as applicable.
(D) Data demonstrating the absence of sample cross contamination
due to index swapping (misassignment).
(E) Data demonstrating that the pre-analytical steps such as DNA
extraction are robust such that sources of variability in these steps
and procedures do not diminish the accuracy and precision of the
device.
(F) Data demonstrating that acceptable, as determined by FDA,
device performance is maintained across the range of claimed DNA input
concentrations for the assay.
(vi) Design verification and validation for software within the
whole exome sequencing constituent device must include the following:
(A) Detailed description of the software, including specifications
and requirements for the format of data input and output, such that
users can determine if the device conforms to user needs and intended
uses.
(B) Device design must include a detailed strategy to ensure
cybersecurity risks that could lead to loss of genetic data security,
are adequately addressed and mitigated (including device interface
specifications and how safe reporting of the genetic test is maintained
when software is updated). Verification and validation must include
security testing to demonstrate effectiveness of the associated
controls.
(C) Device design must ensure that a record of critical events,
including a record of all genetic test orders using the whole exome
sequencing constituent device, device malfunctions, and associated
acknowledgments, is stored and accessible for an adequate period to
allow for auditing of communications between the whole exome sequencing
constituent device and downstream clinical genetic tests, and to
facilitate the sharing of pertinent information with the responsible
parties for those devices.
(vii) A protocol reviewed and determined acceptable by FDA, that
specifies the verification and validation activities that will be
performed for anticipated bioinformatic software modifications to
reevaluate performance claims or performance specifications. This
protocol must include a process for assessing whether a modification to
the bioinformatics software could significantly affect the safety or
effectiveness of the device. The protocol must include assessment
metrics, acceptance criteria, and analytical methods for the
performance testing of changes, as applicable. The protocol must also
include the process for communicating to developers of
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downstream clinical genetic tests the impact of the bioinformatics
software change on the whole exome sequencing constituent system
genetic data output so they may implement appropriate corresponding
actions.
Dated: September 6, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-20550 Filed 9-10-24; 8:45 am]
BILLING CODE 4164-01-P