[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
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 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.
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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.

-----------------------------------------------------------------------

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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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
------------------------------------------------------------------------
    Identified risks to health               Mitigation measures
------------------------------------------------------------------------
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.
------------------------------------------------------------------------

    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

[[Page 73568]]

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