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.

Rules and Regulations Federal Register

73565 

Vol. 89, No. 176 

Wednesday, September 11, 2024 

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, 

Zivana.Tezak@fda.hhs.gov. 

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 


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73566 Federal Register / Vol. 89, No. 176 / Wednesday, September 11, 2024 / Rules and Regulations 

1FDA 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. 

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. 

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 failure to 

provide results.

Certain design verification and validation, including certain analytical studies and clinical studies; and Certain labeling information, including certain performance information and device limitations. 

Incorrect application or interpretation of results.Certain design verification and validation, including certain clinical studies; and Certain labeling information, 

including certain performance information and device limitations. 

User error and improper use of the 

device.

Certain design verification and 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 

■ 1. The authority citation for part 866 

continues to read as follows: 

Authority: 21 U.S.C. 351, 360, 360c, 360e, 

360j, 360l, 371. 

■ 2. Add § 866.6000 to subpart G to read 

as follows: 

§ 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 

§ 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 

§ 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 


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Federal Register / Vol. 89, No. 176 / Wednesday, September 11, 2024 / Rules and Regulations 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 hardwarebased 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 nonreference 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, interrun, 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 preanalytical 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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73568 Federal Register / Vol. 89, No. 176 / Wednesday, September 11, 2024 / Rules and Regulations 

1 88 FR 70616, 70617 (October 12, 2023). 

2SCAQMD, Final 2016 Air Quality Management 

Plan, March 2017, pp. 4–25, 4–28 and 4–29. The 

2016 South Coast AQMP designates the warehouse 

measure as MOB–03 (‘‘Emission Reductions at 

Warehouse Distribution Centers’’). 

3 84 FR 52005 (October 1, 2019). 

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 

DEPARTMENT OF THE TREASURY 

Internal Revenue Service 

26 CFR Part 1 

Income Taxes 

CFR Correction 

This rule is being published by the 

Office of the Federal Register to correct 

an editorial or technical error that 

appeared in the most recent annual 

revision of the Code of Federal 

Regulations. 

In Title 26 of the Code of Federal 

Regulations, Part 1 (§§ 1.410 to 1.440), 

revised as of April 1, 2024, in section 

1.430(h)(2)–1, remove paragraph (ii) 

immediately following paragraph (b)(2). 

[FR Doc. 2024–20701 Filed 9–10–24; 8:45 am] 

BILLING CODE 0099–10–P 

ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Part 52 

[EPA–R09–OAR–2023–0494; FRL–11442– 

02–R9] 

Air Plan Approval; California; South 

Coast Air Quality Management District 

AGENCY: Environmental Protection 

Agency (EPA). 

ACTION: Final rule. 

SUMMARY: The Environmental Protection 

Agency (EPA) is taking final action on 

a revision to the South Coast Air Quality 

Management District (SCAQMD or ‘‘the 

District’’) portion of the California State 

Implementation Plan (SIP). This 

revision concerns the regulation of 

emissions of oxides of nitrogen (NOX) 

and particulate matter (PM) associated 

with warehouses as indirect sources that 

attract or may attract mobile source 

emissions. The EPA is approving 

SCAQMD Rule 2305, ‘‘Warehouse 

Indirect Source Rule—Warehouse 

Actions and Investments to Reduce 

Emissions (WAIRE) Program,’’ to 

regulate these emission sources under 

the Clean Air Act (CAA or ‘‘the Act’’) as 

a SIP strengthening. 

DATES: This rule is effective October 11, 

2024. 

ADDRESSES: The EPA has established a 

docket for this action under Docket ID 

No. EPA–R09–OAR–2023–0494. All 

documents in the docket are listed on 

the https://www.regulations.gov 

website. Although listed in the index, 

some information is not publicly 

available, e.g., Confidential Business 

Information (CBI) or other information 

whose disclosure is restricted by statute. 

Certain other material, such as 

copyrighted material, is not placed on 

the internet and will be publicly 

available only in hard copy form. 

Publicly available docket materials are 

available through https://

www.regulations.gov, or please contact 

the person identified in the FOR FURTHER

INFORMATION CONTACT section for 

additional availability information. If 

you need assistance in a language other 

than English or if you are a person with 

a disability who needs a reasonable 

accommodation at no cost to you, please 

contact the person identified in the FOR

FURTHER INFORMATION CONTACT section. 

FOR FURTHER INFORMATION CONTACT: La 

Kenya Evans-Hopper, EPA Region IX, 75 

Hawthorne St., San Francisco, CA 

94105; phone: (415) 972–3245; email: 

evanshopper.lakenya@epa.gov. 

SUPPLEMENTARY INFORMATION: 

Throughout this document, ‘‘we,’’ ‘‘us,’’ 

and ‘‘our’’ refer to the EPA. 

Table of Contents 

I. Proposed Action 

II. Public Comments and EPA Responses 

III. EPA Action 

IV. Incorporation by Reference 

V. Statutory and Executive Order Reviews 

I. Proposed Action 

On October 12, 2023 (88 FR 70616) 

(‘‘proposed rule’’), the EPA proposed to 

approve SCAQMD Rule 2305 as a 

revision to the SCAQMD portion of the 

California SIP. Table 1 lists the 

SCAQMD rule addressed by the 

proposed rule with the dates that it was 

adopted by the SCAQMD and submitted 

by the California Air Resources Board 

(CARB). 

TABLE 1—SUBMITTED RULE 

Local agency Rule No. Rule title Adopted Submitted 

SCAQMD ................................ 2305 Warehouse Indirect Source Rule—Warehouse Actions and 

Investments to Reduce Emissions (WAIRE) Program.

05/07/2021 08/13/2021 

As described in the proposed rule, the 

purpose of SCAQMD Rule 2305 is to 

reduce local and regional emissions of 

NOX and PM, and to facilitate local and 

regional emission reductions associated 

with warehouses and the mobile sources 

attracted to warehouses in the 

SCAQMD, to meet State and Federal air 

quality standards for ozone and fine PM 

(PM2.5).1 The rule applies within the 

jurisdiction of the SCAQMD, which 

includes all of Orange County, the nondesert portions of Los Angeles and San 

Bernardino counties, and all of 

Riverside County (except for the Palo 

Verde Valley in far eastern Riverside 

County). 

Through the adoption of the 2016 

South Coast Air Quality Management 

Plan (AQMP), the SCAQMD adopted 

certain ‘‘facility-based mobile source 

measures,’’ including a measure under 

which the SCAQMD committed to 

assess and identify potential actions to 

further reduce emissions from emission 

sources associated with warehouse 

distribution centers.2 In 2019, the EPA 

approved the ozone portions of the 2016 

South Coast AQMP, including the 

commitment to develop facility-based 

mobile source measures, including the 

measure focused on warehouse 

distribution centers.3 The 2016 AQMP 

does not include an emission reduction 

estimate for the facility-based mobile 

source measure related to warehouses. 

In 2021, after assessing potential actions 

to further reduce emissions associated 


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