Unknown. Final amendment; final order

5,185 words·~24 min read·/register/2024/09/11/2024-20550·

A research copy — for the controlling text, always check the official state or federal source. Not legal advice.

--- schema: federal-register doc_type: fedreg source_file: FR-2024-09-11.xml --- 89 176 Wednesday, September 11, 2024 Contents Agriculture Agriculture Department See Animal and Plant Health Inspection Service See Food Safety and Inspection Service Animal Animal and Plant Health Inspection Service NOTICES Agency Information Collection Activities; Proposals, Submissions, and Approvals: Self-Certification Medical Statement, 73621-73622 2024-20544 Census Bureau Census Bureau NOTICES Agency Information Collection Activities;

Proposals, Submissions, and Approvals: Generic Clearance for 2030 Census Small-Scale Tests, Evaluations, and Database Updates, 73623-73624 2024-20547 Centers Medicare Centers for Medicare & Medicaid Services NOTICES Agency Information Collection Activities; Proposals, Submissions, and Approvals, 73655-73656 2024-20527 Children Children and Families Administration NOTICES Agency Information Collection Activities; Proposals, Submissions, and Approvals: Children's Bureau Regional Partnership Grants Final Report Outline, 73656 2024-20425 Commerce Commerce Department See Census Bureau See Foreign-Trade Zones Board See Industry and Security Bureau See International Trade Administration See National Oceanic and Atmospheric Administration Commodity Futures Commodity Futures Trading Commission NOTICES Meetings;

Sunshine Act, 73636 2024-20781 Education Department Education Department NOTICES Agency Information Collection Activities; Proposals, Submissions, and Approvals: Carl D. Perkins Career and Technical Education Act State Plan Guide, 73639 2024-20611 Consolidated Annual Report for the Carl D. Perkins Career and Technical Education Act, 73638-73639 2024-20614 Expanding Opportunity Through Quality Charter Schools Program: Technical Assistance To Support Monitoring, Evaluation, Data Collection, and Dissemination of Best Practices, 73637-73638 2024-20430 Regional Educational Laboratory Midwest:

Teacher Preparation Program Completion: What Factors Play a Role, 73637 2024-20437 Election Election Assistance Commission NOTICES Meetings; Sunshine Act, 73639-73640 2024-20660 Employment and Training Employment and Training Administration NOTICES Agency Information Collection Activities; Proposals, Submissions, and Approvals: H-2A Temporary Agricultural Labor Certification Program and Agricultural Recruitment System, 73725 2024-20605 Energy Department Energy Department See Federal Energy Regulatory Commission NOTICES Privacy Act;

Systems of Records, 73640-73643 2024-20554 Environmental Protection Environmental Protection Agency RULES Air Quality State Implementation Plans; Approvals and Promulgations: California; South Coast Air Quality Management District, 73568-73588 2024-20349 Phasedown of Hydrofluorocarbons: Address Vacated Provisions, 73588-73592 2024-20191 State Hazardous Waste Management Program: North Carolina; Final Authorization of Revisions; Withdrawal, 73592 2024-20338 PROPOSED RULES Outer Continental Shelf Air Regulation:

Massachusetts; State Requirements Incorporated, 73617-73620 2024-20119 Equal Equal Employment Opportunity Commission NOTICES Agency Information Collection Activities; Proposals, Submissions, and Approvals, 73649-73651 2024-20610 Federal Aviation Federal Aviation Administration PROPOSED RULES Airworthiness Directives: Airbus SAS Airplanes, 73608-73612 2024-20381 Special Conditions: Aerocon Engineering Company, Airbus Model A350-941 Airplane; Forward Lower Lobe Crew Rest Compartment Installation, 73604-73608 2024-20519 Federal Communications Federal Communications Commission RULES Process Reform for Executive Branch Review of Certain FCC Applications and Petitions Involving Foreign Ownership, 73601-73602 2024-20535 NOTICES Agency Information Collection Activities;

Proposals, Submissions, and Approvals, 73652-73654 2024-20530 2024-20531 Federal Advisory Committee Act: Task Force for Reviewing the Connectivity and Technology Needs of Precision Agriculture in the United States, 73651 2024-20536 Hearings, Meetings, Proceedings, etc.: Communications Security, Reliability, and Interoperability Council, 73652-73653 2024-20537 Privacy Act; Systems of Records, 73651 2024-20573 Federal Emergency Federal Emergency Management Agency NOTICES Disaster or Emergency Declaration and Related Determination:

Amendment No. 13, 73685-73686 2024-20455 Chickasaw Nation, 73693-73694 2024-20506 Florida, 73671, 73694 2024-20440 2024-20507 Florida; Amendment No. 1, 73697 2024-20489 Florida; Amendment No. 2, 73686 2024-20494 Georgia, 73692-73693 2024-20442 Georgia; Amendment No. 1, 73698 2024-20443 Iowa; Amendment No. 6, 73695-73696 2024-20509 Iowa; Amendment No. 7, 73669-73670 2024-20481 Iowa; Amendment No. 8, 73694 2024-20491 Iowa; Amendment No. 9, 73677 2024-20486 Kansas, 73670 2024-20492 Kentucky, 73672-73673, 73678 2024-20457 2024-20493 Kentucky;

Amendment No. 1, 73673, 73677 2024-20490 2024-20501 Kentucky; Amendment No. 15, 73682-73683 2024-20456 Kentucky; Amendment No. 2, 73689 2024-20483 Kentucky; Amendment No. 3, 73684, 73688 2024-20458 2024-20502 Minnesota; Amendment No. 3, 73684-73685 2024-20505 Minnesota; Amendment No. 4, 73686 2024-20498 Missouri, 73683 2024-20488 Montana, 73689 2024-20487 New Hampshire; Amendment No. 1, 73677, 73699 2024-20495 2024-20508 New Hampshire; Amendment No. 2, 73696-73699 2024-20459 2024-20482 New Mexico;

Amendment No. 4, 73678 2024-20504 New Mexico; Amendment No. 5, 73697-73698 2024-20496 New Mexico; Amendment No. 6, 73686 2024-20497 North Carolina, 73683-73684 2024-20444 North Carolina; Amendment No. 1, 73699 2024-20445 North Carolina; Amendment No. 2, 73683 2024-20446 North Carolina; Amendment No. 3, 73687 2024-20447 Puerto Rico, 73685, 73698 2024-20450 2024-20511 Puerto Rico; Amendment No. 1, 73695 2024-20451 South Carolina, 73691 2024-20441 South Dakota, 73695 2024-20503 Texas;

Amendment No. 17, 73670 2024-20480 Texas; Amendment No. 3, 73688 2024-20499 Texas; Amendment No. 4, 73687 2024-20510 Vermont, 73692 2024-20448 Vermont; Amendment No. 1, 73688, 73691-73692 2024-20449 2024-20484 Virgin Islands, 73696 2024-20452 Virgin Islands; Amendment No. 1, 73687 2024-20453 Virgin Islands; Amendment No. 2, 73693 2024-20454 West Virginia; Amendment No. 2, 73697 2024-20485 Flood Hazard Determinations, 73671-73682, 73689-73691 2024-20521 2024-20522 2024-20523 2024-20524 2024-20525 Federal Energy Federal Energy Regulatory Commission NOTICES Application:

Pacific Gas and Electric Co., 73643-73644 2024-20590 Combined Filings, 73646, 73649 2024-20586 2024-20587 Environmental Assessments; Availability, etc.: Ampersand Christine Falls Hydro, LLC, 73647 2024-20593 Appalachian Power Co., 73648 2024-20591 Environmental Review: MS Hub Capacity Expansion Project, Mississippi Hub, LLC, 73645-73646 2024-20588 Licenses; Exemptions, Applications, Amendments, etc.: South Sutter Water District, 73644-73645 2024-20592 Request Under Blanket Authorization:

Columbia Gas Transmission, LLC, 73647-73648 2024-20589 Technical Conference: Energy Efficiency Resource Participation in Regional Transmission Organizations/Independent System Operators Markets, 73648-73649 2024-20585 Water Quality Certification Application: Consolidated Hydro New York, LLC, 73643 2024-20594 Federal Financial Federal Financial Institutions Examination Council NOTICES Hearings, Meetings, Proceedings, etc.: Appraisal Subcommittee, 73654 2024-20607 Appraisal Subcommittee;

Cancellation, 73654 2024-20600 Federal Motor Federal Motor Carrier Safety Administration NOTICES Exemption Application: Commercial Driver's License; Hawaii Department of Transportation, 73744-73745 2024-20613 Review of Guidance, 73746 2024-20596 Food and Drug Food and Drug Administration RULES Medical Devices: Immunology and Microbiology Devices; Classification of the Whole Exome Sequencing Constituent Device, 73565-73568 2024-20550 NOTICES Approval of Product Under Voucher: Rare Pediatric Disease Priority Review Voucher;

Opzelura (ruxolitinib), 73661-73662 2024-20556 Patent Extension Regulatory Review Period: Technegas, 73660-73661 2024-20555 Voquenza Dual Pak, 73658-73660 2024-20551 Voquenza Triple Pak, 73656-73658 2024-20552 Ztalmy, 73662-73663 2024-20549 Food Safety Food Safety and Inspection Service NOTICES Agency Information Collection Activities; Proposals, Submissions, and Approvals: Accredited Laboratories, 73622-73623 2024-20553 Foreign Trade Foreign-Trade Zones Board NOTICES Authorization of Production Activity:

Mercury Marine (Electric Inboard and Outboard Motors), Foreign-Trade Zone 41, Fond Du Lac, WI, 73625 2024-20561 Space Exploration Technologies Corp. (Internet Satellite Dish Kits), Foreign-Trade Zone 50, Hawthorne, CA, 73624 2024-20562 General Services General Services Administration NOTICES Record of Decision: Buildings at 202, 214 and 220 South State Street, Chicago, IL, 73654-73655 2024-20439 Health and Human Health and Human Services Department See Centers for Medicare & Medicaid Services See Children and Families Administration See Food and Drug Administration See Health Resources and Services Administration See National Institutes of Health See Substance Abuse and Mental Health Services Administration RULES World Trade Center Health Program:

Expanded Eligibility for Pentagon and Shanksville, PA Responders, 73592-73601 2024-20540 Health Resources Health Resources and Services Administration NOTICES Supplemental Award: Autism Longitudinal Data Project, 73664-73665 2024-20570 Supplemental Funding: Rural Behavioral Health Workforce Centers; Northern Border Region, 73663-73664 2024-20584 Homeland Homeland Security Department See Federal Emergency Management Agency See Transportation Security Administration See U.S. Citizenship and Immigration Services NOTICES Hearings, Meetings, Proceedings, etc.:

Technical Mapping Advisory Council, 73699-73700 2024-20538 Housing Housing and Urban Development Department NOTICES Agency Information Collection Activities; Proposals, Submissions, and Approvals: Record of Employee Interview, 73705-73706 2024-20571 Request for Comment: Modifying HUD's Elevated Blood Lead Level Threshold for Children Under Age 6 Who Are Living in Certain HUD-Assisted Target Housing Covered by the Lead Safe Housing Rule, 73702-73705 2024-20532 Industry Industry and Security Bureau PROPOSED RULES Reporting Requirements for the Development of Advanced Artificial Intelligence Models and Computing Clusters, 73612-73617 2024-20529 Inter-American Inter-American Foundation NOTICES Privacy Act;

Systems of Records, 73706-73719 2024-20583 2024-20595 Internal Revenue Internal Revenue Service RULES Income Taxes; CFR Correction, 73568 2024-20701 NOTICES Agency Information Collection Activities; Proposals, Submissions, and Approvals, 73752-73761 2024-20548 2024-20568 Agency Information Collection Activities; Proposals, Submissions, and Approvals: Tax-Exempt Organization Forms, 73746-73752 2024-20539 Quarterly Publication of Individuals Who Have Chosen To Expatriate: Correction, 73746 2024-20543 International Trade Adm International Trade Administration NOTICES Antidumping or Countervailing Duty Investigations, Orders, or Reviews:

Certain Cut-to-Length Carbon-Quality Steel Plate From the Republic of Korea, 73626-73627 2024-20581 Certain Cut-to-Length Carbon-Quality Steel Plate Products From the Republic of Korea, 73625-73626 2024-20580 Certain Passenger Vehicle and Light Truck Tires From the People's Republic of China, 73628-73631 2024-20582 Circular Welded Carbon-Quality Steel Pipe From the People's Republic of China, 73632 2024-20564 Laminated Woven Sacks From the Socialist Republic of Vietnam, 73627-73628, 73633-73634 2024-20567 2024-20569 Decision on Application for Duty-Free Entry of Scientific Instruments:

Massachusetts Institute of Technology et al., 73632-73633 2024-20534 International Trade Com International Trade Commission NOTICES Antidumping or Countervailing Duty Investigations, Orders, or Reviews: Corrosion-Resistant Steel Products From Australia, Brazil, Canada, Mexico, Netherlands, South Africa, Taiwan, Turkey, United Arab Emirates, and Vietnam, 73721-73723 2024-20597 Investigations; Determinations, Modifications, and Rulings, etc.: Certain Semiconductor Devices, and Methods of Manufacturing Same and Products Containing the Same, 73719-73721 2024-20514 Plastic Decorative Ribbon From China, 73719 2024-20601 Utility Scale Wind Towers From China and Vietnam, 73723 2024-20599 Justice Department Justice Department NOTICES Agency Information Collection Activities;

Proposals, Submissions, and Approvals: Annual Certification Report and Equitable Sharing Agreement, 73723-73724 2024-20428 Authorization To Release Consumer/Credit Information, 73724-73725 2024-20426 Labor Department Labor Department See Employment and Training Administration See Occupational Safety and Health Administration NOTICES Requests for Nominations: Federal Advisory Council on Occupational Safety and Health, 73726-73727 2024-20528 NASA National Aeronautics and Space Administration NOTICES Hearings, Meetings, Proceedings, etc.:

Advisory Council, 73728-73729 2024-20575 National Institute National Institutes of Health NOTICES Hearings, Meetings, Proceedings, etc.: National Eye Institute, 73665 2024-20433 National Institute of Arthritis and Musculoskeletal and Skin Diseases, 73665 2024-20500 National Oceanic National Oceanic and Atmospheric Administration RULES Pacific Halibut Fisheries of the West Coast: Inseason Action for the 2024 Area 2A Pacific Halibut Directed Commercial Fishery, 73602-73603 2024-20608 NOTICES Adjustment of Fees for Seafood Inspection Services, 73635 2024-20558 Hearings, Meetings, Proceedings, etc.:

North Pacific Fishery Management Council, 73636 2024-20565 2024-20566 Ocean Exploration Advisory Board, 73634-73635 2024-20432 National Science National Science Foundation NOTICES Agency Information Collection Activities; Proposals, Submissions, and Approvals: Research Experience and Mentoring Survey, 73729-73730 2024-20606 Occupational Safety Health Adm Occupational Safety and Health Administration NOTICES Agency Information Collection Activities; Proposals, Submissions, and Approvals:

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National Grandparents Day (Proc. 10805), 73557-73558 2024-20711 National Hispanic-Serving Institutions Week (Proc. 10804), 73555-73556 2024-20703 EXECUTIVE ORDERS Federal Government: Workforce Development; Investing in America and in American Workers (EO 14126), 73559-73564 2024-20712 ADMINISTRATIVE ORDERS Terrorist Attacks; Continuation of National Emergency (Notice of September 9, 2024), 74099-74101 2024-20799 U.S. Elections, Foreign Interference or Undermining Public Confidence;

Continuation of National Emergency (Notice of September 9, 2024), 74103-74104 2024-20800 Securities Securities and Exchange Commission RULES Guidance: Form N-PORT and Form N-CEN Reporting; Open-End Fund Liquidity Risk Management Programs, 73764-73800 2024-19819 NOTICES Application: Great Elm Capital Corp., et al., 73739 2024-20574 Self-Regulatory Organizations; Proposed Rule Changes: Cboe BYX Exchange, Inc., 73902-73948 2024-20464 Cboe BZX Exchange, Inc., 73852-73899 2024-20465 Cboe Exchange, Inc., 73802-73849 2024-20463 ICE Clear Credit LLC, 73734-73739 2024-20460 Investors Exchange LLC, 74000-74047 2024-20470 MIAX PEARL LLC, 73950-73997 2024-20478 Nasdaq BX, Inc., 74050-74097 2024-20466 Small Business Small Business Administration NOTICES Disaster Declaration:

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To subscribe to the Federal Register Table of Contents electronic mailing list, go to https://public.govdelivery.com/accounts/USGPOOFR/subscriber/new, enter your e-mail address, then follow the instructions to join, leave, or manage your subscription. 89 176 Wednesday, September 11, 2024 Rules and Regulations 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 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 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

(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 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 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]

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