[Federal Register Volume 87, Number 247 (Tuesday, December 27, 2022)]
[Rules and Regulations]
[Pages 79251-79253]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-28035]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2021-N-0851]


Medical Devices; Immunology and Microbiology Devices; 
Classification of the Human Leukocyte Antigen Typing Companion 
Diagnostic Test

AGENCY: Food and Drug Administration, Department of Health and Human 
Services (HHS).

ACTION: Final amendment; final order.

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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is 
classifying the human leukocyte antigen typing companion diagnostic 
test 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 human leukocyte antigen typing companion 
diagnostic test'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 December 27, 2022. The classification 
was applicable on November 28, 2022.

FOR FURTHER INFORMATION CONTACT: Karen Fikes, Center for Biologics 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 72, Rm. 7301, Silver Spring, MD, 20993-0002, 240-
402-7911.

SUPPLEMENTARY INFORMATION: 

I. Background

    Upon request, FDA has classified the human leukocyte antigen typing 
companion diagnostic test as class II (special controls), which we have 
determined will provide a reasonable assurance of safety and 
effectiveness. In addition, we believe this action will enhance 
patients' access to beneficial innovation, in part by placing the 
device into a lower device class than the automatic class III 
assignment.
    The automatic assignment of class III occurs by operation of law 
and without any action by FDA, regardless of the level of risk posed by 
the new device. Any device that was not in commercial distribution 
before May 28, 1976, is automatically classified as, and remains 
within, class III and requires premarket approval unless and until FDA 
takes an action to classify or reclassify the device (see 21 U.S.C. 
360c(f)(1)). We refer to these devices as ``postamendments devices'' 
because they were not in commercial distribution prior to the date of 
enactment of the Medical Device Amendments of 1976, which amended the 
Federal Food, Drug, and Cosmetic Act (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. 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 
less-burdensome 510(k) process, when necessary, to market their device.

II. De Novo Classification

    On July 1, 2022, One Lambda, Inc., submitted a request for De Novo 
classification of the SeCORE CDx HLA Sequencing System. 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 November 28, 2022, 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 
866.5960.\1\ We have named the generic type of device human leukocyte 
antigen typing companion diagnostic test, and it is identified as a 
prescription genotyping or phenotyping in vitro diagnostic product 
intended for use as an aid in identifying patients who have specific 
human leukocyte antigen (HLA) allele(s) or express specific HLA 
antigen(s) and may benefit from treatment with a corresponding 
therapeutic product or are likely to be at increased risk for serious 
adverse

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reactions as a result of treatment with a corresponding therapeutic 
product.
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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--Human Leukocyte Antigen Typing Companion Diagnostic Test Risks
                         and Mitigation Measures
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            Identified risks                   Mitigation measures
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Inaccurate test results (false positive  Labeling, design verification
 or false negative results) can result    and validation, clinical
 in adverse health consequences.          validity data, bridging study.
Failure of software to correctly         Software verification and
 interpret test results can result in     validation.
 adverse health consequences.
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    FDA has determined that special controls, in combination with the 
general controls, address these risks to health and provide reasonable 
assurance of safety and effectiveness. In order for a device to fall 
within this classification, and thus avoid automatic classification in 
class III, it would have to comply with the special controls named in 
this final order. The necessary special controls appear in the 
regulation codified by this order. This device is subject to premarket 
notification requirements under section 510(k) of the FD&C Act.

III. Analysis of Environmental Impact

    The Agency has determined under 21 CFR 25.34(b) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

IV. Paperwork Reduction Act of 1995

    This final order establishes special controls that refer to 
previously approved collections of information found in other FDA 
regulations 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 21 CFR 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 part 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.  866.5960 to subpart F to read as follows:


Sec.  866.5960  Human leukocyte antigen typing companion diagnostic 
test.

    (a) Identification. A human leukocyte antigen (HLA) typing 
companion diagnostic (CDx) test is a prescription genotyping or 
phenotyping in vitro diagnostic product intended for use as an aid in 
identifying patients who have specific HLA allele(s) or express 
specific HLA antigen(s) and may benefit from treatment with a 
corresponding therapeutic product or are likely to be at increased risk 
for serious adverse reactions as a result of treatment with a 
corresponding therapeutic product.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) The intended use of the device must specify the target HLA 
allele(s) or antigen(s), the patient population(s), and the 
corresponding therapeutic product(s).
    (2) Design verification and validation must include:
    (i) Detailed documentation of an analytical accuracy study that 
uses well-characterized samples including clinical samples from 
intended use population(s) focusing on the target allele(s) needed for 
patient selection;
    (ii) Detailed documentation of precision studies (repeatability, 
reproducibility) that evaluate possible sources of variation that may 
affect test results;
    (iii) Detailed documentation of a study determining range of input 
sample concentrations that meet performance specifications;
    (iv) Detailed description of the ambiguity resolution method, if 
applicable;
    (v) For a sequencing-based assay, documentation of coverage and 
predefined coverage threshold of target genomic regions, pertinent 
variant types, and sequence contexts;
    (vi) For multiplex assays, documentation of a risk assessment and 
design specifications that are in place to prevent incorrect reactivity 
assignment;
    (vii) Description of a plan on how to ensure the performance of the 
device does not change when new HLA alleles are identified, and/or when 
reactivity assignments are changed; and
    (viii) Detailed description of device software including standalone 
software, or software and bioinformatics analysis pipeline, if 
applicable, incorporated in the instruments, and documentation of 
software including the level of concern and associated risks, software 
requirement specifications, software design specifications (e.g., 
algorithms, alarms and device limitations), hazard analysis, 
traceability matrix, verification and validation testing, unresolved 
anomalies, hardware requirements, and effective cybersecurity 
management.
    (3) Clinical validity data (which may include summary reports from 
clinical trials, comparison studies using clinical samples, or through 
an alternative approach determined to be appropriate by FDA), 
demonstrating the following, as applicable:
    (i) Which patients identified by the HLA CDx test are most likely 
to benefit from the corresponding therapeutic product; and
    (ii) Which patients identified by the HLA CDx test are likely to be 
at increased risk for serious adverse reactions as a result of 
treatment with the corresponding therapeutic product.
    (4) If the HLA test used in the clinical trials is different from 
the HLA CDx test

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in the premarket notification submission, the submission must include 
results of a bridging study, or an alternative approach determined to 
be appropriate by FDA.

    Dated: December 20, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-28035 Filed 12-23-22; 8:45 am]
BILLING CODE 4164-01-P


