[Federal Register Volume 85, Number 26 (Friday, February 7, 2020)]
[Rules and Regulations]
[Pages 7215-7218]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-01725]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2019-N-5325]


Medical Devices; Immunology and Microbiology Devices; 
Classification of Human Immunodeficiency Virus Drug Resistance 
Genotyping Assay Using Next Generation Sequencing Technology

AGENCY: Food and Drug Administration, HHS.

ACTION: Final amendment; final order.

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[[Page 7216]]

SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
classifying the human immunodeficiency virus (HIV) drug resistance 
genotyping assay using next generation sequencing (NGS) technology 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 HIV drug resistance genotyping assay using 
NGS technology'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, in part by reducing 
regulatory burdens.

DATES: This order is effective on February 7, 2020. The classification 
was applicable on November 5, 2019.

FOR FURTHER INFORMATION CONTACT: Sana F. Hussain, Center for Biologics 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993, 240-402-
7911.

SUPPLEMENTARY INFORMATION: 

I. Background

    Upon request, FDA has classified the HIV drug resistance genotyping 
assay using NGS technology 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 reducing 
regulatory burdens 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 (Pub. L. 94-295), 
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 \1\ finding a new device to be substantially equivalent under 
section 513(i) of the FD&C Act to a predicate device that does not 
require premarket approval (see 21 U.S.C. 360c(i)). We determine 
whether a new device is substantially equivalent to a predicate 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).
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    \1\ In December 2019, FDA began adding the term ``Final 
amendment'' to the ``ACTION'' caption for these documents, typically 
styled ``Final order'', to indicate that they ``amend'' the Code of 
Federal Regulations. This editorial 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 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 established the first procedure for De Novo classification 
(Pub. L. 105-115). Section 607 of the Food and Drug Administration 
Safety and Innovation Act modified the De Novo application process by 
adding a second procedure (Pub. L. 112-144). 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 within 
class III, the De Novo classification is considered to be the initial 
classification of the device.
    We believe this De Novo classification will enhance patients' 
access to beneficial innovation, in part by reducing regulatory 
burdens. 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 21 U.S.C. 360c(f)(2)(B)(i)). As a 
result, other device sponsors do not have to submit a De Novo request 
or premarket approval in order to market a substantially equivalent 
device (see 21 U.S.C. 360c(i), defining ``substantial equivalence''). 
Instead, sponsors can use the 510(k) process, when necessary, to market 
their device.

II. De Novo Classification

    On March 19, 2019, Vela Diagnostics USA Inc. submitted a request 
for De Novo classification of the SENTOSA SQ HIV Genotyping Assay. 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 5, 2019, FDA issued an order to the 
requester classifying the device into class II. FDA is codifying the 
classification of the device by adding 21 CFR 866.3955. We have named 
the generic type of device ``Human immunodeficiency virus drug 
resistance genotyping assay using next generation sequencing 
technology,'' and it is identified as a prescription in vitro 
diagnostic device intended for use in detecting HIV genomic mutations 
that confer resistance to specific antiretroviral drugs. The device is 
intended to be used as an aid in monitoring and treating HIV infection.
    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.

[[Page 7217]]



     Table 1--In Vitro HIV Drug Resistance Genotype Assay Using NGS
                Technology Risks and Mitigation Measures
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         Identified risks                    Mitigation measures
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Inaccurate detection of resistance  Device description information,
 mutation(s).                        including performance
                                     characteristics, and performance
                                     studies in labeling.
                                    Device description validation
                                     procedures and performance studies
                                     meeting acceptance criteria.
                                    Device limitations in labeling for
                                     genetic mutation detection.
Incorrect interpretation of test    Device description information,
 results.                            performance characteristics, and
                                     performance studies in labeling.
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    FDA has determined that special controls, in combination with the 
general controls, address these risks to health and provide reasonable 
assurance of safety and effectiveness. For a device to fall within this 
classification, and thus avoid automatic classification in class III, 
it would have to comply with the special controls named in this final 
order. The necessary special controls appear in the regulation codified 
by this order. This device is subject to premarket notification 
requirements under section 510(k) of the FD&C Act.
    At the time of classification, HIV drug resistance genotyping 
assays using NGS technology are for prescription use only. Prescription 
devices are exempt from the requirement for adequate directions for use 
for the layperson under section 502(f)(1) of the FD&C Act and 21 CFR 
801.5, as long as the conditions of 21 CFR 801.109 are met (referring 
to 21 U.S.C. 352(f)(1)).
    Section 510(m)(2) of the FD&C Act provides that FDA may exempt a 
class II device from the premarket notification requirements under 
section 510(k) if, after notice of our intent to exempt and 
consideration of comments, we determine by order that premarket 
notification is not necessary to provide reasonable assurance of safety 
and effectiveness of the device. We are not announcing intent to exempt 
at this time.

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 FDA collections of information. 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 the guidance document ``De 
Novo Classification Process (Evaluation of Automatic Class III 
Designation)'' have been approved under OMB control number 0910-0844; 
the collections of information in 21 CFR part 820, regarding quality 
system regulation, have been approved under OMB control number 0910-
0073; the collections of information in part 807, subpart E, regarding 
premarket notification submissions, have been approved under OMB 
control number 0910-0120, and the collections of information in 21 CFR 
part 801, 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.  [thinsp]866.3955 to subpart D to read as follows:


Sec.  866.3955   Human immunodeficiency virus (HIV) drug resistance 
genotyping assay using next generation sequencing technology.

    (a) Identification. The HIV drug resistance genotyping assay using 
next generation sequencing (NGS) technology is a prescription in vitro 
diagnostic device intended for use in detecting HIV genomic mutations 
that confer resistance to specific antiretroviral drugs. The device is 
intended to be used as an aid in monitoring and treating HIV infection.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) The intended use of the device must:
    (i) Specify the analyte (RNA or DNA), the genes in which mutations 
are detected, the clinical indications appropriate for test use, the 
sample type, and the specific population(s) for which the device in 
intended.
    (ii) State that the device in not intended for use as an aid in the 
diagnosis of infection with HIV or to confirm the presence of HIV 
infection, or for screening donors of blood, plasma, or human cells, 
tissues, and cellular and tissue-based products.
    (2) The labeling must include:
    (i) A detailed device description, including but not limited to, 
all procedures from collection of the patient sample to reporting the 
final result, all device components, the control elements incorporated 
into the test procedure, instrument requirements, and reagents required 
for use but not provided as part of the device.
    (ii) Performance characteristics from analytical studies and all 
intended specimen types.
    (iii) A list of specific mutations detected.
    (iv) The name and version of the standardized database used for 
sequence comparison and results derivation.
    (v) A detailed explanation of the interpretation of test results, 
including acceptance criteria for evaluating the validity of a test 
run.
    (vi) A limitation statement that the device is intended to be used 
in conjunction with clinical history and other laboratory findings. 
Results of this test are intended to be interpreted by a physician or 
equivalent.
    (vii) A limitation statement that lack of detection of drug 
resistance mutations does not preclude the possibility of genetic 
mutation.
    (viii) A limitation statement indicating the relevant genetic 
mutations that are included in the standardized database of HIV genomic 
sequences used for comparison and results derivation but that are not 
detected by the test.

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    (ix) A limitation statement that detection of a genomic drug 
resistance mutation may not correlate with phenotypic gene expression.
    (x) A limitation statement that the test does not detect all 
genetic mutations associated with antiviral drugs.
    (xi) A limitation statement listing the HIV types for which the 
test is not intended, if any.
    (3) Device verification and validation must include:
    (i) Design of primer sequences and rationale for sequence 
selection.
    (ii) Computational path from collected raw data to reported result.
    (iii) Detailed documentation of analytical studies including, but 
not limited to, characterization of the cutoff, analytical sensitivity, 
inclusivity, reproducibility, interference, cross reactivity, 
instrument and method carryover/cross contamination, sample stability, 
and handling for all genomic mutations claimed in the intended use.
    (iv) Precision studies that include all genomic mutations claimed 
in the intended use.
    (v) Detailed documentation of a multisite clinical study evaluating 
the sensitivity and specificity of the device. Clinical study subjects 
must represent the intended use population and device results for all 
targets claimed in the intended use must be compared to Sanger 
sequencing or other methods found acceptable by FDA. Drug resistance-
associated mutations at or above the 20 percent frequency level must 
detect the mutations in greater than 90 percent of at least 10 
replicates, for each of drug class evaluated.
    (vi) Documentation that variant calling is performed at a level of 
coverage that supports positive detection of all genomic mutations 
claimed in the intended use.
    (vii) Detailed documentation of limit of detection (LoD) studies in 
which device performance is evaluated by testing a minimum of 100 HIV-
positive clinical samples including samples with analyte concentrations 
near the clinical decision points and near the LoD.
    (A) The LoD for the device must be determined using a minimum of 10 
HIV-1 group M genotypes if applicable. A detection rate at 1 x LoD 
greater than or equal to 95 percent must be demonstrated for mutations 
with a frequency greater than 20 percent.
    (B) The LoD of genetic mutations at frequency levels less than 20 
percent must be established.
    (viii) A predefined HIV genotyping bioinformatics analysis pipeline 
(BAP). The BAP must adequately describe the bioinformatic analysis of 
the sequencing data, including but not limited to read alignment, 
variant calling, assembly, genotyping, quality control, and final 
result reporting.
    (ix) A clear description of the selection and use of the 
standardized database that is used for sequence comparison and results 
derivation.
    (4) Premarket notification submissions must include the information 
in paragraphs (b)(3)(i) through (ix) of this section.

    Dated: January 27, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-01725 Filed 2-6-20; 8:45 am]
 BILLING CODE 4164-01-P