[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