Microbiology Devices; Reclassification of Nucleic Acid-Based Hepatitis C Virus Ribonucleic Acid Assay Devices, To Be Renamed Nucleic Acid-Based Hepatitis C Virus Ribonucleic Acid Tests
| Published date | 02 April 2020 |
| Citation | 85 FR 18483 |
| Record Number | 2020-06820 |
| Section | Proposed rules |
| Court | Food And Drug Administration |
Federal Register, Volume 85 Issue 64 (Thursday, April 2, 2020)
[Federal Register Volume 85, Number 64 (Thursday, April 2, 2020)]
[Proposed Rules]
[Pages 18483-18490]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-06820]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2020-N-1088]
Microbiology Devices; Reclassification of Nucleic Acid-Based
Hepatitis C Virus Ribonucleic Acid Assay Devices, To Be Renamed Nucleic
Acid-Based Hepatitis C Virus Ribonucleic Acid Tests
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed amendment; proposed order; request for comments.
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SUMMARY: The Food and Drug Administration (FDA or Agency) is proposing
to reclassify nucleic acid-based hepatitis C virus (HCV) ribonucleic
acid (RNA) devices intended for the qualitative or quantitative
detection or genotyping of HCV RNA, postamendments class III devices
(product codes MZP and OBF), into class II (general controls and
special controls), subject to premarket notification. FDA is also
proposing a new device classification regulation with the name
``nucleic acid-based Hepatitis C virus (HCV) ribonucleic acid tests''
along with the special controls that the Agency believes are necessary
to provide a reasonable assurance of safety and effectiveness for these
devices. FDA is proposing this reclassification on its own initiative.
If finalized, this order will reclassify these types of devices from
class III (general controls and premarket approval) to class II
(general controls and special controls) and reduce the regulatory
burdens associated with these devices, as these types of devices will
no longer be required to submit a premarket approval application (PMA),
but can instead submit a premarket notification (510(k)) and obtain
clearance before marketing their device.
DATES: Submit either electronic or written comments on the proposed
order by June 1, 2020. Please see section XI of this document for the
proposed effective date when the new requirements apply and for the
proposed effective date of a final order based on this proposed order.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before June 1, 2020. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of June 1, 2020. Comments received
by Mail/Hand Delivery/Courier (for written/paper submissions) will be
considered timely.
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed below (see ``Written/Paper Submissions'' and
``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2020-N-1088 for ``Reclassification of Nucleic Acid-Based Hepatitis
C Virus Ribonucleic Acid Assay Devices, To Be Renamed Nucleic Acid-
Based Hepatitis C Virus Ribonucleic Tests.'' Received comments, those
filed in a timely manner (see ADDRESSES) will be placed in the docket
and, except for those submitted as ``Confidential Submissions,''
publicly viewable at https://www.regulations.gov or at the Dockets
Management Staff between 9 a.m. and 4 p.m., Monday through Friday.
Confidential Submissions: To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20
[[Page 18484]]
and other applicable disclosure law. For more information about FDA's
posting of comments to public dockets, see 80 FR 56469, September 18,
2015, or access the information at:https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Silke Schlottmann, Division of
Microbiology Devices, Center for Devices and Radiological Health, Food
and Drug Administration, 10903 New Hampshire Ave., Bldg. 66, Rm. 3258,
Silver Spring, MD 20993-0002, 301-796-9551,
[email protected].
SUPPLEMENTARY INFORMATION:
I. Background--Regulatory Authorities
The FD&C Act, as amended by the Medical Device Amendments of 1976
(the 1976 amendments) (Pub. L. 94-295), the Safe Medical Devices Act of
1990 (Pub. L. 101-629), Food and Drug Administration Modernization Act
of 1997 (Pub. L. 105-115), the Medical Device User Fee and
Modernization Act of 2002 (Pub. L. 107-250), the Medical Devices
Technical Corrections Act (Pub. L. 108-214), the Food and Drug
Administration Amendments Act of 2007 (Pub. L. 110-85), and the Food
and Drug Administration Safety and Innovation Act (Pub. L. 112-144),
among other amendments, establishes a comprehensive system for the
regulation of medical devices intended for human use. Section 513 of
the FD&C Act (21 U.S.C. 360c) established three categories (classes) of
devices, reflecting the regulatory controls needed to provide
reasonable assurance of their safety and effectiveness. The three
categories of devices are class I (general controls), class II (general
controls and special controls), and class III (general controls and
premarket approval).
Section 513(a)(1) of the FD&C Act defines the three classes of
devices. Class I devices are those devices for which the general
controls of the FD&C Act (controls authorized by or under sections 501,
502, 510, 516, 518, 519, or 520 (21 U.S.C. 351, 352, 360, 360f, 360h,
360i, or 360j) or any combination of such sections) are sufficient to
provide reasonable assurance of safety and effectiveness; or those
devices for which insufficient information exists to determine that
general controls are sufficient to provide reasonable assurance of
safety and effectiveness or to establish special controls to provide
such assurance, but because the devices are not purported or
represented to be for a use in supporting or sustaining human life or
for a use which is of substantial importance in preventing impairment
of human health, and do not present a potential unreasonable risk of
illness or injury, are to be regulated by general controls (section
513(a)(1)(A) of the FD&C Act). Class II devices are those devices for
which general controls by themselves are insufficient to provide
reasonable assurance of safety and effectiveness, and for which there
is sufficient information to establish special controls to provide such
assurance, including the promulgation of performance standards,
postmarket surveillance, patient registries, development and
dissemination of guidelines, recommendations, and other appropriate
actions the Agency deems necessary to provide such assurance (section
513(a)(1)(B) of the FD&C Act). Class III devices are those devices for
which insufficient information exists to determine that general
controls and special controls would provide a reasonable assurance of
safety and effectiveness, and are purported or represented to be for a
use in supporting or sustaining human life or for a use which is of
substantial importance in preventing impairment of human health, or
present a potential unreasonable risk of illness or injury (section
513(a)(1)(C) of the FD&C Act).
Devices that were not in commercial distribution prior to May 28,
1976 (generally referred to as postamendments devices) are
automatically classified by section 513(f)(1) of the FD&C Act into
class III without any FDA rulemaking process. Those devices remain in
class III and require premarket approval unless, and until, (1) FDA
reclassifies the device into class I or class II, or (2) FDA issues an
order finding the device to be substantially equivalent, in accordance
with section 513(i) of the FD&C Act, to a predicate device that does
not require premarket approval. FDA determines whether new devices are
substantially equivalent to predicate devices by means of premarket
notification procedures in section 510(k) of the FD&C Act and part 807
(21 CFR part 807), subpart E, of the regulations.
A postamendments device that has been initially classified in class
III under section 513(f)(1) of the FD&C Act may be reclassified into
class I or II under section 513(f)(3) of the FD&C Act. Section
513(f)(3) of the FD&C Act provides that FDA, acting by administrative
order, can reclassify the device into class I or class II on its own
initiative, or in response to a petition from the manufacturer or
importer of the device. To change the classification of the device, the
proposed new class must have sufficient regulatory controls to provide
a reasonable assurance of the safety and effectiveness of the device
for its intended use.
FDA relies upon ``valid scientific evidence,'' as defined in
section 513(a)(3) and 21 CFR 860.7(c)(2), in the classification process
to determine the level of regulation for devices. To be considered in
the reclassification process, the ``valid scientific evidence'' upon
which the Agency relies must be publicly available (see section 520(c)
of the FD&C Act). Publicly available information excludes trade secret
and/or confidential commercial information, e.g., the contents of a
pending PMA (see section 520(c) of the FD&C Act).
In accordance with section 513(f)(3) of the FD&C Act, the Agency is
issuing this proposed order to reclassify nucleic acid-based HCV RNA
devices intended for the qualitative or quantitative detection or
genotyping of HCV RNA, postamendment class III devices, into class II
(general controls and special controls), subject to premarket
notification because the Agency believes the standard in section
513(a)(1)(B) of the FD&C Act is met as there is sufficient information
to establish special controls, which, in addition to general controls,
will provide reasonable assurance of the safety and effectiveness of
the device.\1\
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\1\ In December 2019, FDA began adding the term ``Proposed
amendment'' to the ``ACTION'' caption for these documents, typically
styled ``Proposed order,'' to indicate that they ``propose to
amend'' the Code of Federal Regulations. This editorial change was
made in accordance with the Office of Federal Register's
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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Section 510(m) of the FD&C Act provides that a class II device may
be exempted from the premarket notification requirements under section
510(k) of the FD&C Act if the Agency determines that premarket
notification is not necessary to provide reasonable assurance of the
safety and effectiveness of the device. FDA has determined that
premarket notification is necessary to reasonably assure the safety and
effectiveness nucleic acid-based HCV RNA devices intended for the
qualitative or quantitative detection or genotyping of HCV RNA.
Therefore, the
[[Page 18485]]
Agency does not intend to exempt these proposed class II devices from
premarket notification requirements. If this proposed order is
finalized, persons who intend to market this type of device must submit
to FDA a premarket notification under section 510(k) of the FD&C Act
prior to marketing the device.
II. Regulatory History of the Devices
This proposed order applies to nucleic acid-based HCV RNA devices
intended for the qualitative or quantitative detection or genotyping of
HCV RNA. These are prescription devices assigned product codes MZP (for
qualitative and quantitative HCV RNA tests) and OBF (for HCV RNA
genotyping tests) and are collectively referred to as ``nucleic acid-
based HCV RNA tests.'' On July 3, 2001, FDA approved its first nucleic
acid-based qualitative HCV RNA test for use as a prescription device as
an aid in the diagnosis of active HCV infection in HCV antibody
positive individuals (Roche Molecular Systems, Inc.'s COBAS AMPLICOR
Hepatitis C Virus (HCV) Test, version 2.0) through its PMA process
under section 515 of the FD&C Act (21 U.S.C. 360e). In a July 17, 2002,
Federal Register notice (67 FR 46990), FDA announced the PMA approval
order and the availability of the Summary of Safety and Effectiveness
Data (SSED) for this device. Since the first approval order, FDA has
approved two additional original PMAs for nucleic-acid based
qualitative HCV RNA tests that are prescription devices intended for
use as an aid in the diagnosis of active HCV infection in HCV antibody
positive individuals by a qualified licensed healthcare professional in
conjunction with other relevant clinical and laboratory findings
(hereafter referred to as ``qualitative HCV RNA tests'').
On March 28, 2003, FDA approved its first quantitative nucleic
acid-based HCV RNA test for use as a prescription device in the
management of chronic HCV-infected patients undergoing antiviral
therapy (Bayer Healthcare, LLC's Bayer VERSANT HCV RNA 3.0 Assay
(bDNA)) through its PMA process under section 515 of the FD&C Act. In a
March 10, 2005, Federal Register notice (70 FR 11986), FDA announced
the PMA approval order and the availability of the SSED for this
device. Since the first approval order, FDA has approved four
additional original PMAs for quantitative nucleic acid-based HCV RNA
tests that are prescription devices intended for management of chronic
HCV-infected patients undergoing anti-viral therapy by a qualified
licensed healthcare professional in conjunction with other relevant
clinical and laboratory findings (hereafter referred to as
``quantitative HCV RNA tests''). Three of these tests are approved for
both the qualitative detection of HCV RNA as an aid in the diagnosis of
active HCV infection and for the quantitation of HCV RNA in the
management of chronic HCV-infected patients undergoing antiviral
therapy.
On June 20, 2013, CDRH approved its first nucleic acid-based HCV
genotyping test for use as a prescription device in the qualitative
identification of certain HCV genotypes (Abbott Molecular Inc.'s Abbott
RealTime HCV Genotype II) through its PMA process under section 515 of
the FD&C Act. In an August 19, 2013, Federal Register notice (78 FR
50422), FDA announced the approval order and the availability of the
SSED for this device. Since the first approval order, FDA has approved
one additional original PMA for nucleic acid-based HCV genotyping test
that is a prescription device intended for the qualitative
identification of certain HCV genotypes by a qualified licensed
healthcare professional in conjunction with other relevant clinical and
laboratory findings (hereafter referred to as ``HCV genotyping
tests'').
A review of the medical device reporting databases indicates that
there is a low number of reported events for nucleic acid-based HCV RNA
tests relative to the number of tests conducted using these devices. As
of the date of this proposed order, FDA is aware of three class II
recalls for these devices and no class I recalls.\2\ The class II
recalls occurred between 2004 and 2011 and were related to: (1) An
increased frequency of the interfering background due to the conjugate
used for detection, (2) underquantitation of a subset of genotype 4
patient specimens, and (3) a software discrepancy between the onboard
reagent stability information and that in the package insert. All
recalls have been resolved and no patient harm has been identified.
These facts, coupled with the low number of reported events, indicate a
good safety record for this device class. These recall events reflect
the risks to health identified in section V below, and FDA believes the
special controls proposed herein, in addition to general controls, can
effectively mitigate the risks identified in these recalls.
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\2\ Class II recalls are defined in 21 CFR 7.3(m)(2).
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III. Device Descriptions
Nucleic acid-based HCV RNA tests are postamendments prescription in
vitro diagnostic devices classified into class III under section
513(f)(1) of the FD&C Act. Qualitative and quantitative HCV RNA tests
are described in FDA's SSEDs and product code database (assigned
product code MZP) as a hybridization and/or nucleic acid amplification
assay for the detection and/or quantification of HCV RNA. HCV RNA, when
present in samples, are first amplified by qualitative and quantitative
HCV RNA tests and then detected by labeled probes that produce a
qualitative or quantitative signal indicating either the presence/
absence of HCV or the amount of HCV in the sample, respectively.
FDA is proposing to reclassify qualitative HCV tests, which are
prescription in vitro diagnostic devices intended to determine the
presence of HCV RNA in human serum and/or plasma and are intended for
use as an aid in the diagnosis of active HCV infection in patients with
serological evidence of HCV infection, or other limited circumstances
when active HCV infection of the patient is suspected. FDA is also
proposing to reclassify quantitative HCV tests that are prescription in
vitro diagnostic devices intended to measure the amount of HCV RNA in
human serum and/or plasma and are intended as an aid in the diagnosis
of active HCV infection, as an aid in the management of chronic HCV-
infected patients undergoing or having completed antiviral therapy, or
both. These devices are not intended for screening blood, plasma, cell,
or tissue donors.
HCV genotyping tests are described in FDA's SSEDs and the product
code database (assigned product code OBF) as an in vitro diagnostic
device for qualitative identification of eight clinically relevant HCV
RNA genotypes. FDA is proposing to reclassify HCV genotyping tests that
are nucleic acid-based in vitro diagnostic tests, which are
prescription in vitro diagnostic devices intended to identify HCV
genotypes in patients with active HCV infection. The tests are intended
to be used as an aid in the management of patients with chronic HCV
infection to guide the selection of antiviral treatment.
FDA is proposing to reclassify nucleic acid-based HCV RNA tests
from class III (general controls and premarket approval) to class II
(general controls and special controls) and to establish a new name for
the device type that will be within the classification regulation;
i.e., nucleic acid-based HCV RNA tests. FDA believes that this name and
proposed identification language most accurately describes these
devices. A nucleic acid-based HCV RNA test is tentatively identified as
a device intended for prescription use with
[[Page 18486]]
human serum or plasma from individuals with evidence of HCV antibodies.
The test is intended as an aid in the diagnosis of HCV infection in
specified populations, and/or as an aid in the management of HCV-
infected patients including guiding the selection of genotype-specific
treatment in individuals with chronic HCV infection.
Based upon our review experience and consistent with the FD&C Act
and FDA's regulations in 21 CFR 860.134, FDA believes that these
devices should be reclassified from class III into class II with
special controls because there is sufficient information to establish
special controls that, along with general controls, can provide
reasonable assurance of the devices' safety and effectiveness.
IV. Proposed Reclassification
FDA is proposing to reclassify nucleic acid-based HCV RNA tests. On
March 22, 2018, the Microbiology Devices Panel (Panel) of the Medical
Devices Advisory Committee convened to discuss and make recommendations
regarding the reclassification of nucleic acid-based HCV RNA tests from
class III (general controls and premarket approval) into class II
(general controls and special controls) (Ref. 1). Panel members
unanimously agreed that special controls, in addition to general
controls, are necessary and sufficient to mitigate the risks to the
health of patients presented by these devices and to provide reasonable
assurance of the safety and effectiveness of these devices (Ref. 2). In
addition, Panel members generally agreed with the development of
special controls as presented by FDA.
FDA agrees and believes that at this time, sufficient data and
information exist such that the risks identified in section V below can
be mitigated by establishing special controls that, together with
general controls, can provide a reasonable assurance of the safety and
effectiveness of these devices and therefore proposes these devices to
be reclassified from class III (general controls and premarket
approval) to class II (general controls and special controls).
In accordance with section 513(f)(3) of the FD&C Act and part 860,
subpart C, FDA is proposing to reclassify postamendments nucleic acid-
based HCV RNA tests, to be renamed ``nucleic acid-based Hepatitis C
virus (HCV) ribonucleic acid (RNA) tests,'' from class III into class
II. FDA believes that, at this time, there are sufficient data and
information available to FDA through FDA's accumulated experience with
these devices from review submissions and from published peer-reviewed
literature, as well as the recommendations provided by the Panel, to
demonstrate that the proposed special controls, along with general
controls, would effectively mitigate the risks to health identified in
section V below and provide a reasonable assurance of the safety and
effectiveness of these devices. Absent the special controls identified
in this proposed order, general controls applicable to the device type
are insufficient to provide reasonable assurance of the safety and
effectiveness of these devices. FDA expects that the reclassification
of these devices would enable more manufacturers to develop nucleic
acid-based HCV RNA tests such that patients would benefit from
increased access to safe and effective tests.
FDA is proposing to create a classification regulation for nucleic
acid-based HCV RNA tests that will be reclassified from class III to
class II. Under this proposed order, if finalized, nucleic acid-based
HCV RNA tests will be identified as prescription devices. As such, the
prescription device must satisfy prescription labeling requirements for
in vitro diagnostic products (see 21 CFR 809.10(a)(4) and (b)(5)(ii)).
In this proposed order, if finalized, the Agency has identified the
special controls under section 513(a)(1)(B) of the FD&C Act that,
together with general controls, will provide a reasonable assurance of
the safety and effectiveness for nucleic acid-based HCV RNA tests.
Section 510(m) of the FD&C Act provides that FDA may exempt a class
II device from the premarket notification requirements under section
510(k) of the FD&C Act if FDA determines that premarket notification is
not necessary to provide reasonable assurance of the safety and
effectiveness of the device. For these nucleic acid-based HCV RNA
tests, FDA has determined that premarket notification is necessary to
provide reasonable assurance of the safety and effectiveness of the
devices. Therefore, FDA does not intend to exempt these proposed class
II devices from the 510(k) requirements. If this proposed order is
finalized, persons who intend to market this type of device must submit
a 510(k) to FDA and receive clearance prior to marketing the device.
This proposed order, if finalized, will decrease regulatory burden
on industry, as manufacturers will no longer have to submit a PMA for
these types of devices but can instead submit a 510(k) to the Agency
for review prior to marketing their device. A 510(k) typically results
in a shorter premarket review timeline compared to a PMA, which
ultimately provides more timely access of these types of devices to
patients.
In addition, the Agency believes that certain changes could be made
to nucleic acid-based HCV RNA tests that could significantly affect the
safety and effectiveness of those devices and for which a new 510(k) is
likely required.\3\ Based on FDA's accumulated experience with these
devices, changes that likely could significantly affect the safety and
effectiveness of these devices include, but are not limited to: Changes
to critical reagents, changes to final release specifications, and
changes in shelf life of the device. For more information about when to
submit a new 510(k), manufacturers should refer to FDA's guidance
entitled ``Deciding When to Submit at 510(k) for a Change to an
Existing Device'' (Ref. 3).
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\3\ See 21 CFR 807.81(a)(3)(i).
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V. Risks to Health
It is estimated by the Centers for Disease Control and Prevention
that chronic HCV infection in the United States affects at least
between 2.7 and 3.9 million people (Ref. 4). HCV infection can be
asymptomatic, and accordingly, many HCV-infected individuals are
unaware of their HCV infection. Between 20 percent and 30 percent of
patients with acute infection, defined as the first 6 months after
infection, clear the virus spontaneously while the other 70 percent to
80 percent of individuals become chronically infected with HCV (Ref.
5). Later diagnosis can lead to a more severe disease outcome, and
premature death among those who are chronically infected (Ref. 6).
Patients who are tested and become aware that they are HCV infected may
modify risk behaviors to prevent transmission to others and can be
referred for treatment.
If left untreated, patients with chronic HCV infection have a
significant risk of developing severe liver disease and/or
hepatocellular cancer. Treatment of chronic HCV is highly effective,
resulting in a sustained virological response (SVR) considered
synonymous with cure. SVR is associated with improved clinical outcome,
and a decrease in HCV-associated mortality (Ref. 7). Therefore,
diagnosis of HCV infection through devices such as nucleic acid-based
HCV RNA tests is essential to ensure that patients are linked to the
appropriate care (Ref. 6).
After consideration of FDA's accumulated experience with these
devices from review of previous submissions, recommendations of the
Panel for the classification of these devices (Ref. 2), and published
[[Page 18487]]
literature, FDA has identified the following probable risks to health
associated with nucleic acid-based HCV RNA tests:
Inaccurate interpretation of test results. Inaccurate
interpretation of results by clinicians may negatively influence
patient management decisions. Such decisions may include the
administration of unnecessary treatment and potential adverse effects,
the withholding of treatment, or the choice of an inappropriate
treatment, and could lead to adverse effects on patient health such as
progressive liver disease, cirrhosis and/or hepatocellular cancer, all
of which are known to contribute to patient morbidity and mortality
(Ref. 6). Patients with active HCV infection also risk spreading the
virus to others
Failure of the device to perform as indicated (e.g.,
inaccurately low or high results, false negative, false positive test
results, and inaccurate genotyping results). Inaccurately low results,
false negative results, or inaccurate test results from nucleic acid-
based HCV RNA genotyping tests (i.e., the test result is for a genotype
that is not the one that the patient is actually infected with) due to
failure of the device to perform as indicated may negatively influence
patient management decisions. Such decisions may include the
withholding of treatment or the choice of an inappropriate treatment,
and could lead to adverse effects on patient health such as progressive
liver disease, cirrhosis and/or hepatocellular cancer, all of which are
known to contribute to patient morbidity and mortality (Ref. 6).
Patients with active HCV infection also risk spreading the virus to
others. Inaccurately high or false positive test results due to failure
of the device to perform may contribute to the unnecessary initiation
of treatment. In addition, these results may contribute to potential
adverse effects from HCV antiviral drug therapy in the following
groups: (1) Successfully treated patients who are incorrectly
considered treatment failures, (2) in patients who have spontaneously
cleared HCV, or (3) in patients previously treated but suspected of
reinfection.
Decreased test sensitivity and/or an increased rate of
false negative test reporting. This may occur with patient samples that
contain different genotypes, rare de novo mutations in genomic regions
of HCV targeted by the device, or that are taken during the time that
the patient transitions from acute to chronic infection, which is when
HCV viral load can transiently decrease and/or become undetectable in
samples before the virus enters into chronic replication.
VI. Summary of the Reasons for Reclassification
FDA believes that nucleic acid-based HCV RNA tests should be
reclassified from class III (general controls and premarket approval)
into class II (general controls and special controls) because special
controls, in addition to general controls, can be established to
mitigate the risks to health identified in section V and provide a
reasonable assurance of the safety and effectiveness of these devices.
The proposed special controls are identified by FDA in section VII.
Taking into account the probable health benefits of the use of
these devices and the nature and known incidence of the risks of the
devices, FDA, on its own initiative, is proposing to reclassify these
postamendments class III devices into class II. FDA believes that, when
used as indicated, nucleic acid-based HCV RNA tests can provide
significant benefits to clinicians and patients.
FDA's reasons for reclassification are based on the substantial
scientific and medical information available regarding the nature,
complexity, and risks associated with nucleic acid-based HCV RNA tests
in the identified intended use populations (Ref. 1). The safety and
effectiveness of this device type has become well established since the
initial approval of the first qualitative HCV RNA test in 2001 (for the
detection of HCV RNA in anti-HCV positive individuals), of the first
quantitative HCV RNA test in 2003 (for quantitation of HCV RNA in anti-
HCV positive individuals), and of the first HCV genotyping test in 2013
(for genotyping of HCV RNA).
VII. Proposed Special Controls
FDA believes that these devices can be classified into class II
with the establishment of special controls. FDA believes that the
following special controls, together with general controls, will
provide a reasonable assurance of the safety and effectiveness of
nucleic acid-based HCV RNA tests. Table 1 demonstrates how these
proposed special controls will mitigate each of the identified risks to
health in section V.
The risk of inaccurate interpretation of test results can be
mitigated by special controls requiring certain labeling, including
providing clearly stated warnings and limitations, device description
information, and detailed instructions in the device labeling regarding
the interpretation of test results and principles of operation and
procedure in performing the test. In addition, when intended for Point
of Care use, special controls requiring clinical testing performed in
appropriate settings and additional labeling to provide a brief summary
of the instructions for use can also mitigate the risk of inaccurate
interpretation of test results.
Risks associated with the failure of the device to perform as
indicated (e.g., inaccurately low or high results, false negative,
false positive test results, and inaccurate genotyping results) can be
mitigated through a combination of special controls related to certain
labeling requirements, design verification and validation activities,
and performance studies. Examples of verification and validation
information to be included in the design of the device includes
documentation of a complete device description, calibrators, critical
reagents, traceability, and lot release criteria. In addition, design
verification and validation must include documentation of performance
specifications including analytical and clinical performance criteria.
Required statements in labeling can aid in mitigating the occurrence of
inaccurate results (for example, a statement that test results are
intended to be interpreted by qualified individuals in conjunction with
other relevant clinical and laboratory findings). For purposes of
clarity, certain proposed special controls apply only to those types of
nucleic acid-based HCV tests identified (i.e., HCV RNA tests,
qualitative HCV RNA tests, and/or HCV genotyping tests) because, due to
differences in the results provided by the different tests, those
special controls would not apply to the other types of nucleic acid-
based HCV tests. The risks of decreased test sensitivity or an
increased rate of false negative test reporting can be mitigated by
special controls related to certain labeling, design verification and
validation activities, failure mode analysis, and performance studies.
[[Page 18488]]
Table 1--Risks to Health and Mitigation Measures for Nucleic Acid-Based
HCV RNA Tests
------------------------------------------------------------------------
Identified risks to health Mitigation measures
------------------------------------------------------------------------
Inaccurate interpretation of Certain labeling warnings, limitations,
test results. results interpretation information, and
explanation of procedures.
Failure of the device to Certain labeling warnings, limitations,
perform as indicated. results interpretation information, and
explanation of procedures in labeling.
Certain design verification and
validation information including device
description, calibrators, critical
reagents, traceability, and, lot release
criteria.
Performance criteria including analytical
and# clinical performance criteria.
Decreased test sensitivity Certain labeling warnings, limitations,
and/or an increased rate of results interpretation information, and
false negative test explanation of procedures in labeling.
reporting. Certain design verification and
validation information including device
description, calibrators, critical
reagents, traceability, and lot release
criteria.
Performance criteria including analytical
and clinical performance criteria.
------------------------------------------------------------------------
If this proposed order is finalized, nucleic acid-based HCV RNA
tests will be reclassified into class II (general controls and special
controls) and would be subject premarket notification requirements
under section 510(k) of the FD&C Act. As discussed below, the
reclassification will be codified in Sec. 866.3170 (21 CFR 866.3170).
Firms submitting a premarket notification under section 510(k) of the
FD&C Act for nucleic acid-based HCV RNA tests will be required to
comply with the particular mitigation measures set forth in the special
controls. Adherence to the special controls, in addition to the general
controls, is necessary to provide a reasonable assurance of the safety
and effectiveness of these devices.
VIII. 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.
IX. Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed order contains no new
collection of information. Therefore, clearance by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1995
(PRA) (44 U.S.C. 3501-3521) is not required. This proposed order refers
to previously approved FDA collections of information. These
collections of information are subject to review by OMB under the PRA.
The collections of information in 21 CFR part 820 have been approved
under OMB control number 0910-0073; the collections of information in
part 807, subpart E, have been approved under OMB control number 0910-
0120; and the collections of information in 21 CFR parts 801 and 809
have been approved under OMB control number 0910-0485.
X. Codification of Orders
Under section 513(f)(3) of the FD&C Act, FDA may issue final orders
to reclassify devices. FDA will continue to codify classifications and
reclassifications in the Code of Federal Regulations (CFR). Changes
resulting from final orders will appear in the CFR as newly codified
orders. Therefore, under section 513(f)(3), in the proposed order, we
are proposing to codify nucleic acid-based HCV RNA tests in the new
Sec. 866.3170, under which nucleic acid-based HCV RNA tests would be
reclassified from class III to class II.
XI. Proposed Effective Date
FDA proposes that any final order based on this proposed order
become effective 30 days after its date of publication in the Federal
Register.
XII. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.
* 1. Executive Summary of the FDA Microbiology Devices Panel
Meeting, March 22, 2018. Available at https://www.fda.gov/media/111502/download.
* 2. Transcript of the FDA Microbiology Devices Panel Meeting, March
22, 2018. Available at https://www.fda.gov/media/119966/download.
* 3. ``Deciding When to Submit a 510(k) for a Change to an Existing
Device--Guidance for Industry and Food and Drug Administration
Staff,'' issued October 25, 2017. Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/deciding-when-submit-510k-change-existing-device.
* 4. Department of Health and Human Services--Viral Hepatitis Action
Plan for 2017-2020. Available at https://www.hhs.gov/sites/default/files/National%20Viral%20Hepatitis%20Action%20Plan%202017-2020.pdf.
5. Aisyah, D.N., L. Shallcross, A.J. Hully, et. al., ``Assessing
Hepatitis C Spontaneous Clearance and Understanding Associated
Factors--A Systematic Review and Meta-Analysis.'' Journal of Viral
Hepatitis, 25(6): 680-698, 2018.
6. Moorman, A.C., J. Xing, S. Ko, et al., ``Late Diagnosis of
Hepatitis C Virus Infection in the Chronic Hepatitis Cohort Study
(CHeCS): Missed Opportunities for Intervention.'' Hepatology, 61(5):
1479-1484, 2015.
7. Ioannou, G.N., P.K. Green, and K. Berry, ``HCV Eradication
Induced by Direct-Acting Antiviral Agents Reduces the Risk of
Hepatocellular Carcinoma.'' Journal of Hepatology, 68(1): 25-33,
2018.
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, it is
proposed that 21 CFR part 866 be 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. 866.3170 to subpart D to read as follows:
[[Page 18489]]
Sec. 866.3170 Nucleic acid-based hepatitis c virus ribonucleic acid
tests.
(a) Identification. A nucleic acid-based hepatitis C virus (HCV)
ribonucleic acid (RNA) test is identified as an in vitro diagnostic
device intended for prescription use as an aid in the diagnosis of HCV
infection in specified populations, and/or as an aid in the management
of HCV-infected patients including guiding the selection of genotype-
specific treatment in individuals with chronic HCV infection. The test
is intended for use with human serum or plasma from individuals with
evidence of HCV antibodies. The test is not intended for use as a donor
screening test for the presence of HCV antibodies in blood, blood
products, or tissue donors.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) For all nucleic acid-based HCV RNA tests, the labeling required
under 21 CFR 809.10(b) must include:
(i) A prominent statement that the test is not intended for use as
a donor screening test for the presence of HCV RNA from human cells,
tissues, and cellular and tissue-based products.
(ii) A detailed explanation of the principles of operation and
procedures for performing the assay.
(iii) A detailed explanation of the interpretation of results.
(iv) Limitations, which must be updated to reflect current clinical
practice and disease presentation and management. These limitations
must include, but are not limited to, statements that indicate:
(A) The specimen types for which the device has been cleared and
that use of this test kit with specimen types other than those
specifically cleared for this device may result in inaccurate test
results.
(B) When applicable, that assay performance characteristics have
not been established in populations of immunocompromised or
immunosuppressed patients or, other populations where test performance
may be affected.
(C) Test results are to be interpreted by qualified licensed
healthcare professionals in conjunction with the individual's clinical
presentation, history, and other laboratory results.
(2) For all nucleic acid-based HCV RNA tests, the design
verification and validation must include:
(i) Detailed device description, including the device components,
ancillary reagents required but not provided, and an explanation of the
device methodology. Additional information appropriate to the
technology must be included such as design of primers and probes,
rationale for the selected gene targets, specifications for amplicon
size, and degree of nucleic acid sequence conservation.
(ii) For devices with assay calibrators, the design and nature of
all primary, secondary, and subsequent quantitation standards used for
calibration as well as their traceability to a standardized reference
material that FDA has determined is appropriate (e.g., a recognized
consensus standard). In addition, analytical testing must be performed
following the release of a new lot of the standard material that was
used for device clearance or approval, or when there is a transition to
a new calibration standard.
(iii) Documentation and characterization (e.g., determination of
the identity, supplier, purity, and stability) of all critical reagents
(including nucleic acid sequences for primers and probes) and protocols
for maintaining product integrity.
(iv) Detailed documentation of analytical performance studies
conducted as appropriate to the technology, specimen types tested, and
intended use of the device, including, but not limited to, limit of
detection (LoD), upper and lower limits of quantitation (ULoQ and LLoQ,
respectively), linearity, precision, endogenous and exogenous
interferences, cross reactivity, carryover, matrix equivalency, and
sample and reagent stability. Samples selected for use in analytical
studies or used to prepare samples for use in analytical studies must
be from subjects with clinically relevant circulating genotypes in the
United States. Cross-reactivity studies must include samples from HCV
RNA negative subjects with other causes of liver disease, including
autoimmune hepatitis, alcoholic liver disease, chronic hepatitis b
virus, primary biliary cirrhosis, and nonalcoholic steatohepatitis,
when applicable. The effect of each claimed nucleic-acid isolation and
purification procedure on detection must be evaluated.
(v) Risk analysis and management strategies, such as Failure Modes
Effects Analysis and/or Hazard Analysis and Critical Control Points
summaries and their impact on test performance.
(vi) Final release criteria to be used for manufactured test lots
with appropriate evidence that lots released at the extremes of the
specifications will meet the claimed analytical and clinical
performance characteristics as well as the stability claims.
(vii) Multisite reproducibility study that includes the testing of
three independent production lots.
(viii) All stability protocols, including acceptance criteria.
(ix) Final release test results for each lot used in clinical
studies.
(x) Analytical sensitivity and specificity of the test must be the
same or better than that of other cleared or approved tests.
(xi) Lot-to-lot precision studies, as appropriate.
(3) For devices intended for the qualitative detection of HCV RNA,
in addition to the special controls listed in paragraphs (b)(1) and (2)
of this section, the design verification and validation must include
detailed documentation of performance from a multisite clinical study.
Performance must be analyzed relative to an FDA cleared or approved
qualitative HCV RNA test, or a comparator that FDA has determined is
appropriate. This study must be conducted using appropriate patient
samples, with appropriate numbers of HCV positive and negative samples
in applicable risk categories. Additional genotypes must be validated
using appropriate numbers and types of samples. The samples may be a
combination of fresh and repository samples, sourced from within and
outside the United States, as appropriate. The study designs, including
number of samples tested, must be sufficient to meet the following
criteria:
(i) Clinical sensitivity of the test must have a lower bound of the
95 percent confidence interval of greater than or equal to 95 percent.
(ii) Clinical specificity of the test must have a lower bound of
the 95 percent confidence interval of greater than or equal to 96
percent.
(4) For devices intended for the quantitative detection of HCV RNA,
the following special controls, in addition to those listed in
paragraphs (b)(1) and (2) of this section, apply:
(i) Labeling required under 21 CFR 809.10(b) must include a
prominent statement that the test is not intended as a diagnostic test
to confirm the presence of active HCV infection, when applicable.
(ii) Design verification and validation must include the following:
(A) Detailed documentation of the following analytical performance
studies conducted as appropriate to the technology, specimen types
tested, and intended use of the device, including but not limited to:
LoD, ULoQ and LLoQ. LoD, LLoQ, and linearity studies must demonstrate
acceptable device
[[Page 18490]]
performance with all HCV genotypes detected by the device.
(B) Detailed documentation of clinical performance testing from
either:
(1) A multisite clinical study with an appropriate number of
clinical samples from chronically HCV infected patients in which the
results are compared to an FDA-cleared or approved quantitative HCV RNA
test, or a comparator that FDA has determined is appropriate. This
study must include a sufficient number of HCV positive samples
containing an analyte concentration near the LLoQ to describe
performance at this level. Clinical samples must cover the full range
of the device output and must be consistent with the distribution of
these genotypes in the U.S. population. Clinical samples may be
supplemented with diluted clinical samples for those viral load
concentrations that are not sufficiently covered by natural clinical
specimens, or
(2) A clinical study with prospectively collected samples
demonstrating clinical validity of the device.
(C) Detailed documentation of a qualitative analysis near the lower
end of the measuring range demonstrating acceptable performance when
used as an aid in diagnosis.
(5) For devices intended for HCV RNA genotyping, in addition to the
special controls listed in paragraphs (b)(1) and (2) of this section,
design verification and validation must include the following:
(i) Detailed documentation of an analytical performance study
demonstrating the LoD for all HCV genotypes detected by the device.
(ii) Detailed documentation, including results, of a multisite
clinical study that assesses genotyping accuracy (i.e., the proportion
of interpretable results that match with the reference method result)
and the genotyping rate (i.e., the proportion of results that were
interpretable).
(6) For any nucleic acid-based HCV RNA test intended for Point of
Care (PoC) use, the following special controls, in addition to those
listed in paragraphs (b)(1) and (2) of this section, apply:
(i) Clinical studies must be conducted at PoC sites.
(ii) Additional labeling must include a brief summary of the
instructions for use that are appropriate for use in a PoC environment.
Dated: March 27, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-06820 Filed 4-1-20; 8:45 am]
BILLING CODE 4164-01-P
