[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, 
silke.schlottmann@fda.hhs.gov.

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


