[Federal Register Volume 85, Number 64 (Thursday, April 2, 2020)]
[Proposed Rules]
[Pages 18490-18496]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-06821]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2020-N-1082]


Microbiology Devices; Reclassification of Certain Hepatitis C 
Virus Antibody Assays Devices, To Be Renamed Hepatitis C Virus Antibody 
Tests

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed amendment; proposed order; request for comments.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or Agency) is proposing 
to reclassify certain hepatitis C virus (HCV) antibody assay devices 
intended for the qualitative detection of HCV, postamendments class III 
devices (product code MZO) into class II (general controls and special 
controls), subject to premarket notification. FDA is also proposing a 
new device classification regulation with the name ``hepatitis C virus 
(HCV) antibody 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 under the Federal Food, Drug, and Cosmetic Act (FD&C Act) 
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 if they are postmarked or the delivery service 
acceptance receipt is on or before that date.

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-1082 for ``Reclassification of Certain Hepatitis C Virus 
Antibody Assay Devices, To Be Renamed Hepatitis C Virus Antibody 
Tests.'' Received comments, those filed in a timely manner (see 
ADDRESSES) will be placed in the docket and, except for

[[Page 18491]]

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 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: Maria Ines Garcia, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, Rm. 3104, Silver Spring, MD 20993-0002, 301-
796-7017, Maria.Garcia@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: 

I. Background--Regulatory Authorities

    The FD&C Act, as amended by the Medical Device Amendments of 1976 
(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 hepatitis C virus (HCV) 
antibody tests intended for the qualitative detection of HCV, 
postamendment class III devices, into class II (general controls and 
special

[[Page 18492]]

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\
---------------------------------------------------------------------------

    \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 (OFR) 
interpretations of the Federal Register Act (44 U.S.C. chapter 15), 
its implementing regulations (1 CFR 5.9 and parts 21 and 22), and 
the Document Drafting Handbook.
---------------------------------------------------------------------------

    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 of HCV antibody tests intended for the qualitative 
detection of HCV. Therefore, the 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.

II. Regulatory History of the Devices

    This proposed order applies to HCV antibody assay device for use as 
a prescription device as an aid in the diagnosis of HCV infection. 
These are prescription devices that are assigned product code MZO. On 
August 30, 2001, FDA approved its first HCV antibody test (Ortho-
Clinical Diagnostics, Inc.'s VITROS IMMUNODIAGNOSTIC PRODUCTS ANTI-HCV 
REAGENT PACK AND CALIBRATOR) intended for use as a prescription device 
as an aid in the diagnosis of HCV infection by a qualified licensed 
healthcare professional in conjunction with other relevant clinical and 
laboratory findings through its PMA process under section 515 of the 
FD&C Act (21 U.S.C. 360e). In a May 22, 2002, Federal Register notice 
(67 FR 36009), 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 nine additional 
original PMAs for HCV antibody tests that are prescription devices 
intended for use as an aid in the diagnosis of HCV infection by a 
qualified licensed healthcare professional in conjunction with other 
relevant clinical and laboratory findings (hereafter referred to as 
``HCV antibody test'').
    A review of the medical device reporting databases indicates that 
there is a low number of reported events for HCV antibody tests 
relative to the number of tests conducted using these devices. Events 
reported included false positive results, low test results, false 
negative results, unspecified incorrect or inadequate results, 
mechanical problems, and leak/splash. As of the date of this proposed 
order, FDA is aware of two class III recalls, \2\ two class II recalls, 
\3\ and no class I recalls for these devices.\4\ The class II recalls 
occurred in 2007 and 2014, and were related to: (1) Sporadic lower than 
expected anti-HCV test results, and (2) failure of the instrument to 
open (actuate) some reagent packs from certain lots. 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.
---------------------------------------------------------------------------

    \2\ Class III recalls are defined in 21 CFR 7.3(m)(3).
    \3\ Class II recalls are defined in 21 CFR 7.3(m)(2).
    \4\ Class I recalls are defined in 21 CFR 7.3(m)(1).
---------------------------------------------------------------------------

III. Device Description

    HCV antibody tests are postamendments prescription devices for the 
qualitative detection of HCV and are classified into class III under 
section 513(f)(1) of the FD&C Act. HCV antibody tests are described in 
FDA's SSEDs and product code database (assigned product code MZO) as 
devices for the qualitative detection of antibodies to HCV in human 
serum and plasma. HCV antibodies, when present in samples, bind to HCV 
antigens to form a complex that is bound to a solid phase (e.g. 
microparticles, microtiter plate or else). Detection of the complexes 
can be performed using different methods that measure the presence/
absence of HCV antibodies in the sample. HCV antibody tests are 
intended for use as aids in the presumptive diagnosis of HCV infection 
in persons with signs and symptoms of hepatitis and in persons at risk 
of acquiring HCV infection. These devices are not intended for 
screening blood, plasma, cell or tissue donors. This proposed order 
does not apply to HCV antibody tests that are intended for home use or 
over-the-counter use.
    FDA is proposing to reclassify HCV antibody 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., hepatitis C 
virus (HCV) antibody tests. FDA believes that this name and proposed 
identification language most accurately describes these devices. An HCV 
antibody test is tentatively identified as a device intended for use 
with human serum, plasma, or other matrices as a prescription device 
that aids in the diagnosis of HCV infection in persons with signs and 
symptoms of hepatitis and in persons at risk for hepatitis C infection. 
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. The test is not 
intended for screening blood, plasma, cell, or tissue donors.
    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 HCV antibody tests. On March 22, 
2018, FDA held a public meeting of the Microbiology Devices Panel 
(Panel) of the Medical Devices Advisory Committee convened to discuss 
and make recommendations regarding the reclassification of HCV antibody 
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 
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

[[Page 18493]]

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 21 CFR 
part 860, subpart C, FDA is proposing to reclassify postamendments HCV 
antibody tests to be renamed ``hepatitis C virus (HCV) antibody 
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 HCV antibody tests such that 
patients would benefit from increased access to safe and effective 
tests.
    FDA is proposing to create a classification regulation for HCV 
antibody tests that will be reclassified from class III to class II. 
Under this proposed order, if finalized, HCV antibody 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 HCV antibody 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 HCV antibody tests, FDA has determined 
that premarket notification is necessary to provide reasonable 
assurance of the safety and effectiveness of these devices. Therefore, 
FDA does not intend to exempt this 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 HCV antibody tests that could significantly affect the safety and 
effectiveness of those devices and for which a new 510(k) is likely 
required.\5\ 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).
---------------------------------------------------------------------------

    \5\ See 21 CFR 807.81(a)(3)(i).
---------------------------------------------------------------------------

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 patients with chronic HCV infection through devices such 
as hepatitis C virus antibody 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 FDA review submissions, recommendations of the Panel for 
the classification of these devices (Ref. 2), and published literature, 
FDA has identified the following probable risks to health associated 
with HCV Antibody Tests:
     Inaccurate interpretation of test results. Inaccurate 
interpretation of test results by clinicians may negatively influence 
patient management decisions. A reactive test result misinterpreted as 
non-reactive may delay or prevent a patient with HCV infection from 
being identified and linked to care. Missed identification of patients 
with chronic HCV infection 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). A reactive test incorrectly 
interpreted as non-reactive also may contribute to public health risk 
by leading to inadvertent transmission of virus by an infected person. 
A non-reactive test result incorrectly identified as reactive may 
contribute to unnecessary additional patient testing to exclude active 
HCV infection or potentially delay diagnosis of alternative causes of 
liver disease when present.
     Failure of the device to perform as indicated (e.g., false 
negative results or false positive results). A false negative test 
result due to failure of the device to perform may delay or prevent a 
patient with HCV infection from being identified and linked to care. 
Missed identification of patients with chronic HCV infection 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). A false 
negative/false non-reactive test result also may contribute to public 
health risk by leading to inadvertent transmission of virus by an 
infected person. Factors that may cause decreased test sensitivity and/
or an increased rate of false

[[Page 18494]]

negative results include, but are not limited to, the presence of 
interfering substances in the sample, acute infection at a stage that 
is too early for a device to detect the infection, and antibody 
concentrations that are too low to be detected by the device. They also 
can be caused by misinterpretation of invalid results as negative. A 
false positive test result may contribute to unnecessary additional 
patient testing to exclude active HCV infection or potentially delay 
diagnosis of alternative causes of liver disease when present. Factors 
that may lead to false positive results include device contamination 
from positive samples, cross-reactivity with other antibodies, or 
misinterpretation of invalid results as positive.

VI. Summary of the Reasons for Reclassification

    FDA believes that HCV antibody 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 
theses device 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, HCV antibody 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 HCV antibody 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 HCV antibody test for the qualitative 
detection of HCV in 2001.

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 HCV 
antibody 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 and information on 
principles of operation and procedures in performing the test.
    Risks associated with the failure of the device to perform as 
indicated (e.g., false negative and false positive test results) can be 
mitigated through a combination of special controls including certain 
labeling requirements, certain design verification and validation 
information, and performance studies. Examples of verification and 
validation information to be included in the design of the device 
includes documentation of performance specifications including 
analytical and clinical performance criteria. In addition, design 
verification and validation activities must include documentation of a 
complete device description, critical reagents, risk analysis 
strategies, lot release criteria, stability studies and protocols. 
Required statements in labeling can aid in mitigating the failure of 
the device to perform as indicated, for example including a statement 
that use of the test with specimen types other than those specifically 
identified for use with this device may cause inaccurate test results.

 Table 1--Risks to Health and Mitigation Measures for HCV Antibody Tests
------------------------------------------------------------------------
  Identified risks to health              Mitigation measures
------------------------------------------------------------------------
Inaccurate interpretation of   Certain labeling warnings, limitations,
 test results.                  and explanation of procedures.
Failure of the device to       Certain labeling warnings, limitations,
 perform as indicated.          and explanation of procedures.
                               Performance specifications including
                                analytical and clinical performance
                                criteria.
                               Certain design verification and
                                validation information including
                                documentation of device description,
                                critical reagents, risk analysis
                                strategies, lot release criteria,
                                stability studies and protocols.
------------------------------------------------------------------------

    If this proposed order is finalized, HCV antibody tests will be 
reclassified into class II (general controls and special controls) and 
would be subject to premarket notification requirements under section 
510(k) of the FD&C Act. As discussed below, the intent is for the 
reclassification to be codified in 21 CFR 866.3169. Firms submitting a 
premarket notification under section 510(k) of the FD&C Act for HCV 
antibody 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 
collections 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 
21 CFR parts 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,

[[Page 18495]]

under section 513(f)(3), in the proposed order, we are proposing to 
codify HCV antibody tests in the new 21 CFR 866.3169, under which 
certain HCV antibody 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.  866.3169 to subpart D to read as follows:


Sec.  866.3169   Hepatitis C Virus Antibody Tests.

    (a) Identification. A hepatitis C virus (HCV) antibody test is 
identified as an in vitro diagnostic device intended for use with human 
serum, plasma, or other matrices as a prescription device that aids in 
the diagnosis of HCV infection in persons with signs and symptoms of 
hepatitis and in persons at risk for hepatitis C infection. The test is 
not intended for screening blood, plasma, cell, or tissue donors.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) The labeling required under 21 CFR 809.10(b) must include:
    (i) A prominent statement that the test is not intended for the 
screening of blood, plasma, and cell or tissue donors.
    (ii) Limitations, which must be updated to reflect current clinical 
practice and disease presentation and management. The limitations must 
include, but are not limited to, statements that indicate:
    (A) When appropriate, the performance characteristics of the test 
have not been established in populations of immunocompromised or 
immunosuppressed patients or, other special populations where test 
performance may be affected.
    (B) The detection of HCV antibodies indicates a present or past 
infection with hepatitis C virus, but does not differentiate between 
acute, chronic, or resolved infection.
    (C) The specimen types for which the device has been cleared, and 
that use of the test with specimen types other than those specifically 
cleared for this device may result in inaccurate test results.
    (D) Test results are to be interpreted by qualified licensed 
healthcare professionals in conjunction with the individual's clinical 
presentation, history, and other laboratory results.
    (E) A non-reactive test result may occur early during acute 
infection, prior to development of a host antibody response to 
infection, or when analyte levels are below the limit of detection of 
the test.
    (iii) A detailed explanation of the principles of operation and 
procedures for performing the test.
    (2) Design verification and validation must include the following:
    (i) A detailed device description, including all parts that make up 
the device, ancillary reagents required but not provided, an 
explanation of the device methodology, and design of the antigen(s) and 
capture antibody(ies) sequences, rationale for the selected epitope(s), 
degree of amino acid sequence conservation of the target, and the 
design and nature of all primary, secondary, and subsequent standards 
used for calibration.
    (ii) Documentation and characterization (e.g., supplier, 
determination of identity, and stability) of all critical reagents 
(including description of the antigen(s) and capture antibody(ies)), 
and protocols for maintaining product integrity throughout its labeled 
shelf life.
    (iii) 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.
    (iv) 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.
    (v) Stability studies for reagents must include documentation of an 
assessment of real-time stability for multiple reagent lots using the 
indicated specimen types and must use acceptance criteria that ensure 
that analytical and clinical performance characteristics are met when 
stability is assigned based on the extremes of the acceptance range.
    (vi) All stability protocols, including acceptance criteria.
    (vii) Final release test results for each lot used in clinical 
studies.
    (viii) Multisite reproducibility study that includes the testing of 
three independent production lots.
    (ix) Analytical performance studies and results for determining the 
limit of blank (LoB), limit of detection (LoD), cutoff, precision 
(reproducibility) including lot-to-lot and/or instrument-to-instrument 
precision, interference, cross reactivity, carry-over, hook effect,

[[Page 18496]]

seroconversion panel testing, matrix equivalency, specimen stability, 
reagent stability, and cross-genotype antibody detection sensitivity, 
when appropriate.
    (x) Analytical sensitivity of the test is the same or better than 
that of other cleared or approved tests.
    (xi) Detailed documentation of clinical performance testing from a 
multisite clinical study. Performance must be analyzed relative to an 
FDA cleared or approved HCV antibody test, or a comparator that FDA has 
determined is appropriate. This study must be conducted using 
appropriate patient samples, with an acceptable number of HCV positive 
and negative samples in applicable risk categories. Additional relevant 
patient groups must be validated as appropriate. The samples may be a 
combination of fresh and repository samples, sourced from 
geographically diverse areas. The study designs, including number of 
samples tested, must be sufficient to meet the following criteria:
    (A) Clinical sensitivity of the test must have a lower bound of the 
95 percent confidence interval of greater than or equal to 95 percent.
    (B) Clinical specificity of the test must have a lower bound of the 
95 percent confidence interval of greater than or equal to 96 percent.
    (3) For any HCV antibody 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. 2020-06821 Filed 4-1-20; 8:45 am]
 BILLING CODE 4164-01-P


