[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]
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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.
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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, [email protected].
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\
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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 (OFR)
interpretations of the Federal Register Act (44 U.S.C. chapter 15),
its implementing regulations (1 CFR 5.9 and parts 21 and 22), and
the Document Drafting Handbook.
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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.
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\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).
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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).
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\5\ 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 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
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Identified risks to health Mitigation measures
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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.
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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