Rule2021-25379
Microbiology Devices; Reclassification of Nucleic Acid-Based Hepatitis C Virus Ribonucleic Acid Assay Devices, Renamed to Nucleic Acid-Based Hepatitis C Virus Ribonucleic Acid Tests
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
November 22, 2021
Effective
December 22, 2021
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or the Agency) is issuing a final order 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 renaming and codifying these devices under the classification regulation named "nucleic acid-based hepatitis C virus (HCV) ribonucleic acid tests." FDA is also identifying the special controls that the Agency believes are necessary to provide a reasonable assurance of safety and effectiveness of these devices.
Full Text
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[Federal Register Volume 86, Number 222 (Monday, November 22, 2021)]
[Rules and Regulations]
[Pages 66169-66173]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2021-25379]
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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, Renamed to Nucleic
Acid-Based Hepatitis C Virus Ribonucleic Acid Tests
AGENCY: Food and Drug Administration, HHS.
ACTION: Final amendment; final order.
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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
issuing a final order 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 renaming and codifying these devices under the classification
regulation named ``nucleic acid-based hepatitis C virus (HCV)
ribonucleic acid tests.'' FDA is also identifying the special controls
that the Agency believes are necessary to provide a reasonable
assurance of safety and effectiveness of these devices.
DATES: This order is effective December 22, 2021.
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,
<a href="/cdn-cgi/l/email-protection#085b6164636d265b6b6064677c7c65696666486e6c692660607b266f677e"><span class="__cf_email__" data-cfemail="386b5154535d166b5b5054574c4c55595656785e5c591650504b165f574e">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background--Regulatory Authorities
The Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended,
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 classes of devices, reflecting the regulatory
controls needed to provide reasonable assurance of their safety and
effectiveness. The three classes of devices are class I (general
controls), class II (general and special controls), and class III
(general controls and premarket approval).
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 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 (21 U.S.C.
360(k)) and part 807, subpart E (21 CFR part 807, subpart E).
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 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) of the FD&C Act 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 (21 U.S.C. 360j(c))).
Publicly available information excludes trade secret and/or
confidential commercial information, e.g., the contents of a pending
premarket approval application (PMA) (see section 520(c) of the FD&C
Act).
FDA published a proposed order in the Federal Register of April 2,
2020 (85 FR 18483), 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. FDA
has considered the information available to the Agency, including the
deliberations of the March 22, 2018, Microbiology Devices Panel (2018
Panel), and comments from the public docket and has determined that
there is sufficient information to establish special controls to
effectively mitigate the risks to health identified in section V of the
proposed order, and that these special controls, together with general
controls, provide a reasonable assurance of safety and effectiveness
when applied to nucleic acid-based HCV RNA devices intended for the
qualitative or quantitative detection or genotyping of HCV RNA.
Therefore, in accordance with section 513(f)(3) of the FD&C Act,
FDA, on its own initiative, is issuing this final order to reclassify
nucleic acid-based HCV RNA devices intended for the qualitative or
quantitative detection or genotyping of HCV RNA from class III to class
II (general and special controls).\1\
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\1\ FDA notes that the ``ACTION'' caption for this final order
is styled as ``Final amendment; final order,'' rather than ``Final
order.'' Beginning in December 2019, this editorial change was made
to indicate that the document ``amends'' the Code of Federal
Regulations. The change was made in accordance with the Office of
Federal Register's (OFR) interpretation 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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II. Comments on the Proposed Order
On April 2, 2020, FDA published in the Federal Register a proposed
order to reclassify nucleic acid-based HCV RNA devices intended for the
qualitative or quantitative detection or genotyping of HCV RNA from
class III to class II, subject to premarket notification. The comment
period on the proposed order closed on June 1, 2020. In response to the
proposed order, FDA received comments from industry, healthcare
associations, public health departments, and individual consumers by
the close of the comment period, some of which contained one or more
comments on one or more issues. We describe and respond to the comments
in this section of the document. Certain comments are grouped based on
common themes; we grouped similar comments together under the same
number and listed them numerically.
[[Page 66170]]
The order of response to the commenters is purely for
organizational purposes and does not signify the comment's value or
importance nor the order in which comments were received. Please note
that in some cases we separated different issues discussed by the same
commenter and designated them as distinct comments for purposes of our
responses.
(Comment 1) FDA received numerous comments in favor of the proposed
reclassification of nucleic acid-based HCV RNA devices intended for the
qualitative or quantitative detection or genotyping of HCV RNA from
class III to class II with special controls. Commenters stated they
believed that special controls, along with general controls, could
provide a reasonable assurance of the safety and effectiveness of these
devices. In addition, they believed that the decreased regulatory
burden resulting from the reclassification could encourage further
development of, and provide patients more timely access to, these
devices. Overall, there was a general consensus among the commenters
that the proposed special 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.
(Response 1) Based on the evidence considered, comments received in
response to the proposed order, and deliberations of the 2018 Panel,
FDA agrees with the commenters that reclassification of nucleic acid-
based HCV RNA devices for the qualitative or quantitative detection or
genotyping of HCV RNA from class III into class II and that special
controls, in addition to general controls, can provide a reasonable
assurance of the safety and effectiveness of these devices. In
addition, FDA expects that the reclassification of these devices would
enable more manufacturers to develop them such that patients would
benefit from increased access to safe and effective tests.
(Comment 2) One comment objected to the proposed reclassification
of these devices from class III into class II on the basis that the
commenter was not provided adequate notification of the proposed
reclassification.
(Response 2) FDA disagrees with this comment as FDA provided notice
of our proposed reclassification of these devices with the publication
of the proposed order in the Federal Register on April 2, 2020, in
accordance with section 513(f)(3) of the FD&C Act and 21 CFR part 860.
In addition, as discussed further in the proposed order, a public
meeting of the 2018 Panel was held where FDA discussed the possible
reclassification of nucleic acid-based HCV RNA tests and the Panel
members agreed unanimously with the proposal.
(Comment 3) Several commenters had questions about the scope of the
proposed reclassification order. Several commenters noted that the
proposed reclassification order identified these devices as nucleic-
acid based HCV RNA tests for prescription use and suggested that the
reclassification order should also include tests intended for over-the-
counter (OTC) use. In addition, one commenter suggested that FDA's
reclassification order should also include HCV antigen tests, tests for
hepatitis A and hepatitis B, and also that the reclassification should
include other specimen types for nucleic acid-based HCV RNA tests
beyond those identified in the proposed order (e.g., urine or saliva).
(Response 3) These comments are beyond the scope of FDA's proposed
reclassification order, which applies only to nucleic acid-based HCV
RNA tests that have been previously approved by FDA. FDA has not
approved any nucleic acid-based HCV RNA tests intended for OTC use, and
FDA believes that a nucleic acid-based HCV RNA test intended for OTC
use would be a new type of device not previously classified based on
the criteria at section 513(a)(1) of the FD&C Act and, as a result,
such postamendments device would be automatically classified into class
III by operation of section 513(f)(1) of the FD&C Act.
Similarly, to date, FDA has only approved nucleic acid-based HCV
RNA tests intended for use with human serum or plasma, and new specimen
types are beyond the scope of FDA's proposed reclassification order.
(Comment 4) Several commenters expressed support of FDA's proposal
to rename these devices from ``nucleic acid-based hepatitis C virus
(HCV) ribonucleic acid (RNA) assay devices'' to ``nucleic acid-based
hepatitis C virus (HCV) ribonucleic acid (RNA) tests.'' These
commenters believed that the new name for these devices made clear that
these are diagnostic tests and is consistent with the naming of similar
diagnostic devices.
(Response 4) FDA believes that the new identification name of these
devices--``nucleic acid-based hepatitis C virus (HCV) ribonucleic acid
(RNA) tests''--is both understandable to consumers and industry and is
consistent with the naming of similar diagnostic devices and agrees
with these commenters. As discussed further below in section III, FDA
on its own initiative has revised the device identification of nucleic-
acid based HCV RNA to be codified in Sec. 866.3170(a) (21 CFR
866.3170(a)).
(Comment 5) One commenter suggested that the proposed special
control requiring cross-reactivity studies may not be necessary and
suggested instead that interfering substance studies be conducted
according to ``CLSI-EP-7-A2: Interference Testing in Clinical
Chemistry: Approved Guideline--Second Edition'' (Ref. 1).
(Response 5) FDA disagrees with this comment and believes that the
special control requiring cross-reactivity studies that 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, is necessary to provide a reasonable
assurance of the safety and effectiveness of these devices (see Sec.
866.3170(b)(2)(iv)). FDA also believes that specifying a standard
explicitly as part of the special controls that manufacturers must
follow is not necessary and would prohibit the use of a new standard in
the event that the version of the standard specified in the special
controls is revised and/or updated.
(Comment 6) One commenter suggested that FDA provide additional
details regarding the study design and analysis required for devices
intended for the quantitative detection of HCV RNA by the special
control in Sec. 866.3170(b)(4)(C). In addition, the commenter
requested clarification on the requirement for clinical studies for
nucleic-acid based HCA RNA tests intended for Point of Care (PoC) use
and inquired whether the sample size for such studies should be larger
than for the other clinical studies required by the special controls.
(Response 6) FDA disagrees with this comment and does not believe
that additional specificity is required to provide a reasonable
assurance of the safety and effectiveness of these devices because the
appropriate sample size for a required study may be influenced by the
technology at issue and/or type of device under review.
FDA recommends that device manufacturers interested in obtaining
FDA feedback on their study design submit a pre-submission (Ref. 2). In
addition, FDA publishes our decision summaries for previously approved
or cleared devices for in vitro diagnostic testing on our website and
these summaries can be useful aids for
[[Page 66171]]
manufacturers to obtain information on the study designs used to
support the marketing authorizations of other nucleic-acid based HCV
RNA tests (Refs. 3 and 4).
III. The Final Order
Based on the information discussed in the preamble to the proposed
order (April 2, 2020), the comments received for the proposed order,
the 2018 Panel delibrations (Ref. 5), and FDA's experiences over the
years in reviewing these devices, FDA concludes that special controls,
in conjunction with general controls, will provide a reasonable
assurance of the safety and effectiveness of nucleic-acid based HCV RNA
tests. FDA is adopting its findings under section 513(f)(3) of the FD&C
Act, as published in the preamble to the proposed order. FDA is issuing
this final order to reclassify nucleic acid-based HCV RNA devices
intended for the qualitative or quantitative detection or genotyping of
HCV RNA from class III to class II, and to establish special controls
by revising 21 CFR part 866. In this final order, the Agency has
identified the special controls under section 513(a)(1)(B) of the FD&C
Act that, together with general controls, provide a reasonable
assurance of the safety and effectiveness of these devices.
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. FDA has determined that premarket
notification is necessary to provide a reasonable assurance of the
safety and effectiveness of nucleic-acid based HCV RNA tests.
Therefore, these devices are not exempt from premarket notification
requirements. Persons who intend to market a new nucleic-acid based HCV
RNA device intended for the qualitative or quantitative detection or
genotyping of HCV RNA must submit to FDA a premarket notification,
obtain clearance, and demonstrate compliance with the special controls
included in this final order, prior to marketing the device.
These devices are assigned the generic name ``nucleic-acid based
hepatitis C virus ribonucleic acid tests'' and are identified as in
vitro diagnostic devices 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. These tests are intended for use with human serum or
plasma. These tests are not intended for use as a donor screening test
for the presence of HCV antibodies in blood, blood products, or tissue
donors.
Under this final order, nucleic acid-based HCV RNA tests are
identified as prescription use only devices and as such, nucleic acid-
based HCV RNA tests must satisfy prescription labeling requirements for
in vitro diagnostic products (see 21 CFR 809.10(a)(4) and (b)(5)(ii)).
Under 21 CFR 807.81, the device continues to be subject to 510(k)
requirements.
As part of the process for issuance of this final order and on its
own initiative, FDA has identified previously approved nucleic-acid
based HCV RNA tests for use as an aid in diagnosis of HCV infection
without prior evidence of HCV antibodies. In this final order, FDA has
revised the device identification of nucleic-acid based HCV RNA tests
to be codified in Sec. 866.3170(a) to clarify that nucleic acid-based
HCV RNA tests can include devices used as an aid for diagnosis of HCV
infection in specified populations without prior evidence of HCV
antibodies because FDA believes that it may be appropriate to use these
devices as a one-step diagnostic assay and in the absence of evidence
of HCV antibodies.
IV. Codification of Orders
Prior to the amendments in the Food and Drug Administration Safety
and Innovation Act (Pub. L. 112-144) (FDASIA), section 513(e) of the
FD&C Act provided for FDA to issue regulations to reclassify devices.
Although section 513(e), as amended by FDASIA, requires FDA to issue
final orders rather than regulations, it also provides for FDA to
revoke previously issued regulations by order. 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 changes to codified classification determinations or as
newly codified orders. Therefore, under section 513(e)(1)(A)(i), as
amended by FDASIA, in this final order, we are proposing to codify the
classification of nucleic-acid based hepatitis C virus ribonucleic acid
tests in the new Sec. 866.3170, under which nucleic-acid based HCV RNA
tests would be reclassified into class II.
V. 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.
VI. Paperwork Reduction Act of 1995
This final order establishes special controls that refer to
previously approved FDA collections. These collections of information
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). The
collections of information in part 807, subpart E have been approved
under OMB control number 0910-0120; the collections of information in
21 CFR parts 801and 809 have been approved under OMB control number
0910-0485; and the collections of information in 21 CFR part 820 have
been approved under OMB control number 0910-0073.
VII. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-
402-7500, 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. References without
asterisks are not on public display at <a href="https://www.regulations.gov">https://www.regulations.gov</a>
because they have copyright restrictions. 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. Clinical and Laboratory Standards Institute. Interference Testing
in Clinical Chemistry; Approved Guideline--Second Edition. CLSI
document EP07-A2. Wayne, PA: Clinical and Laboratory Standards
Institute; 2005.
*2. ``Requests for Feedback and Meetings for Medical Device
Submissions: The Q-Submission Program--Guidance for Industry and
Food and Drug Administration Staff,'' issued May 7, 2019 (available
at <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program</a>).
*3. FDA's Premarket Approval Database available on FDA's website at
<a href="https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm">https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm</a>.
*4. FDA's 510(k) Premarket Notification Database available on FDA's
website at <a href="https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm">https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm</a>.
*5. Transcript of the FDA Microbiology Devices Panel Meeting, March
22, 2018
[[Page 66172]]
(available at <a href="https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM630139.pdf">https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM630139.pdf</a>).
List of Subjects in 21 CFR Part 866
Biologics, Laboratories, Medical devices.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
866 is amended as follows:
PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES
0
1. The authority citation for part 866 continues to read as follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.
0
2. Add Sec. 866.3170 to subpart D to read as follows:
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. 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 Sec. 809.10(b) of this chapter 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
[[Page 66173]]
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 Sec. 809.10(b) of this chapter 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 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: November 16, 2021.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2021-25379 Filed 11-19-21; 8:45 am]
BILLING CODE 4164-01-P
</pre><script data-cfasync="false" src="/cdn-cgi/scripts/5c5dd728/cloudflare-static/email-decode.min.js"></script></body>
</html>Indexed from Federal Register on November 22, 2021.
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