[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 [www.gpo.gov]
[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, 
[email protected].

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 https://www.regulations.gov. References without 
asterisks are not on public display at https://www.regulations.gov 
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 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program).
*3. FDA's Premarket Approval Database available on FDA's website at 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm.
*4. FDA's 510(k) Premarket Notification Database available on FDA's 
website at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm.
*5. Transcript of the FDA Microbiology Devices Panel Meeting, March 
22, 2018

[[Page 66172]]

(available at https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM630139.pdf).

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


