[Federal Register Volume 88, Number 10 (Tuesday, January 17, 2023)]
[Rules and Regulations]
[Pages 2518-2520]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-00480]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 862

[Docket No. FDA-2022-N-3335]


Medical Devices; Clinical Chemistry and Clinical Toxicology 
Devices; Classification of the Prognostic Test for Assessment of Liver 
Related Disease Progression

AGENCY: Food and Drug Administration, HHS.

ACTION: Final amendment; final order.

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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is 
classifying the prognostic test for assessment of liver related disease 
progression into class II (special controls). The special controls that 
apply to the device type are identified in this order and will be part 
of the codified language for the prognostic test for assessment of 
liver related disease progression's classification. We are taking this 
action because we have determined that classifying the device into 
class II (special controls) will provide a reasonable assurance of 
safety and effectiveness of the device. We believe this action will 
also enhance patients' access to beneficial innovative devices.

DATES: This order is effective January 17, 2023. The classification was 
applicable on August 20, 2021.

FOR FURTHER INFORMATION CONTACT: Irene Tebbs, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, Rm. 3526, Silver Spring, MD 20993-0002, 340-402-0283, 
[email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    Upon request, FDA has classified the prognostic test for assessment 
of liver related disease progression as class II (special controls), 
which we have determined will provide a reasonable assurance of safety 
and effectiveness. In addition, we believe this action will enhance 
patients' access to beneficial innovation, in part by placing the 
device into a lower device class than the automatic class III 
assignment.
    The automatic assignment of class III occurs by operation of law 
and without any action by FDA, regardless of the level of risk posed by 
the new device. Any device that was not in commercial distribution 
before May 28, 1976, is automatically classified as, and remains 
within, class III and requires premarket approval unless and until FDA 
takes an action to classify or reclassify the device (see 21 U.S.C. 
360c(f)(1)). We refer to these devices as ``postamendments devices'' 
because they were not in commercial distribution prior to the date of 
enactment of the Medical Device Amendments of 1976, which amended the 
Federal Food, Drug, and Cosmetic Act (FD&C Act).
    FDA may take a variety of actions in appropriate circumstances to 
classify or reclassify a device into class I or II. We may issue an 
order finding a new device to be substantially equivalent under section 
513(i) of the FD&C Act (see 21 U.S.C. 360c(i)) to a predicate device 
that does not require premarket approval. We determine whether a new 
device is substantially equivalent to a predicate device by means of 
the procedures for premarket notification under section 510(k) of the 
FD&C Act (21 U.S.C. 360(k)) and part 807 (21 CFR part 807).
    FDA may also classify a device through ``De Novo'' classification, 
a common name for the process authorized under section 513(f)(2) of the 
FD&C Act. Section 207 of the Food and Drug Administration Modernization 
Act of 1997 (Pub. L. 105-115) established the first procedure for De 
Novo classification. Section 607 of the Food and Drug Administration 
Safety and Innovation Act (Pub. L. 112-144) modified the De Novo 
application process by adding a second procedure. A device sponsor may 
utilize either procedure for De Novo classification.
    Under the first procedure, the person submits a 510(k) for a device 
that has not previously been classified. After receiving an order from 
FDA classifying the device into class III under section 513(f)(1) of 
the FD&C Act, the person then requests a classification under section 
513(f)(2).
    Under the second procedure, rather than first submitting a 510(k) 
and then a request for classification, if the person determines that 
there is no legally marketed device upon which to base a determination 
of substantial equivalence, that person requests a classification under 
section 513(f)(2) of the FD&C Act.
    Under either procedure for De Novo classification, FDA is required 
to classify the device by written order within 120 days. The 
classification will be according to the criteria under section 
513(a)(1) of the FD&C Act. Although the device was automatically placed 
within class III, the De Novo classification is considered to be the 
initial classification of the device.
    When FDA classifies a device into class I or II via the De Novo 
process, the device can serve as a predicate for future devices of that 
type, including for 510(k)s (see section 513(f)(2)(B)(i) of the FD&C 
Act). As a result, other device sponsors do not have to submit a De 
Novo request or premarket approval application to market a 
substantially equivalent device (see section 513(i) of the FD&C Act, 
defining ``substantial equivalence''). Instead, sponsors can use the 
less-burdensome 510(k) process, when necessary, to market their device.

II. De Novo Classification

    On November 4, 2020, FDA received Siemens Healthcare Diagnostics 
Inc.'s request for De Novo classification of the ADVIA Centaur Enhanced 
Liver Fibrosis. FDA reviewed the request in order to classify the 
device under the

[[Page 2519]]

criteria for classification set forth in section 513(a)(1) of the FD&C 
Act.
    We classify devices into class II if general controls by themselves 
are insufficient to provide reasonable assurance of safety and 
effectiveness, but there is sufficient information to establish special 
controls that, in combination with the general controls, provide 
reasonable assurance of the safety and effectiveness of the device for 
its intended use (see 21 U.S.C. 360c(a)(1)(B)). After review of the 
information submitted in the request, we determined that the device can 
be classified into class II with the establishment of special controls. 
FDA has determined that these special controls, in addition to the 
general controls, will provide reasonable assurance of the safety and 
effectiveness of the device.
    Therefore, on August 20, 2021, FDA issued an order to the requester 
classifying the device into class II. In this final order, FDA is 
codifying the classification of the device by adding 21 CFR 
862.1622.\1\ We have named the generic type of device prognostic test 
for assessment of liver related disease progression, and it is 
identified as a device intended to measure one or more analytes 
obtained from human samples as an aid in assessing progression of liver 
related disease. This device is not intended for diagnosis of any 
disease, for monitoring the effect of any therapeutic product, for 
assessing progression to hepatocellular carcinoma, or for assessing 
disease progression in individuals with viral hepatitis. It is also not 
intended for the detection of viruses, viral antigens, or antibodies to 
viruses.
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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) 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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    FDA has identified the following risks to health associated 
specifically with this type of device and the measures required to 
mitigate these risks in table 1.

    Table 1--Prognostic Test for Assessment of Liver Related Disease
                Progression Risks and Mitigation Measures
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       Identified risks                   Mitigation measures
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False negative results         Certain design verification and
 leading to delayed             validation activities, including certain
 assessment or treatment.       clinical studies; and
                               Certain labeling information, including
                                certain warnings and performance
                                information.
False positive results         Certain design verification and
 leading to unnecessary         validation activities, including certain
 medical procedures.            clinical studies; and
                               Certain labeling information, including
                                certain warnings and performance
                                information.
------------------------------------------------------------------------

    FDA has determined that special controls, in combination with the 
general controls, address these risks to health and provide reasonable 
assurance of safety and effectiveness. For a device to fall within this 
classification, and thus avoid automatic classification in class III, 
it would have to comply with the special controls named in this final 
order. The necessary special controls appear in the regulation codified 
by this order. This device is subject to premarket notification 
requirements under section 510(k) of the FD&C Act.

III. 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.

IV. Paperwork Reduction Act of 1995

    This final order establishes special controls that refer to 
previously approved collections of information found in other FDA 
regulations and guidance. 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 21 CFR part 860, subpart D, regarding De Novo 
classification have been approved under OMB control number 0910-0844; 
the collections of information in 21 CFR part 814, subparts A through 
E, regarding premarket approval, have been approved under OMB control 
number 0910-0231; the collections of information in part 807, subpart 
E, regarding premarket notification submissions, have been approved 
under OMB control number 0910-0120; the collections of information in 
21 CFR part 820, regarding quality system regulation, have been 
approved under OMB control number 0910-0073; and the collections of 
information in 21 CFR parts 801and 809, regarding labeling, have been 
approved under OMB control number 0910-0485.

List of Subjects in 21 CFR Part 862

    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 
862 is amended as follows:

PART 862--CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES

0
1. The authority citation for part 862 continues to read as follows:

    Authority:  21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.


0
2. Add Sec.  862.1622 to subpart B to read as follows:


Sec.  862.1622   Prognostic test for assessment of liver related 
disease progression.

    (a) Identification. A prognostic test for assessment of liver 
related disease progression is intended to measure one or more analytes 
obtained from human samples as an aid in assessing progression of liver 
related disease. This device is not intended for diagnosis of any 
disease, for monitoring the effect of any therapeutic product, for 
assessing progression to hepatocellular carcinoma, or for assessing 
disease progression in individuals with viral hepatitis. It is also not 
intended for the detection of viruses, viral antigens, or antibodies to 
viruses.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) Design verification and validation must include clinical 
validation data providing:
    (i) Information demonstrating clinical performance in a population 
of patients with liver disease for the different risk categories (e.g., 
at lower risk, at higher risk) for progression of their disease using 
well characterized clinical specimens representing the intended use 
population collected from multiple

[[Page 2520]]

intended clinical sites, or an alternative study design determined to 
be appropriate by FDA.
    (ii) Information demonstrating that the outcomes measured and the 
length of followup are clinically relevant for the progression of the 
specified liver disease.
    (iii) Information demonstrating that the clinical criteria for 
determining whether the target disease is present and that the 
exclusion and inclusion criteria for subjects who have the target 
disease are appropriate.
    (iv) Information demonstrating test performance of the complete 
test system, including any sample collection and processing steps.
    (v) Information, provided or referenced, generated in samples from 
non-diseased individuals, that demonstrate the upper and lower 
reference intervals for the output provided by the device.
    (2) The labeling required under 21 CFR 809.10(b) must include:
    (i) A warning statement that test results are not intended to 
diagnose disease or for monitoring the effect of any therapeutic 
product.
    (ii) A warning statement that test results are intended to be used 
in conjunction with other clinical and diagnostic findings, consistent 
with professional standards of practice, including information obtained 
by alternative methods, and clinical evaluation, as appropriate.
    (iii) A warning statement that describes any limitations on the 
clinical interpretation(s) of the test results.
    (iv) Detailed information on device performance, including any 
limitations to the data generated in the clinical study(ies) and 
information on device performance in relevant subgroups (e.g., severity 
of liver disease at the beginning of the observation period) observed 
in the clinical study(ies).
    (v) Information on the analytical performance of the device, 
including demonstration of reproducibility across multiple sites and 
multiple reagent lots, or an alternative reproducibility study design 
determined to be appropriate by FDA.

    Dated: January 6, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-00480 Filed 1-13-23; 8:45 am]
BILLING CODE 4164-01-P