Document ID: FDA-2021-N-0993-0001
Agency: fda
Document Type: Rule
Title: Medical Devices; Ophthalmic Devices; Classification of the Retinal Diagnostic Software Device
Posted Date: 2022-01-21T05:00Z

[Federal Register Volume 87, Number 14 (Friday, January 21, 2022)]
[Rules and Regulations]
[Pages 3203-3205]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-01147]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 886

[Docket No. FDA-2021-N-0993]

Medical Devices; Ophthalmic Devices; Classification of the 
Retinal Diagnostic Software Device

AGENCY: Food and Drug Administration, Department of Health and Human 
Services (HHS).

ACTION: Final amendment; final order.

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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is 
classifying the retinal diagnostic software device 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 retinal diagnostic software device'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 21, 2022. The classification was 
applicable on April 11, 2018.

FOR FURTHER INFORMATION CONTACT: Elvin Ng, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, Rm. 1304, Silver Spring, MD 20993-0002, 240-402-4662, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Upon request, FDA has classified the retinal diagnostic software 
device 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, by placing the device into a lower device class 
than the automatic class III assignment.

[[Page 3204]]

    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 established the first procedure for De Novo classification 
(Pub. L. 105-115). Section 607 of the Food and Drug Administration 
Safety and Innovation Act modified the De Novo application process by 
adding a second procedure (Pub. L. 112-144). 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 shall 
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.
    We believe this De Novo classification will enhance patients' 
access to beneficial innovation. 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 January 12, 2018, FDA received IDx, LLC's request for De Novo 
classification of the IDx-DR. FDA reviewed the request in order to 
classify the device under the 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 April 11, 2018, 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 
886.1100.\1\ We have named the generic type of device retinal 
diagnostic software device, and it is identified as a prescription 
software device that incorporates an adaptive algorithm to evaluate 
ophthalmic images for diagnostic screening to identify retinal diseases 
or conditions.
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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--Retinal Diagnostic Software Device Risks and Mitigation
                                Measures
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       Identified risks                    Mitigation measures
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False positive results leading  Clinical performance testing; Software
 to additional unnecessary       verification, validation, and hazard
 medical procedures.             analysis; and Protocol for technical
 Diagnostic software     specification changes.
 failure.
 Software failure.....
False negative results leading  Clinical performance testing; Software
 to delay of further             verification, validation, and hazard
 evaluation or treatment.        analysis; Protocol for technical
 Diagnostic software     specification changes; and Labeling.
 failure.
 Software failure.....
Operator failure to provide     Labeling, Training, and Human factors
 images that meet input          validation testing.
 quality specifications.
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[[Page 3205]]

    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.
    At the time of classification, retinal diagnostic software devices 
are for prescription use only. Prescription devices are exempt from the 
requirement for adequate directions for use for the layperson under 
section 502(f)(1) of the FD&C Act (21 U.S.C. 352(f)(1)) and 21 CFR 
801.5, as long as the conditions of 21 CFR 801.109 are met.

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 the guidance document ``De Novo Classification 
Process (Evaluation of Automatic Class III Designation)'' 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 
part 801, regarding labeling, have been approved under OMB control 
number 0910-0485.

List of Subjects in 21 CFR Part 886

    Medical devices, Ophthalmic goods and services.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
886 is amended as follows:

PART 886--OPHTHALMIC DEVICES

0
1. The authority citation for part 886 continues to read as follows:

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

0
2. Add Sec.  886.1100 to subpart B to read as follows:

Sec.  886.1100   Retinal diagnostic software device.

    (a) Identification. A retinal diagnostic software device is a 
prescription software device that incorporates an adaptive algorithm to 
evaluate ophthalmic images for diagnostic screening to identify retinal 
diseases or conditions.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) Software verification and validation documentation, based on a 
comprehensive hazard analysis, must fulfill the following:
    (i) Software documentation must provide a full characterization of 
technical parameters of the software, including algorithm(s).
    (ii) Software documentation must describe the expected impact of 
applicable image acquisition hardware characteristics on performance 
and associated minimum specifications.
    (iii) Software documentation must include a cybersecurity 
vulnerability and management process to assure software functionality.
    (iv) Software documentation must include mitigation measures to 
manage failure of any subsystem components with respect to incorrect 
patient reports and operator failures.
    (2) Clinical performance data supporting the indications for use 
must be provided, including the following:
    (i) Clinical performance testing must evaluate sensitivity, 
specificity, positive predictive value, and negative predictive value 
for each endpoint reported for the indicated disease or condition 
across the range of available device outcomes.
    (ii) Clinical performance testing must evaluate performance under 
anticipated conditions of use.
    (iii) Statistical methods must include the following:
    (A) Where multiple samples from the same patient are used, 
statistical analysis must not assume statistical independence without 
adequate justification.
    (B) Statistical analysis must provide confidence intervals for each 
performance metric.
    (iv) Clinical data must evaluate the variability in output 
performance due to both the user and the image acquisition device used.
    (3) A training program with instructions on how to acquire and 
process quality images must be provided.
    (4) Human factors validation testing that evaluates the effect of 
the training program on user performance must be provided.
    (5) A protocol must be developed that describes the level of change 
in device technical specifications that could significantly affect the 
safety or effectiveness of the device.
    (6) Labeling must include:
    (i) Instructions for use, including a description of how to obtain 
quality images and how device performance is affected by user 
interaction and user training;
    (ii) The type of imaging data used, what the device outputs to the 
user, and whether the output is qualitative or quantitative;
    (iii) Warnings regarding image acquisition factors that affect 
image quality;
    (iv) Warnings regarding interpretation of the provided outcomes, 
including:
    (A) A warning that the device is not to be used to screen for the 
presence of diseases or conditions beyond its indicated uses;
    (B) A warning that the device provides a screening diagnosis only 
and that it is critical that the patient be advised to receive followup 
care; and
    (C) A warning that the device does not treat the screened disease;
    (v) A summary of the clinical performance of the device for each 
output, with confidence intervals; and
    (vi) A summary of the clinical performance testing conducted with 
the device, including a description of the patient population and 
clinical environment under which it was evaluated.

    Dated: January 14, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-01147 Filed 1-20-22; 8:45 am]
BILLING CODE 4164-01-P