(199 days)
Not Found
Yes
The device description explicitly states that the AEYE-DS device is based on the main technological principle of Artificial Intelligence (AI) software as a medical device and uses artificial intelligence technology to analyze images.
No
The device is described as a "retinal diagnostic software device" used for "diagnostic screening to identify retinal diseases" and to "automatically detect more than mild diabetic retinopathy." It does not provide any treatment or therapy.
Yes
The device description explicitly states, "AEYE-DS is a retinal diagnostic software device that incorporates an algorithm to evaluate ophthalmic images for diagnostic screening to identify retinal diseases or conditions. Specifically, the AEYE-DS is designed to perform diagnostic screening for the condition of more-than-mild diabetic retinopathy (mtmDR)." This clearly indicates its purpose as a diagnostic tool.
Yes
The device description explicitly states that AEYE-DS is a "retinal diagnostic software device" and is comprised of "5 software components". While it interacts with a fundus camera (Topcon NW400) for image acquisition, the device itself, as described and submitted for 510(k), is the software that analyzes these images. The description focuses solely on the software's functionality and components.
Based on the provided information, the AEYE-DS device is not an In Vitro Diagnostic (IVD).
Here's why:
- IVD Definition: In Vitro Diagnostics are medical devices used to examine specimens taken from the human body, such as blood, urine, or tissue, to provide information for diagnosis, monitoring, or screening.
- AEYE-DS Function: The AEYE-DS device analyzes digital funduscopic images of the eye. These images are obtained directly from the patient's body using a fundus camera (Topcon NW400). It does not analyze specimens taken from the body.
- Intended Use: The intended use is to automatically detect more than mild diabetic retinopathy (mtmDR) by analyzing these images, not by analyzing biological samples.
Therefore, while the AEYE-DS is a diagnostic medical device that uses AI and image processing, it falls under the category of in vivo diagnostic imaging devices, not in vitro diagnostics.
No
The letter does not state that the FDA has reviewed and approved or cleared a Predetermined Change Control Plan for this specific device. The "Control Plan Authorized (PCCP) and relevant text" section explicitly states "Not Found".
Intended Use / Indications for Use
The AEYE-DS device is indicated for use by health care providers to automatically detect more than mild diabetic retinopathy (mtmDR) in adults diagnosed with diabetes who have not been previously diagnosed with diabetic retinopathy. The AEYE-DS is indicated for use with the Topcon NW400.
Product codes (comma separated list FDA assigned to the subject device)
PIB
Device Description
AEYE-DS is a retinal diagnostic software device that incorporates an algorithm to evaluate ophthalmic images for diagnostic screening to identify retinal diseases or conditions. Specifically, the AEYE-DS is designed to perform diagnostic screening for the condition of more-than-mild diabetic retinopathy (mtmDR).
The AEYE-DS is comprised of 5 software components: (1) Client; (2) Service; (3) Analytics; (4) Reporting and Archiving; and (5) System Security. The device configuration of these modules is presented in the figure below, indicating which components are local to the user and which are remotely located.
The AEYE-DS device is based on the principle of operation, whereby a fundus camera is used to obtain retinal images. The fundus camera is attached to a computer, where the Client module/software is installed. The Client module/software guides the user to acquire the images and enables the user to interact with the server-based analysis software over a secure internet connection. Using the Client module/software, users identify the fundus images per eye to be dispatched to the Service module/software. The Service module/software is installed on a server hosted at a secure datacenter, receives the fundus images and transfers them to the Analytics module/software. The Analytics module/software, which runs alongside the Service module/software, processes the fundus images and returns information on the image quality and the presence or absence of mtmDR to the Service module/software. The Service module/software then returns the results to the Client module/software.
Mentions image processing
The Analytics module/software, which runs alongside the Service module/software, processes the fundus images and returns information on the image quality and the presence or absence of mtmDR to the Service module/software.
Mentions AI, DNN, or ML
The AEYE-DS device is based on the main technological principle of Artificial Intelligence (AI) software as a medical device. The software as a medical device uses artificial intelligence technology to analyze specific disease features from fundus retinal images for diagnostic screening of diabetic retinopathy.
Input Imaging Modality
fundus retinal images, digital funduscopic images, color fundus images
Anatomical Site
retinal, Eye
Indicated Patient Age Range
adults, ≥22 years of age
Intended User / Care Setting
health care providers; Hospitals, Clinics
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
A total of 531 subjects were screened and enrolled in the study. The study population represented the target population for the use of this device and consisted of stable, visually asymptomatic subjects who were previously diagnosed with diabetes and had no prior diagnosis of mtmDR. Subjects participated in a routine retinal screening test for diabetic retinopathy (DR) in hospitals, primary care clinics or medical research centers. Patients of both genders, all ethnicities and ≥22 years of age were recruited to the study. General patient demographics, medical history, concomitant medications, fundoscopy system used, OCT system used, etc., were obtained for each study subject.
Novice operators, who had not previously performed ocular imaging, obtained fundoscopy images from each eye of the patient, using the Topcon Model NW400 funduscopic camera. Upon submission of the fundoscopy images to the AEYE-DS client software, a diagnostic result (and PDF diagnostics report) of more than mild DR (mtmDR) detected or more than mild DR not detected was produced. A result of 'insufficient quality' was determined if the novice operator reached a maximum of 6 image submission attempts and one or more of the images was still of insufficient image quality. After the novice operator generated an AEYE-DS diagnostic output, each participant underwent additional retinal imaging captured by a professional ophthalmic photographer, to obtain dilated four widefield stereo color fundus images, lens photography for media opacity assessment and macular optical coherence tomography (OCT) imaging. The professional images were sent to an independent reading center where the severity of retinopathy and diabetic macular edema (DME) were determined according to the Early Treatment for Diabetic Retinopathy Study severity (ETDRS) scale. The Reading Center diagnostic results formed the reference standard (ground truth) for the study.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Clinical Performance Data:
The AEYE-DS device performance for automated more than mild Diabetic Retinopathy (mtmDR) detection from digital funduscopic images was demonstrated in a pivotal clinical study. The study was a prospective, multi-center, single-arm, blinded study. The study was conducted at 8 study sites in the United States (7 sites) and Israel (1 site), with active enrollment from October 2020 through November 2021. A total of 531 subjects were screened and enrolled in the study.
AEYE-DS correctly identified 53 of the 57 fully analyzable subjects with mtmDR+, thus the sensitivity was 92.98% [CI: 83.30%; 97.24%] with a lower one-sided 97.5% confidence bound of 83.3%, which is higher than the pre-defined performance goal of 82%. Specificity was 91.36% [CI: 88.22%; 93.72%] with a lower one-sided 97.5% confidence bound of 88.22%, which is higher than the pre-defined performance goal of 87%.
The powered secondary endpoint of this study was the sensitivity and specificity of the AEYE-DS device to detect mtmDR from digital funduscopic images, acquired by the Topcon NW400 fundoscopy device, based on four images (one macula centered image and one optic disc centered image per eye). Diagnostic results and AEYE-DS device diagnostic results and showed a sensitivity and specificity of 94.74% [CI: 85.63%; 98.19%] and 88.64% [CI: 85.18%; 91.38%], respectively. The sensitivity is 94.74% with a lower one-sided 97.5% confidence bound of 85.63%, which is higher than the performance goal of 82%, therefore the null hypothesis is rejected in favor of the alternative hypothesis for the sensitivity. The specificity is 88.64% with a lower one-sided 97.5% confidence bound of 85.18%, which is slightly lower than the performance goal of 87%, therefore the null hypothesis is not rejected in favor of the alternative hypothesis for the specificity.
Precision Study:
Overall, twenty two (22) participants were included in the final statistical analysis. All 22 participants completed the entire AEYE-DS device imaging protocol and diagnostic output twelve consecutive times, imaged by three different novice operators, using two different Topcon NW400 fundoscopy devices. Overall, 12 image sets/diagnoses were obtained for each participant, for a total of 264 image sets/diagnoses in total.
- Intra-Operator Repeatability (1 image per eye): OA 98.48%, APA 98.00%, ANA 98.78%.
- Between Operator Reproducibility (1 image per eye): OA 97.73%, APA 97.96%, ANA 98.80%.
- Between-Device Reproducibility (1 image per eye): OA 98.48%, APA 97.96%, ANA 98.80%.
- Intra-Operator Repeatability (2 images per eye): OA 96.97%, APA 96.55%, ANA 97.30%.
- Between Operator Reproducibility (2 images per eye): OA 95.45%, APA 96.49%, ANA 97.33%.
- Between-Device Reproducibility (2 images per eye): OA 95.45%, APA 94.74%, ANA 96.00%.
Human Factors Validation Study:
Usability of the AEYE-DS device was also assessed in a human factors validation study, including User Manual comprehension and usability of the device in the hands of potential users. Once the users underwent initial, one-time training and practice, all users stated that the device was easy and straightforward and all were successful in submitting images for diagnosis and obtaining a diagnosis output result and PDF report. All users stated that the user manual was clear and easy to use.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
For 1 image per eye (Topcon NW400):
Sensitivity: 93% [CI: 83.3%; 97.2%]
Specificity: 91.4% [CI: 88.2%; 93.7%]
Imageability: 99.1% [CI: 97.8%; 99.7%]
PPV: 60.2% [CI: 49.8%; 69.8%]
NPV: 99% [CI: 97.3%; 99.6%]
For 2 images per eye (Topcon NW400):
Sensitivity: 94.7% [CI: 85.6%; 98.2%]
Specificity: 88.6% [CI: 85.2%; 91.4%]
Imageability: 99.1% [CI: 97.8%; 99.7%]
PPV: 54% [CI: 44.3%; 63.4%]
NPV: 99.2% [CI: 97.6%; 99.7%]
Precision Tables based on 1 image per eye:
Intra-Operator Repeatability: OA 98.48% (130/132) [94.64% ;99.58% ], APA 98.00% [93.00% ;99.45% ], ANA 98.78% [95.66% ;99.66% ]
Between Operator Reproducibility: OA 97.73% (43/44) [88.19% ;99.60% ], APA 97.96% [89.31% ;99.64% ], ANA 98.80% [93.49% ;99.79% ]
Between-Device Reproducibility: OA 98.48% (65/66) [91.90% ;99.73% ], APA 97.96% [89.31% ;99.64% ], ANA 98.80% [93.49% ;99.79% ]
Precision Tables based on 2 images per eye:
Intra-Operator Repeatability: OA 96.97% (128/132) [92.47% ;98.82%], APA 96.55% [91.47% ;98.65%], ANA 97.30% [93.26% ;98.94%]
Between Operator Reproducibility: OA 95.45% (42/44) [84.87% ;98.74% ], APA 96.49% [88.08% ;99.03% ], ANA 97.33% [90.79% ;99.27% ]
Between-Device Reproducibility: OA 95.45% (63/66) [87.47% ;98.44% ], APA 94.74% [85.63% ;98.19% ], ANA 96.00% [88.89% ;98.63% ]
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 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.
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November 10, 2022
Image /page/0/Picture/1 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: on the left, there is the Department of Health & Human Services logo, and on the right, there is the text "FDA U.S. FOOD & DRUG ADMINISTRATION" in blue. The FDA logo is a symbol of the agency's mission to protect and promote public health through the regulation and supervision of food safety, tobacco, pharmaceuticals, medical devices, and other related products.
AEYE Health, Inc. % John Smith MD, JD Partner Hogan Lovells US LLP 555 13th Street NW Washington, District of Columbia 20004
Re: K221183
Trade/Device Name: Aeye-ds Regulation Number: 21 CFR 886.1100 Regulation Name: Retinal Diagnostic Software Device Regulatory Class: Class II Product Code: PIB Dated: October 7, 2022 Received: October 7, 2022
Dear Dr. Smith:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal
1
statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Elvin Y. Ng -S
Elvin Ng Assistant Director DHT1A: Division of Ophthalmic Devices OHT1: Office of Ophthalmic, Anesthesia, Respiratory, ENT and Dental Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration
Indications for Use
510(k) Number (if known)
Device Name
AEYE-DS
Indications for Use (Describe)
The AEYE-DS device is indicated for use by health care providers to automatically detect more than mild diabetic retinopathy (mtmDR) in adults diagnosed with diabetes who have not been previously diagnosed with diabetic retinopathy. The AEYE-DS is indicated for use with the Topcon NW400.
Type of Use (Select one or both, as applicable)
X Prescription Use (Part 21 CFR 801 Subpart D)
□ Over-The-Counter Use (21 CFR 801 Subpart C)
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510(K) SUMMARY
AEYE-DS DEVICE
510(k) Number K221183
| Applicant Name: | AEYE Health Inc. |
|---|---|
| Contact Person: | Zack Dvey-Aharon, Ph.D. |
| Contact: | AEYE Health Inc. |
| 200 Park Ave | |
| New York, NY, 10166 USA | |
| E-mail: info@aeyehealth.com | |
| +1 866 262 7343 | |
| Date Prepared: | November 9, 2022 |
| Trade Name: | AEYE-DS |
| Classification Name: | 21 CFR 886.1100; (Product Code PIB) |
| Retinal Diagnostic Software Device | |
| Classification: | Class II |
Predicate Device:
The AEYE-DS device is substantially equivalent to the following predicate device:
| Predicate | Device | Manufacturer | 510(k) No. |
|---|---|---|---|
| Main | IDx-DR | IDx LLC | DEN180001 |
Device Description:
AEYE-DS is a retinal diagnostic software device that incorporates an algorithm to evaluate ophthalmic images for diagnostic screening to identify retinal diseases or conditions. Specifically, the AEYE-DS is designed to perform diagnostic screening for the condition of more-than-mild diabetic retinopathy (mtmDR).
The AEYE-DS is comprised of 5 software components: (1) Client; (2) Service; (3) Analytics; (4) Reporting and Archiving; and (5) System Security. The device configuration of these modules is presented in the figure below, indicating which components are local to the user and which are remotely located.
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Image /page/4/Figure/0 description: This image shows a diagram of a system for healthcare providers to analyze fundus images. The diagram is divided into two sections: "Local to User" and "Remote". The "Local to User" section includes a healthcare provider, a user computer, and a client module. The "Remote" section includes secure servers, an analytics module, a service module, a system security module, and a reporting and archiving module. The diagram shows the flow of fundus images from the healthcare provider to the client module, then to the analytics module, and finally to the reporting and archiving module.
Figure 1: Device Configuration
The AEYE-DS device is based on the main technological principle of Artificial Intelligence (AI) software as a medical device. The software as a medical device uses artificial intelligence technology to analyze specific disease features from fundus retinal images for diagnostic screening of diabetic retinopathy.
The AEYE-DS device is based on the principle of operation, whereby a fundus camera is used to obtain retinal images. The fundus camera is attached to a computer, where the Client module/software is installed. The Client module/software guides the user to acquire the images and enables the user to interact with the server-based analysis software over a secure internet connection. Using the Client module/software, users identify the fundus images per eye to be dispatched to the Service module/software. The Service module/software is installed on a server hosted at a secure datacenter, receives the fundus images and transfers them to the Analytics module/software. The Analytics module/software, which runs alongside the Service module/software, processes the fundus images and returns information on the image quality and the presence or absence of mtmDR to the Service module/software. The Service module/software then returns the results to the Client module/software.
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Intended Use/Indication for Use:
The AEYE-DS device is indicated for use by health care providers to automatically detect more than mild diabetic retinopathy (mtmDR) in adults diagnosed with diabetes who have not been previously diagnosed with diabetic retinopathy. The AEYE-DS is indicated for use with the Topcon NW400.
Prescription Use only: Federal law restricts this device for sale by or on the order of a physician.
Performance Standards:
The AEYE-DS device complies with the following FDA recognized consensus standards:
- Software Verification and Validation Testing Software verification and validation . testing were conducted, and documentation was provided as recommended by FDA's Guidance for Industry and FDA Staff, "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices." The software for this device was considered as a "Major" level of concern, since a failure or latent flaw in the software could result in serious injury to the patient through incorrect or delayed information or through the action of a care provider.
- IEC 62304 Edition 1.1 2015-06 CONSOLIDATED VERSION Medical device . software – Software life cycle processes
- ISO 14971 Medical devices Application of risk management to medical devices .
Non-Clinical (Bench) Performance Data:
Software validation testing in compliance with FDA guidelines for software validation and IEC 62304 standard requirements was also conducted.
The software hazard analysis was performed as part of the system hazard analysis. The hazards of the software influencing the operations of the system, the hardware problems impairing the software's integrity, and the incorrect operations of the system by the user that could affect the software's correct functioning, were handled as part of the system hazard analysis. The risks and the risk reductions are found in the Risk Analysis for the AEYE-DS device.
The cybersecurity requirements for the AEYE-DS device were identified according to the Content of Premarket Submissions for Management of Cybersecurity in Medical Devices. A threat analysis was performed and documented in the Cybersecurity Report. Updates to the software are also detailed in the Cybersecurity Report.
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The results of the performance tests, including software validation, cybersecurity and hazard analysis demonstrated that the AEYE-DS device (version 5.00) is substantially equivalent to the predicate devices.
Animal Performance Data / Histology Data:
Not Applicable
Clinical Performance Data:
The AEYE-DS device performance for automated more than mild Diabetic Retinopathy (mtmDR) detection from digital funduscopic images was demonstrated in a pivotal clinical study. The study was a prospective, multi-center, single-arm, blinded study. The study was conducted at 8 study sites in the United States (7 sites) and Israel (1 site), with active enrollment from October 2020 through November 2021. A total of 531 subjects were screened and enrolled in the study. The study population represented the target population for the use of this device and consisted of stable, visually asymptomatic subjects who were previously diagnosed with diabetes and had no prior diagnosis of mtmDR. Subjects participated in a routine retinal screening test for diabetic retinopathy (DR) in hospitals, primary care clinics or medical research centers. Patients of both genders, all ethnicities and ≥22 years of age were recruited to the study. General patient demographics, medical history, concomitant medications, fundoscopy system used, OCT system used, etc., were obtained for each study subject.
Novice operators, who had not previously performed ocular imaging, obtained fundoscopy images from each eye of the patient, using the Topcon Model NW400 funduscopic camera. Upon submission of the fundoscopy images to the AEYE-DS client software, a diagnostic result (and PDF diagnostics report) of more than mild DR (mtmDR) detected or more than mild DR not detected was produced. A result of 'insufficient quality' was determined if the novice operator reached a maximum of 6 image submission attempts and one or more of the images was still of insufficient image quality. After the novice operator generated an AEYE-DS diagnostic output, each participant underwent additional retinal imaging captured by a professional ophthalmic photographer, to obtain dilated four widefield stereo color fundus images, lens photography for media opacity assessment and macular optical coherence tomography (OCT) imaging. The professional images were sent to an independent reading center where the severity of retinopathy and diabetic macular edema (DME) were determined according to the Early Treatment for Diabetic Retinopathy Study severity (ETDRS) scale. The Reading Center diagnostic results formed the reference standard (ground truth) for the study. As part of the final clinical assessment, each participant was categorized as mtmDR+ or mtmDR-, based on the worst of two eyes. The final clinical assessment based on the worst of two eyes was compared with the AEYE- DS output, at the participant level.
The baseline demographic data and characteristics analysis showed that the mean age was 55 years (range 21-88), 47% were male and 53% were African-American, 39% White
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and 29% Hispanic or Latino, the remainder were of other racial/ethnic origins. Approximately 95% of the subjects in the study were diagnosed with type 2 diabetes while approximately 5% percent were diagnosed with type 1 diabetes. Duration of diabetes since diagnosis ranged from 1 day to approximately 44 years, with a mean of approximately 10 years (SD=7.9). Most recent HbA1c levels were reported for 446 (86.3%) subjects. HbA1c levels ranged from 5% to 15.6% with a mean of 8.26% (SD=2.15).
The primary efficacy objective of this study was the sensitivity and specificity of the AEYE-DS device to detect mtmDR on digital funduscopic images, acquired by the Topcon NW400 fundoscopy device, based on two macula-centered images (one image from each eye of the patient).
AEYE-DS correctly identified 53 of the 57 fully analyzable subjects with mtmDR+, thus the sensitivity was 92.98% [CI: 83.30%; 97.24%] with a lower one-sided 97.5% confidence bound of 83.3%, which is higher than the pre-defined performance goal of 82%. Sensitivity was identical when calculated for fundus-based mtmDR+ and for multi-modal mtmDR+. Of the 405 fully analyzable subjects who were mtmDR-, according to the Reading Center diagnosis, 370 subjects were correctly identified by AEYE-DS as mtmDR-, based on fundus images alone. Thus, the specificity is 91.36% [CI: 88.22%; 93.72%] with a lower one-sided 97.5% confidence bound of 88.22%, which is higher than the pre-defined performance goal of 87%. Specificity was almost identical when calculated for multi-modal mtmDR-. Therefore, the null hypotheses for sensitivity and specificity were rejected and it is concluded that the study is deemed successful. Positive Predictive Value (PPV) was 60.23% [CI: 49.78%; 69.82%] and the Negative Predictive Value (NPV) was 98.93% [CI: 97.28%; 99.58%]. The PPV was influenced by the actual prevalence of mtmDR+ patients in the pivotal study diabetic population (i.e., 12.3%), as this was not an enriched study.
Further sub-analyses showed that there were no significant effects of sex, race/ethnicity, HbA1c (10%), age (55 years), diabetic duration since diagnosis (10 years, if available) and lens status on sensitivity and specificity. As sequential enrollment provided a sufficient number of mtmDR+ subjects, enrichment was not performed. Therefore, subset analysis by cohort (not enriched, enriched) was not performed.
The powered secondary endpoint of this study was the sensitivity and specificity of the AEYE-DS device to detect mtmDR from digital funduscopic images, acquired by the Topcon NW400 fundoscopy device, based on four images (one macula centered image and one optic disc centered image per eye). Diagnostic results and AEYE-DS device diagnostic results and showed a sensitivity and specificity of 94.74% [CI: 85.63%; 98.19%] and 88.64% [CI: 85.18%; 91.38%], respectively. The sensitivity is 94.74% with a lower one-sided 97.5% confidence bound of 85.63%, which is higher than the performance goal of 82%, therefore the null hypothesis is rejected in favor of the alternative hypothesis for the sensitivity. The specificity is 88.64% with a lower one-sided 97.5% confidence bound of 85.18%, which is slightly lower than the
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performance goal of 87%, therefore the null hypothesis is not rejected in favor of the alternative hypothesis for the specificity. The Positive Predictive Value (PPV) was 54% [CI: 44.26%; 63.44%] and the Negative Predictive Value (NPV) was 99.17% [CI: 97.59%; 99.72%]. Sensitivity and specificity (and PPV and NPV) results were the same when calculated for fundus-based mtmDR+ and for multi-modal mtmDR+. The sensitivity of the AEYE-DS device based on 4 images passed the study performance goals, but the specificity was slightly lower. The implications of the slightly lower specificity mean that more subjects may be determined to be mtmDR+ and sent for follow-up ophthalmic examinations than necessary. As the sensitivity results were successful and even higher than the sensitivity with 2 images, and true-mtmDR+ subjects will not be missed by the AEYE-DS device, the price of a slightly lower specificity based on 4 images is not too high and does not involve any risks. In any case, as the use of two images is less complicated and time consuming than four images, it is more probable that AEYE-DS device users will rely on the use of 2 (macula-centered) images per eye. For this reason, the Instructions for Use will allow the use of 2 or 4 images per eye to obtain an EYE-DS diagnostic output.
| AEYE-DS Device | ||
|---|---|---|
| 1 image per eye | ||
| (Topcon NW400) | 2 images per eye | |
| (Topcon NW400) | ||
| Sensitivity: | 93% [CI: 83.3%; 97.2%] | 94.7% [CI: 85.6%; 98.2%] |
| Specificity: | 91.4% [CI: 88.2%; 93.7%] | 88.6% [CI: 85.2%; 91.4%] |
| Imageability: | 99.1% [CI: 97.8%; 99.7%] | 99.1% [CI: 97.8%; 99.7%] |
| PPV: | 60.2% [CI: 49.8%; 69.8%] | 54% [CI: 44.3%; 63.4%] |
| NPV: | 99% [CI: 97.3%; 99.6%] | 99.2% [CI: 97.6%; 99.7%] |
Key results from the pivotal study are summarized in the table below.
The imageability results from the pivotal study. reflecting data on the usability in the hands of the study novice operators, reported >99% imageability for the AEYE-DS device using the Topcon NW400 fundoscopy camera. In obtaining 2 sufficient quality images per eye, the vast majority of the study subjects (413 (88%)) did not require pupil dilation in the study, resulting in 91.67% sensitivity and 91.78% specificity, based on 1 image per eye. The endpoint analyses results show that the sensitivity and specificity for non-mydriatic (non-dilated subjects) are almost identical to the pivotal study efficacy results presented for the device. Moreover, it is apparent that only a small percent (~12%) of subjects required pupil dilation in order to obtain a diagnostic output. In this small percent of mydriatic (dilated) subjects, the results showed 100% sensitivity and 87.50% specificity, based on 1 image per eye.
Precision Study
Overall, twenty two (22) participants were included in the final statistical analysis. All 22 participants completed the entire AEYE-DS device imaging protocol and diagnostic output
9
twelve consecutive times, imaged by three different novice operators, using two different Topcon NW400 fundoscopy devices. Overall, 12 image sets/diagnoses were obtained for each participant, for a total of 264 image sets/diagnoses in total. Per protocol, operators allowed subjects at least 8 minutes between successive imaging. The results are presented in the following tables.
Precision Tables based on 1 image per eye:
| Intra-Operator Repeatability | Repeat 2 - mtmDR | ||
|---|---|---|---|
| Repeat 1 - mtmDR | mtmDR + | mtmDR - | Insufficient quality |
| mtmDR + | 49 | 0 | 0 |
| mtmDR - | 2 | 81 | 0 |
| Insufficient quality | 0 | 0 | 0 |
| OA | 98.48% (130/132) [94.64% ;99.58% ] | ||
| APA | 98.00% [93.00% ;99.45% ] | ||
| ANA | 98.78% [95.66% ;99.66% ] | ||
| AUA | Not presented as all cases were of sufficient quality |
| Between
Operator
| Reproducibility | Operator 3 | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Operator 1 | mtmDR + | ||||||||
| Operator 2 | mtmDR - | ||||||||
| Operator 2 | Insufficient quality | ||||||||
| Operator 2 | |||||||||
| mtmDR + | mtmDR - | I Q | mtmDR + | mtmDR - | I Q | mtmDR + | mtmDR - | I Q | |
| mtmDR + | 16 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| mtmDR - | 0 | 1 | 0 | 0 | 27 | 0 | 0 | 0 | 0 |
| Insufficient | |||||||||
| quality | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| OA | 97.73% (43/44) [88.19% ;99.60% ] | ||||||||
| APA | 97.96% [89.31% ;99.64% ] | ||||||||
| ANA | 98.80% [93.49% ;99.79% ] | ||||||||
| AUA | Not presented as all cases were of sufficient quality |
| Between-Device Reproducibility | Device 2 mtmDR | ||
|---|---|---|---|
| Device 1 - mtmDR | mtmDR + | mtmDR - | Insufficient quality |
| mtmDR + | 24 | 1 | 0 |
| mtmDR - | 0 | 41 | 0 |
| Insufficient quality | 0 | 0 | 0 |
| OA | 98.48% (65/66) [91.90% ;99.73% ] | ||
| APA | 97.96% [89.31% ;99.64% ] | ||
| ANA | 98.80% [93.49% ;99.79% ] | ||
| AUA | Not presented as all cases were of sufficient quality |
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Precision Tables based on 2 images per eye:
| Intra-Operator Repeatability | Repeat 2 - mtmDR | ||
|---|---|---|---|
| Repeat 1 - mtmDR | mtmDR + | mtmDR - | Insufficient quality |
| mtmDR + | 56 | 1 | 0 |
| mtmDR - | 3 | 72 | 0 |
| Insufficient quality | 0 | 0 | 0 |
| OA | 96.97% (128/132) [92.47% ;98.82%] | ||
| APA | 96.55% [91.47% ;98.65%] | ||
| ANA | 97.30% [93.26% ;98.94%] | ||
| AUA | Not presented as all cases were of sufficient quality |
| Between
Operator
Reproducibility
| Operator 1 | Operator 3 | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| mtmDR + | |||||||||
| Operator 2 | mtmDR - | ||||||||
| Operator 2 | Insufficient quality | ||||||||
| Operator 2 | |||||||||
| mtmD | |||||||||
| R+ | mtmDR |
- | I
Q | mtmDR
-
| mtmDR
- | I
Q | mtmDR
-
| mtmDR
- | I
Q |
| mtmDR + | 18 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| mtmDR - | 0 | 1 | 0 | 0 | 24 | 0 | 0 | 0 | 0 |
| Insufficient
quality | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| OA | 95.45% (42/44) [84.87% ;98.74% ] | | | | | | | | |
| APA | 96.49% [88.08% ;99.03% ] | | | | | | | | |
| ANA | 97.33% [90.79% ;99.27% ] | | | | | | | | |
| AUA | Not presented as all cases were of sufficient quality | | | | | | | | |
| Between-Device Reproducibility | Device 2 mtmDR | |||
|---|---|---|---|---|
| Device 1 - mtmDR | mtmDR + | mtmDR - | Insufficient quality | |
| mtmDR + | 27 | 1 | 0 | |
| mtmDR - | 2 | 36 | 0 | |
| Insufficient quality | 0 | 0 | 0 | |
| OA | 95.45% (63/66) [87.47% ;98.44% ] | |||
| APA | 94.74% [85.63% ;98.19% ] | |||
| ANA | 96.00% [88.89% ;98.63% ] | |||
| AUA | Not presented as all cases were of sufficient quality |
Human Factors Validation Study
Usability of the AEYE-DS device was also assessed in a human factors validation study, including User Manual comprehension and usability of the device in the hands of potential users. Once the users underwent initial, one-time training and practice, all users stated that the device was easy and straightforward and all were successful in submitting images for diagnosis and obtaining a diagnosis output result and PDF report. All users stated that the user manual was clear and easy to use.
In summary, the AEYE-DS device using 2 or 4 images acquired from the Topcon NW400 fundoscopy device demonstrates successful performance, in terms of sensitivity, specificity, PPV and NPV, as well as imageability, usability, and precision.
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Substantial Equivalence:
The subject AEYE-DS device, manufactured by AEYE Health Inc., is substantially equivalent to the cleared IDx-DR device (manufactured by IDx LLC and the subject of De Novo DEN180001).
| Technological
Characteristic | AEYE-DS Device | IDx-DR Device
(DEN180001) |
|---------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Product Code,
Class | PIB
Class II | PIB
Class II |
| Indications for
Use | The AEYE-DS is indicated for use by
health care providers to automatically
detect more than mild diabetic
retinopathy (mtmDR) in adults
diagnosed with diabetes who have not
been previously diagnosed with
diabetic retinopathy. The AEYE-DS is
indicated for use with the Topcon
NW400. | IDx-DR is indicated for use by health
care providers to automatically detect
more than mild diabetic retinopathy
(mtmDR) in adults diagnosed with
diabetes who have not been previously
diagnosed with diabetic retinopathy.
IDx-DR is indicated for use with the
Topcon NW400. |
| Target Population | Adult subjects diagnosed with Diabetes | Adult subjects diagnosed with Diabetes |
| Anatomical Sites | Eye examination | Eye examination |
| Environment
Used | Hospitals, Clinics | Hospitals, Clinics |
| Energy Used /
Delivered | Not Applicable | Not Applicable |
| Design: | A fundus camera is attached to a
computer, where the AEYE-DS Client
module is installed. The Client module
allows the user to interact with the
server-based analysis software over a
secure internet connection. Using the
Client module, users identify one
(macular) or two (macular and disc)
fundus images per eye to be dispatched
to the Service module. The Service is
installed on a server hosted at a secure
datacenter. The Analytics module,
which runs alongside the Service
module, processes the fundus images
and returns information on the image
quality and the presence or absence of
mtmDR to the Service module. The
Service then returns the results to the
Client module. | A fundus camera is attached to a
computer, where the Idx-DR Client
software is installed. The Client
software allows the user to interact with
the server-based analysis software over
a secure internet connection. Using the
Client software, users identify two
fundus images per eye to be dispatched
to Idx-Service. Idx-Service is installed
on a server hosted at a secure
datacenter. Idx-DR Analysis, which
runs inside Idx-Service, processes the
fundus images and returns information
on the image quality and the presence or
absence of mtmDR to Idx-Service. Idx-
Service then returns the results to the
Idx-DR Client. |
| Technological
Characteristic | AEYE-DS Device | IDx-DR Device
(DEN180001) |
| -Mechanism of
Action | Artificial Intelligence software as a
medical device | Artificial Intelligence software as a
medical device |
| - Components | The AEYE-DS device consists of the
following components:
- Client software on computer
connected to fundoscopy camera - Server including Service software and
Analytics software | The Idx-DR device consists of the
following components: - Client software on computer
connected to fundoscopy camera - Server including Service software and
Analytics software |
| - Inputs | Macula and disc centered color fundus
images with at least 45° field of view, 2
images per eye; Or
Macula centered color fundus images
with at least 45° field of view, 1 image
per eye. | Macula and disc centered color fundus
images with 45° field of view, 2 images
per eye |
| - Outputs | More than mild diabetic retinopathy
(mtmDR) detected, not detected or
insufficient quality | More than mild diabetic retinopathy
(mtmDR) detected, not detected or
insufficient quality |
| - Indicated
Cameras | Topcon NW400 camera | Topcon NW400 camera |
| - Minimum image
size | 1000 x 1000 pixels per image | 1000 x 1000 pixels per image |
| Performance | 1 image per eye (Topcon NW400)
Sensitivity: 93% [CI: 83.3%; 97.2%]
Specificity: 91.4% [CI: 88.2%;
93.7%]
Imageability: 99.1% [CI: 97.8%;
99.7%]
PPV: 60.2% [CI: 49.8%; 69.8%]
NPV: 99% [CI: 97.3%; 99.6%] | 1 image per eye (Topcon NW400)
NOT APPLICABLE |
| | 2 images per eye (Topcon NW400)
Sensitivity: 94.7% [CI: 85.6%;
98.2%]
Specificity: 88.6% [CI: 85.2%;
91.4%]
Imageability: 99.1% [CI: 97.8%;
99.7%]
PPV: 54% [CI: 44.3%; 63.4%]
NPV: 99.2% [CI: 97.6%; 99.7%] | 2 images per eye (Topcon NW400)
Sensitivity: 87.4% (95%CI, 81.9% -
92.9%).
Specificity: 89.5% (95% CI, 86.9%-
93.1%)
Imageability: 96%
PPV (Positive Predictive Value): 73%
NPV (Negative Predictive Value): 96% |
| Technological
Characteristic | AEYE-DS Device | IDx-DR Device
(DEN180001) |
| Human Factors | The AEYE-DS device uses the Client
module as the user interface. The safe
and efficient use of the device was
established in a Usability study with
novice operators. | The IDx-DR device uses the Client
software as the user interface. The safe
and efficient use of the device was
established in a Usability study with
novice operators. |
| Standards Met | IEC 62304 and
FDA Guidance for the Content of
Premarket Submissions for Software
Contained in Medical Devices
ISO 14971
FDA Guidance - Content of Premarket
Submissions for Management of
Cybersecurity in Medical Devices | FDA Guidance for the Content of
Premarket Submissions for Software
Contained in Medical Devices
ISO 14971
FDA Guidance - Content of Premarket
Submissions for Management of
Cybersecurity in Medical Devices |
| Materials | No patient contacting materials | No patient contacting materials |
| Biocompatibility | Not Applicable | Not Applicable |
| Compatibility
With the
Environment and
Other Devices | The AEYE-DS device is compatible for
use with the Topcon NW400 device.
Compatibility with the environment is
not applicable. | The IDx-DR device is compatible for
use with the Topcon NW400 device.
Compatibility with the environment is
not applicable. |
| Sterility | Not Applicable | Not Applicable |
| Electrical Safety | Not Applicable | Not Applicable |
| Mechanical Safety | Not Applicable | Not Applicable |
| Chemical Safety | Not Applicable | Not Applicable |
| Thermal Safety | Not Applicable | Not Applicable |
| Radiation Safety | Not Applicable | Not Applicable |
Table 1: Comparison of the AEYE-DS Device to the predicate IDx-DR Device (DEN180001)
12
13
Conclusions:
The subject AEYE-DS device, manufactured by AEYE Health Inc., is substantially equivalent to the cleared IDx-DR device (manufactured by IDx LLC and the subject of De Novo DEN180001).
The subject AEYE-DS device has the same intended use and indications for use as the cleared IDx-DR device. The subject device and the cleared IDx-DR device are similar in terms of their intended prescription use only, suitable for the adult population diagnosed with diabetes, indicated for use in the same anatomical site (i.e., for eye examinations) and to be used in hospital or clinic settings..
The subject AEYE-DS and cleared IDx-DR devices are composed of the same components,
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including a Client module, and a Server including the Service and Analytics modules. The AEYE- DS and the IDx-DR devices are both compatible for use with the Topcon NW400 device. The subject AEYE-DS device has the same mechanism of operation and uses the same underlying technology as the predicate IDx-DR device. That is, a user interface Client module communicates with the Server, where the fundus images (one macular and one disc centered image per eye) are received and analyzed in the Analytics module to provide information regarding the presence or absence of mtmDR, which is returned to the Client module. The only difference in the mechanism of action is the additional ability of the AEYE-DS device to receive only one (macular) fundus image per eye and process these images to return similar information on the presence or absence of mtmDR. Both the AEYE-DS (whether based on 1 or 2 images per eye) and the IDx-DR device are based on Artificial Intelligence (AI) software as a medical device.
The performance characteristics, including the sensitivity, specificity, imageability, PPV and NPV of the AEYE-DS device are substantially equivalent to the cleared IDx-DR device, whether based on 1 or 2 images per eye, as demonstrated in the clinical studies performed with the AEYE-DS device. The human factors incorporated into the subject AEYE-DS device and the cleared IDx- DR device are similar. Both devices use the Client module as the user interface and the safe and efficient use of the device was established in a Usability study with novice operators for both devices. The subject device, as the cleared device, complies with same relevant consensus standards and FDA guidance document requirements, including software validation, cybersecurity and risk analysis.
Consequently, it can be concluded that the subject AEYE-DS device is substantially equivalent to the predicate IDx-DR device, approved in De Novo DEN18001 and therefore, the AEYE-DS device may be legally marketed in the USA.