IDx-DR v2.3

{0}------------------------------------------------ Image /page/0/Picture/0 description: The image shows the date June 17, 2022. The text is written in a clear, sans-serif font. The date is formatted with the month, day, and year. The text is centered and takes up most of the image. Image /page/0/Picture/1 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue. Digital Diagnostics Inc. % Kelliann Payne Partner Hogan Lovells US LLP 1735 Market St., Floor 23 Philadelphia, Pennsylvania 19103 Re: K213037 Trade/Device Name: IDx-DR v2.3 Regulation Number: 21 CFR 886.1100 Regulation Name: Retinal Diagnostic Software Device Regulatory Class: Class II Product Code: PIB Dated: September 21, 2021 Received: May 17, 2022 Dear Kelliann Payne: 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. 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You must comply with all the Act's {1}------------------------------------------------ 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 mediation-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 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 {2}------------------------------------------------ # Indications for Use 510(k) Number (if known) K213037 Device Name IDx-DR v2.3 Indications for Use (Describe) IDx-DR is indicated for use by healthcare providers to automatically detect more than mild diabetic retimopathy (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. | <b>Type of Use (Select one or both, as applicable)</b> | |--------------------------------------------------------| |--------------------------------------------------------| | <div style="display:inline-block"><span style="font-size: 20px; vertical-align: middle;">☒</span> Research Use (21 CFR 201.320(b))</div> | <div style="display:inline-block"><span style="font-size: 20px; vertical-align: middle;">☐</span> Over-The-Counter Use (21 CFR 201.66)</div> | |------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------| |------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------| > Prescription Use (Part 21 CFR 801 Subpart D) __ Over-The-Counter Use (21 CFR 801 Subpart C) ### CONTINUE ON A SEPARATE PAGE IF NEEDED. 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Submitter Digital Diagnostics Inc. 2300 Oakdale Blvd. Coralville, IA 52241 Phone: 319-248-5620 Contact Person: Ashley Miller Date Prepared: June 14, 2022 #### II. Device Name of Device: IDx-DR v2.3 Common or Usual Name: Diabetic Retinopathy Detection Device Classification Name: Retinal diagnostic software device Regulatory Class: II Regulation: 21 CFR 886.1100 Product Code: PIB #### III. Device Description The IDx-DR device is an autonomous, artificial intelligence (AI)-based system for the automated detection of more than mild diabetic retinopathy (mtmDR). It consists of several component parts (see Figure 1 below). The component parts of IDx-DR are summarized as follows: - IDx-DR Analysis: Software that analyzes the patient's images and determines ● exam quality and the presence/absence of mtmDR. - . IDx-DR Client: A software application component running on a computer, usually connected to the fundus camera, at the user site. Using this software, the user can transfer images to IDx-DR Analysis via IDx-DR Service and receive results back. - . IDx-DR Service: IDx-DR Service comprises a general exam analysis service delivery software package. IDx-DR Service contains a webserver front-end that securely handles incoming requests, a database that stores user information, and a logging system that records information about each transaction through IDx-DR Service. IDx-DR Service is also primarily responsible for device cybersecurity. The Topcon NW400 fundus camera is attached to a computer, where IDx-DR Client is installed. Guided by the IDx-DR Client, end-users acquire two fundus images per eye to {4}------------------------------------------------ be dispatched to IDx-DR Service. IDx-DR Service is installed on a server hosted at a secure datacenter. From IDx-DR Service, images are transferred to IDx-DR Analysis System. No information other than the fundus images is required to perform the analysis. IDx-DR Analysis System, which runs on dedicated servers hosted in the same secure datacenter as IDx-DR Service, processes the fundus images and returns information on the exam quality and the presence or absence of more than mild diabetic retinopathy (mtmDR) to IDx-DR Service. IDx-DR Service then transports the results to the IDx-DR Client that displays them to the user. Image /page/4/Figure/2 description: This image shows a diagram of the IDx secure server system. The diagram shows the flow of data from the patient and camera to the IDx-DR client on the customer's computer. The exam images are then sent to the IDx web service on the IDx secure servers, where they are analyzed by the IDx-DR analysis software. The results are then sent back to the IDx-DR client on the customer's computer. Figure 1: IDx-DR Components #### IV. Indications for Use IDx-DR is indicated for use by healthcare 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. #### V. Predicate Device IDx-DR, Diabetic Retinopathy Detection Device, K203629 This predicate has not been subject to a design-related recall. No reference devices were used in this submission. #### VI. Purpose of Submission The purpose of this 510(k) submission is to modify the following: the image quality classifier of the IDx-DR Analysis System, from version 2.1.1 to 2.3.0; update IDx-DR Service from version 1.1.2 to 1.2.0; and update IDx-DR Client from v3.3.0 to v3.5.0. {5}------------------------------------------------ #### VII. Comparison of Technological Characteristics with the Predicate Device The main technological principle for both the subject and predicate devices is Al-based technology to analyze specific pathologic features from fundus retinal images. The subject device has the same intended use and indications for use as those cleared under K203629. The major technological differences that exist between each component of the subject and predicate devices are described below. # IDx-DR Service - Updated to look up the IDx-DR Analysis System version and sends it to IDx-DR Client for display on the user interface. # IDx-DR Client - Updated to provide clear language of "exam completed" after repeated imaging . attempts have resulted in an insufficient image quality output. The result output and report will remain unchanged, indicating exam quality was insufficient and a diagnostic result is not provided. - . Updated to visually communicate image quality feedback by adding a green checkmark or a red "X" to images on the submission feedback screen. ## IDx-DR Analysis System - . The image quality classifier of the subject device was replaced with a new image quality classifier. - Updated to improve the speed of the device. . Table 1 provides a comparison between the technical characteristics and indications for use of the subject and predicate devices. | | Subject Device<br>IDx-DR v2.3 | Predicate Device<br>IDx-DR v2.0, K203629 | Discussion | |-----------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------| | Component<br>Software<br>Versions | IDx-DR Client v3.5.0<br>IDx-DR Analysis System v2.3.0<br>IDx-DR Service v1.2.0 | IDx-DR Client v3.2.0<br>IDx-DR Analysis System v2.1.1<br>IDx-DR Service v1.1.2 | See above for the<br>major<br>technological<br>differences<br>between each<br>component of the<br>subject and<br>predicate device. | | Technological<br>Principle | Artificial intelligence<br>software as a medical device. | Artificial intelligence<br>software as a medical device. | Equivalent | | | Subject Device<br>IDx-DR v2.3 | Predicate Device<br>IDx-DR v2.0, K203629 | Discussion | | Indications for Use | For use by healthcare<br>providers to automatically<br>detect more than mild diabetic<br>retinopathy in adults<br>diagnosed with diabetes who<br>have not been previously<br>diagnosed with diabetic<br>retinopathy. | For use by healthcare<br>providers to automatically<br>detect more than mild diabetic<br>retinopathy in adults<br>diagnosed with diabetes who<br>have not been previously<br>diagnosed with diabetic<br>retinopathy. | Equivalent | | Indicated<br>Camera | Topcon NW400 fundus<br>camera | Topcon NW400 fundus<br>camera | Equivalent | | Inputs | Macula- and disc-centered<br>color fundus images with 45°<br>field of view, 2 per eye. | Macula- and disc-centered<br>color fundus images with 45°<br>field of view, 2 per eye. | Equivalent | | Outputs | Detection of diabetic<br>retinopathy and referral<br>decision:<br>• mtmDR detected: Refer to<br>an eye care professional<br>• mtmDR not detected:<br>Rescreen in 12 months<br>• Insufficient image quality | Detection of diabetic<br>retinopathy and referral<br>decision:<br>• mtmDR detected: Refer to<br>an eye care professional<br>• mtmDR not detected:<br>Rescreen in 12 months<br>• Insufficient image quality | Equivalent | | Architecture | User facing client software<br>transfers images to and<br>receives results from analysis<br>software through a web<br>server. | User facing client software<br>transfers images to and<br>receives results from analysis<br>software through a web<br>server. | Equivalent | | Workflow | The graphical user interface<br>includes on-screen prompts to<br>guide the user through the<br>image acquisition workflow<br>one image at a time and<br>submission of the exam | The graphical user interface<br>includes on-screen prompts to<br>guide the user through the<br>image acquisition workflow<br>one image at a time and<br>submission of the exam. | Equivalent | ## Table 1: Comparison of the Subject and Predicate Device {6}------------------------------------------------ ## VIII. Performance Data The following performance data were provided in support of the substantial equivalence determination. # A. Summary of Non-clinical Studies IDx-DR was identified as having a major level of concern as defined in the FDA guidance document Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices. The software documentation includes: {7}------------------------------------------------ - 1. Software/Firmware Description - 2. Device Hazard Analysis - 3. Software Requirement Specifications - 4. Architecture Design Chart - 5. Software Design Specifications - 6. Traceability - 7. Software Development Environment Description - 8. Verification and Validation Documentation - 9. Revision Level History - 10. Unresolved Anomalies - 11. Cybersecurity A comprehensive risk analysis was performed on IDx-DR with identification and detailed description of the hazards, their causes and severity, as well as acceptable methods for control of the identified hazards. A description of acceptable verification and validation activities, at the unit, integration, and system level, including test protocols with pass/fail criteria and a report of the results, was provided. The expected impact of various hardware features on performance was assessed and minimum specifications for acceptable images for analysis were specified. The cybersecurity considerations of data confidentiality, data integrity, data availability, denial of service attacks, and malware were adequately addressed utilizing platform controls, application controls, and procedure controls, and evidence was provided for the intended performance of the controls. Risks related to failure of various software components and their potential impact on patient reports and operator failures were also adequately addressed in the risk analysis. This software documentation information provided sufficient evidence of safe and effective software performance. A full characterization of the technical parameters of all of the components of the software, including a description of the algorithms that analyzes the patient's images to determine exam quality and the diagnostic screening of diabetic retinopathy, has been provided. IDx-DR requires one optic disc-centered image and one macula centered image from a fundus camera with at least 22 pixels per degree on the retina. So, a 1000 pixel field of view diameter for a 45 degree field of view image. The IDx-DR artificial intelligence device design has the ability to perform analysis on the specific disease features that are important to a retina specialist for diagnostic screening of diabetic retinopathy. Future algorithm improvements will be made under a consistent medically relevant framework. A protocol was provided to mitigate the risk of algorithm changes leading to changes in the device technical specifications, which would lead to changes in false positive or false negative results. These changes could significantly affect clinical functionality or performance specifications directly associated with the intended use of the device. The protocol specifies the level of change in device {8}------------------------------------------------ specifications that could significantly affect the safety or effectiveness of the device, triggering the requirement for a new 510(k) premarket notification submission before commercial introduction. The protocol incorporates a risk management approach and other approaches provided in the FDA guidance document Deciding When to Submit a 510(k) for a Software Change to an Existing Device: Guidance for Industry and FDA Staff in development, validation, and execution of the device changes. ### Usability Usability validation testing was performed under simulated-use to assess the user interface (IDx-DR Client) of the subject device. The testing was performed in an environment equivalent to the intended use environment of IDx-DR with subjects that had no prior experience using the IDx-DR Client. The critical task for the IDx-DR system is the ability to capture four images of sufficient quality. The purpose of the usability validation test plan was to demonstrate that the intended image capture workflow and training methodology can successfully be used by the intended operators to capture four retinal images. The results of the usability validation study indicated that no existing critical tasks were impacted by the modification and no new critical tasks were introduced, and demonstrated that previously untrained camera operators could capture four retinal images of sufficient quality following the imaging protocol and using the indicated camera system and standardized training and operating materials. ### B. Summary of Clinical Performance Testing A retrospective study was conducted to validate the clinical performance of the modified IDx-DR ("IDx-DR v2.3). Data previously collected from the pivotal study of the predicate ("IDx-DR v2.0"; Abràmoff et al. Digital Medicine 2018;1:39) was analyzed to evaluate the performance of the upgraded Analysis component. The three co-primary endpoints are sensitivity, specificity, and "diagnosability" (the proportion of evaluated participants for whom IDx-DR returns a diagnostic result). The secondary endpoints are positive predictive value (PPV) and negative predictive value (NPV). Data from the 892 participants evaluated during the pivotal study were used to evaluate the modified algorithm; of these, images from 850 participants were available for analysis and diagnosable by the clinical reference standard, thus were evaluable for performance. Of the "first submission" images (i.e., first images taken and without pharmacologic pupil dilation), IDx-DR v2.3 was able to analyze images from 552 of the 850 participants (64.9%) and IDx-DR v2.0 was able to analyze images from 533 of the 850 subjects (62.7%). Of the "final submission" images (after following the as-needed pharmacologic pupil dilation image acquisition protocol), IDx-DR v2.3 was able to analyze images from 809 of the 850 participants (95.2%) and IDx-DR v2.0 was able to analyze images from 819 of the 850 participants (96.4%). {9}------------------------------------------------ Table 2 presents the diagnosability for participants who were diagnosable by both the subject and predicate devices based on images from the "first" and "final submission" for each participant from the pivotal study. | Table 2: Diagnosability Results for the Subject and Predicate Devices Based on First | | | |--------------------------------------------------------------------------------------|---------------------------------------|---------------------------------| | and Final Submissions | | | | Characteristic | Pivotal Study Device<br>(IDx-DR v2.0) | Subject Device<br>(IDx-DR v2.3) | | Diagnosability of first<br>submission images<br>Point Estimate | 62.71% (533/850) | 64.94% (552/850) | | 95% Confidence Interval1 | (59.40%, 65.89%) | (61.67%, 68.08%) | | Diagnosability of final<br>submission images<br>Point Estimate | 96.35% (819/850) | 95.18% (809/850) | | 95% Confidence Interval2 | (94.86%, 97.51%) | (93.51%, 96.52%) | 1 Calculated using the modified Wald method 2 Calculated using an exact binomial model Table 3 presents the sensitivity and specificity for participants who were diagnosable by both the subject and predicate devices based on images from the "final submission" for each participant from the pivotal study. ## Table 3: Performance Results for the Subject and Predicate Devices Based on Final Submissions | Characteristic | Pivotal Study Device<br>(IDx-DR v2.0) | Subject Device<br>(IDx-DR v2.3) | |--------------------------------|---------------------------------------|---------------------------------| | Sensitivity*<br>Point Estimate | 87.37% (173/198) | 87.69% (171/195) | | 95% Confidence Interval¹ | (81.93%, 91.66%) | (82.24%, 91.95%) | | Specificity*<br>Point Estimate | 89.53% (556/621) | 90.07% (553/614) | | 95% Confidence Interval¹ | (86.85%, 91.83%) | (87.42%, 92.32%) | ¹ Calculated using an exact binomial model *Excludes exam quality insufficient images, 31 for IDx-DR v2.0, 41 for IDx-DR v2.3 Table 4 presents the PPV and NPV for participants who were diagnosable by both the subject and predicate devices based on images from the "final submission" for each subject from the pivotal study. {10}------------------------------------------------ | Characteristic | Pivotal Study Device<br>(IDx-DR v2.0) | Subject Device<br>(IDx-DR v2.3) | |---------------------------------------------|---------------------------------------|---------------------------------| | Positive Predictive Value<br>Point Estimate | 72.69% (173/238) | 73.71% (171/232) | | 95% Confidence Interval1 | (66.56%, 78.25%) | (67.55%, 79.25%) | | Negative Predictive Value<br>Point Estimate | 95.70% (556/581) | 95.84% (553/577) | | 95% Confidence Interval1 | (93.71%, 97.20%) | (93.87%, 97.32%) | ### Table 4: Secondary Performance for the Subject and Predicate Devices Based on Final Submissions 1 Calculated using an exact binomial model Additional analyses were performed to include submissions that were non-diagnosable by the respective version of IDx-DR but were diagnosable by the reference standard. Table 5 presents the worst-case imputations for IDx-DR v2.0 and IDx-DR v2.3 based on images from the final submission for each participant from the pivotal study, wherein the non-diagnosable submissions are assumed to have IDx-DR results disagreeing with the reference standard. | Characteristic | Pivotal Study Device<br>(IDx-DR v2.0) | Subject Device<br>(IDx-DR v2.3) | |---------------------------|---------------------------------------|---------------------------------| | Sensitivity | | | | Point Estimate | 85.22% (173/203) | 84.24% (171/203) | | 95% Confidence Interval1 | (79.58%, 89.80%) | (78.48%, 88.96%) | | Specificity | | | | Point Estimate | 85.94% (556/647) | 85.47% (553/647) | | 95% Confidence Interval1 | (83.02%, 88.52%) | (82.52%, 88.10%) | | Positive Predictive Value | | | | Point Estimate | 65.53% (173/264) | 64.53% (171/265) | | 95% Confidence Interval1 | (59.46%, 71.25%) | (58.44%, 70.29%) | | Negative Predictive Value | | | | Point Estimate | 94.88% (556/586) | 94.53% (553/585) | | 95% Confidence Interval1 | (92.77%, 96.52%) | (92.37%, 96.23%) | Table 5: Worst-Case Final Submission Performance by IDx-DR Device Version 1 Calculated using an exact binomial model Table 6 presents the best-case imputations for IDx-DR v2.0 and IDx-DR v2.3 based on images from the final submission for each participant from the pivotal study, wherein the non-diagnosable submissions are assumed to have IDx-DR results agreeing with the reference standard. {11}------------------------------------------------ | Characteristic | Pivotal Trial Device<br>(IDx-DR v2.0) | Subject Device<br>(IDx-DR v2.3) | |---------------------------|---------------------------------------|---------------------------------| | Sensitivity | | | | Point Estimate | 87.68% (178/203) | 88.18% (179/203) | | 95% Confidence Interval1 | (82.36%, 91.87%) | (82.92%, 92.28%) | | Specificity | | | | Point Estimate | 89.95% (582/647) | 90.57% (586/647) | | 95% Confidence Interval1 | (87.37%, 92.16%) | (88.05%, 92.71%) | | Positive Predictive Value | | | | Point Estimate | 73.25% (178/243) | 74.58% (179/240) | | 95% Confidence Interval1 | (67.22%, 78.71%) | (68.58%, 79.97%) | | Negative Predictive Value | | | | Point Estimate | 95.88% (582/607) | 96.07% (586/610) | | 95% Confidence Interval1 | (93.98%, 97.32%) | (94.20%, 97.46%) | Table 6: Best-Case Final Submission Performance by IDx-DR Device Version ¹Calculated using an exact binomial model The results of the clinical study support a determination of substantial equivalence between IDx-DR v2.3 and IDx-DR v2.0. #### IX. Conclusions The modified IDx-DR device is substantially equivalent to the predicate IDx-DR device cleared under K203629. The modifications do not raise new questions of safety and effectiveness of the device. The subject and predicate devices have the same indications for use, technological characteristics, and performance specifications.