A Multi-center Study to Evaluate Performance of an Automated Device for the Detection of Diabetic Retinopathy

From January 2017 to July 2017, 900 participants were prospectively enrolled in this observational study at 10 primary care practice sites throughout the United States. The study was approved by the institutional review board for each site, and all participants provided written informed consent. The study, which was funded by IDx LLC, was designed by the authors with input from the U.S. Food and Drug Administration (FDA) on the endpoints, statistical testing, and study design. Emmes Corp, a contract research organization (CRO), provided overall project management, including data management and independent monitoring and auditing services for all sites. CCR, Inc., an Algorithm Integrity Provider (AIP), was contracted to lock the AI system, hold any intermediate and final results and images in escrow, and interdict access to these by the Sponsor, from prior to the start of the study until final data lock. Because the Sponsor was thus interdicted from access to the AI system, the AIP performed all necessary maintenance and servicing activities during the study as well as throughout closeout.

The target population was asymptomatic persons, ages of 22 and older, who had been diagnosed with diabetes and had not been previously diagnosed with DR. A diagnosis of diabetes was defined as meeting the criteria established by either the World Health Organization (WHO) or the American Diabetes Association (ADA); Hemoglobin A1c (HbA1c) ≥ 6.5% based on repeated assessments; Fasting Plasma Glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L) based on repeated assessments; Oral Glucose Tolerance Test (OGTT) with two-hour plasma glucose (2-hr PG) ≥ 200 mg/dL (11.1 mmol/L) using the equivalent of an oral 75 g anhydrous glucose dose dissolved in water; or symptoms of hyperglycemia or hyperglycemic crisis with a random plasma glucose (RPG) ≥ 200 mg/dL (11.1 mmol/L).

To help enroll a sufficient number of mtmDR participants for the evaluation of sensitivity, a stepwise enrichment strategy, as indicated in the prespecified protocol, was utilized mid-study to recruit sufficient numbers of mtmDR participants. The enrichment strategy sought higher risk participants with elevated HbA1c (>9.0%) levels or elevated Fasting Plasma Glucose; this enrichment was independently activated by the statistician while always remaining masked to the AI system outputs and the ETDRS disease levels. To account for any unintentional spectrum bias in the no/mild population, the study pre-defined a specificity outcome parameter to correct for any potential spectrum bias resulting from this enrichment strategy as co-primary.

All primary care sites in the study identified one or more inhouse operator trainees to perform the AI system protocol. After installation of the equipment by the Sponsor at the site, but before any participant was recruited, AI system operator trainees had to attest that they had not previously performed ocular imaging. Also, before start of study recruitment at each site, AI system operator trainees underwent a one-time standardized 4 h training program. They were trained how to acquire images, how to improve image quality if the AI system gave an insufficient quality output, and how to put images for analysis into the AI system. No additional training was provided to any of the AI system operators for the duration of the study. Independently, FPRC certified expert photographers were identified in geographic locations close to each site by the CRO, and documented 4W-D FPRC certification was required before any participant was imaged. The CRO independently completed site initiation visits at each site to ensure each site met all the good clinical practice requirements prior to start of enrollment.

Study protocol. All participants gave written informed consent to participate in both the AI system protocol, as well as the FPRC imaging protocol, using two different cameras: