A Multi-center Study to Evaluate Performance of an Automated Device for the Detection of Diabetic Retinopathy
Conditions: Diabetic Retinopathy
Sponsor: Digital Diagnostics, Inc.

 
 
IDX-DR1 PROTOCOL  
 
 
IDX, LLC 
 
 
 
Clinical Study Protocol 
TITLE: A MULTICENTER STUDY TO EVALUATE PERFORMANCE OF AN AUTOMATED 
DEVICE FOR THE DETECTION OF DIABETIC RETINOPATHY  
Protocol Number: 
IDx-DR1 
Version: 
2 
Version Date: 
August 17, 2017 
Investigational Product: 
IDx-DR 
IDE Number: 
IDE exempt; subject to abbreviated requirements under 21 CFR 
812.2(b) 
Sponsor: 
IDx, LLC  
485 Hwy 1 W  
Iowa City IA 52246 
Funding Organization: 
IDx, LLC 
Regulatory Consultant 
 
Study Statistician:  
 
Contract Research 
Organization: 
 
Photographic Reading 
Center: 
 
Study Chair & Medical 
Monitor: 
Michael Abramoff, MD, PhD 
 
 
 

 
 
PROTOCOL SYNOPSIS 
TITLE 
A MULTICENTER STUDY TO EVALUATE PERFORMANCE OF AN 
AUTOMATED DEVICE FOR THE DETECTION OF DIABETIC 
RETINOPATHY  
SPONSOR 
IDx LLC 
NUMBER OF SITES 
Up to 15 
RATIONALE 
Diabetes affects 29.1 million people or 9.3% of the population of 
the United States. Results of a study by the Eye Diseases Prevalence 
Research Group reveal that 40% of diabetes patients have some degree 
of diabetic retinopathy (DR) and that as many as 8% have severe, 
vision-threatening forms of DR. Early laser photocoagulation in high-risk 
proliferative diabetic retinopathy (PDR) has been shown to decrease the 
relative risk of vision loss by as much as 52%. Injections of anti-VEGF 
agents in multiple clinical trials have been shown to preserve and 
improve vision in people with PDR and/or diabetic macular edema. 
Despite effective treatment however, tens of thousands of people with 
diabetes are going blind each year largely because they don’t undergo 
annual screening for retinopathy. Currently, only about 60% of people 
with diabetes have a yearly eye exam and there may not be enough 
eye specialists to see the balance. 
 
To address the issue of patient compliance with diabetic retinopathy 
screening, IDx-DR was developed as an automated screening device 
designed to analyze fundus images for the presence of lesions and other 
disease features associated with diabetic retinopathy. This study has 
been designed to validate the safety and efficacy of the device at the 
frontlines of healthcare.  
STUDY DESIGN 
Multicenter Observational Study 
DEVICE 
IDx-DR is a software device intended for use by health care providers to 
screen for more than mild diabetic retinopathy (mtmDR) in adult (22 
years of age or older) people with diabetes who have not been 
previously diagnosed with diabetic retinopathy. The device is indicated 
for use with fundus photographs obtained by the Topcon NW400. A 
result of mtmDR indicates a high risk of moderate non-proliferative 
retinopathy, severe non-proliferative retinopathy (NPDR), proliferative 
retinopathy (PDR), and/or macular edema.   
PRIMARY OBJECTIVE 
To demonstrate the sensitivity and specificity of IDx-DR’s automated 
image analysis for mtmDR when used by health care providers to screen 
for mtmDR in adults (22 years of age or older) diagnosed with diabetes 
who have not been previously diagnosed with diabetic retinopathy.  
NUMBER OF SUBJECTS 
845 subjects after exclusions 
 
 
 
 
 

 
 
TITLE 
A MULTICENTER STUDY TO EVALUATE PERFORMANCE OF AN 
AUTOMATED DEVICE FOR THE DETECTION OF DIABETIC 
RETINOPATHY  
ENDPOINTS 
Sensitivity and Specificity of IDx-DR, analysis per SAP  
SUBJECT ELIGIBILITY 
CRITERIA 
Participant Inclusion Criteria:  
1. Documented diagnosis of diabetes mellitus, e.g.: 
a. Having met the criteria established by either the World 
Health Organization (WHO) or the American Diabetes 
Association (ADA) 
b. Hemoglobin A1c (HbA1c) ≥ 6.5% 
c. Fasting Plasma Glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L) 
d. 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 
e. Symptoms of hyperglycemia or hyperglycemic crisis with 
a random plasma glucose (RPG) ≥ 200 mg/dL (11.1 
mmol/L)  
2. Age 22 or older 
3. Understand the study and volunteer to sign the informed consent 
 
Participant Exclusion Criteria:  
1. Persistent vision loss, blurred vision, or floaters. 
2. Diagnosed with macular edema, severe non-proliferative 
retinopathy, proliferative retinopathy, radiation retinopathy, or 
retinal vein occlusion. 
3. History of laser treatment of the retina or injections into either eye, 
or any history of retinal surgery.  
4. Currently participating in another investigational eye study and 
actively receiving investigational product for DR or DME. 
5. Participant has a condition that, in the opinion of the investigator, 
would preclude participation in the study (e.g., unstable medical 
status 
including 
blood 
pressure 
or 
glycemic 
control, 
microphthalmia or previous enucleation). 
6. Participant is contraindicated for imaging by fundus imaging 
systems used in the study: 
o 
Participant is hypersensitive to light 
o 
Participant recently underwent photodynamic therapy 
(PDT) 
o 
Participant 
is 
taking 
medication 
that 
causes 
photosensitivity 
 
 

 
 
I. 
BACKGROUND 
Diabetic retinopathy (DR) is the most common cause of blindness in the working population of the 
United States [1]. Each year, DR leads to more than 24,000 cases of preventable blindness in the 
United States. An estimated 4.1 million and 899,000 Americans are affected by retinopathy and 
vision-threatening retinopathy, respectively [2].  
Early detection of DR can prevent vision loss and blindness [3-7]; however, a large portion of 
individuals with diabetes do not currently undergo any DR screening. With the prevalence of 
diabetes expected to increase 50% over the next 10 years, screening rates, detection, and treatment 
must be addressed in order to prevent a significant increase in unnecessary blindness across the 
United States [8-10].  
A recent publication [11] reviewed the key research related to eye screening rates for people with 
diabetes, and concluded that screening rates remain poor. A 1990 program launched by the 
American Academy of Ophthalmology (AAO), known as Diabetes 2000, was designed to increase 
nationwide DR screening rates. However, after 20 years of implementation, screening rates continue 
to stagnate, with only 50-60% of diabetic patients properly evaluated [11]. In addition, specific 
disadvantaged groups have increased prevalence of diabetic retinopathy, where low rates of DR 
screening are at least partially associated with lack of access to a specialist exam [12]. A DR 
screening solution at the point of primary care is expected to help address the unmet need, lack of 
access, and racial and ethnic disparity issues that have persisted for decades. 
Some improved compliance with AAO defined screening recommendations has already been 
enabled by telemedicine, a practice associated with reduced incidence of blindness [13]. In a recent 
prospective randomized study of telemedicine, availability of telemedicine resulted in a 50% increase 
in screening compliance [14]. However, implementation of telemedicine requires readers, who 
introduce variability across inter-observer and intra-observer measures. Telemedicine also presents 
issues with training and reader turnover, economic feasibility challenges, IT infrastructure barriers, 
as well as the potential for substantial delay between imaging and the availability of results (often a 
time period of days or weeks) [15].  
An automated screening device would allow for immediate screening results at the point of care, 
standardization of results, and elimination of most overhead costs associated with telemedicine. 
Leaders in the ophthalmic community report that an automated diabetic retinopathy screening device 
in the hands of front line providers would increase screening rates and detect more treatable vision 
threatening retinopathy [14].  
II. 
STUDY RATIONALE 
Diabetes affects 29.1 million people or 9.3% of the population of the United States and there 
are 1.4 million new cases of diagnosed diabetes each year. In 2012, 86 million Americans age 20 and 
older had prediabetes; this was up from 79 million from 2010 [16]. Results of a study by the Eye 
Diseases Prevalence Research Group reveal that 40% of diabetes patients have some degree of 
DR and that as many as 8% have severe, vision-threatening forms of DR. Early laser 
photocoagulation in high-risk proliferative diabetic retinopathy (PDR) has been shown to decrease 
the relative risk of vision loss by as much as 52%. Injections of anti-VEGF agents preserve and 
improve vision in people with PDR and/or diabetic macular edema. Despite effective treatment, 
however, tens of thousands of people with diabetes are going blind each year largely because 
they do not undergo annual screening for retinopathy. Currently, only about 50%-60% of people 
with diabetes have a yearly eye exam and there may not be enough eye specialists to see the 
balance [10, 17-19]. 

 
 
To address the issue of patient compliance with diabetic retinopathy screening, IDx-DR offers an 
automated image interpretation device that enables providers at the frontlines of healthcare to 
increase access to and reduce the cost of screening. This study is designed to assess the sensitivity 
and specificity of the IDx-DR device in screening for more than mild diabetic retinopathy (mtmDR).  
III. 
STUDY OVERVIEW 
The study is a multicenter observational study with primary endpoints to determine the sensitivity 
and specificity of IDx-DR for detection of mtmDR in the primary care setting. IDx-DR is an automated 
software device that is designed to analyze ocular fundus digital color photographs taken in primary 
care settings in order to quickly screen for mtmDR. 
Participants who meet the eligibility criteria will be recruited from sites staffed by primary care 
providers. After assessing eligibility and securing written informed consent, fundus photographs will 
be captured using a commercially available, Food and Drug Administration (FDA) cleared, non-
mydriatic ocular fundus camera – the Topcon NW400 (NW400) fundus camera – by a camera 
operator who does not have previous professional experience in ophthalmic photography. Images 
will be taken according to a specific IDx-DR imaging protocol provided to the NW400 camera 
operator, and then analyzed by the IDx-DR device.  
The photography protocol, as described below, consists of two images of the ocular fundus (one 
optic disc centered, one fovea centered), obtained from both eyes of enrolled participants using the 
NW400. If the NW400 camera operator is unable to obtain adequate images without dilation, the 
participant will be asked to remove contact lenses if they are wearing contacts and undergo re-
imaging under dilation using tropicamide 1% eye drops, administered under the supervision of a 
physician. After generating an IDx-DR screening result, a separate professional ophthalmic 
photographer certified by the Wisconsin Fundus Photography Reading Center (FPRC) will use a 
different, FDA-cleared camera system called the Topcon 3D OCT-1 Maestro (Maestro) to perform 
dilated W-4 four-field fundus photography, macular ocular coherence tomography (OCT) imaging, 
and imaging for the grading of media opacity. W-4 and OCT images using the Maestro will be sent to 
FPRC for primary and secondary reference standard evaluation.  
The FPRC will determine the severity of retinopathy (including the presence of macular edema) 
according to the Early Treatment of Diabetic Retinopathy System (ETDRS) grading system based on 
the W-4 fundus photographs. OCT will also be used to assess the presence of diabetic macular 
edema (DME) according to FPRC grading protocols. Incidental findings will also be documented by 
the FPRC, including review of grading for media opacity.  
In order to assure an adequate range of DR conditions in the study population for sensitivity and 
specificity analysis, the study population will be enriched with participants at higher risk for vtDR. 
The enrichment cohort will be targeted using HbA1c and/or FPG levels, if needed.  
 
 
 
 
  
The performance of the IDx-DR device will be compared to the FPRC readings in terms of sensitivity 
and specificity, in addition to conducting stratification based on media opacities and participant 
demographics, including ethnicity and race, cataract, incidental findings, and referral attrition. 
Endpoints will be calculated according to the Statistical Analysis Plan (SAP).  

 
 
IV. 
CRITERIA FOR EVALUATION 
The primary efficacy endpoints in the study are to demonstrate that IDx’s intended image capture 
workflow – in combination with the IDx-DR device – can successfully be used to provide a diagnostic 
result for 80% or more of participants and have at least 75% sensitivity for mtmDR, and at least 
77.5% specificity for mtmDR. The SAP has further details on the primary and secondary endpoint 
analyses.  
 
V. 
DEVICE SAFETY EVALUATION 
The proposed trial is expected to introduce only minimal risk to both NW400 camera operators and 
participants because the camera systems being used have previously been cleared by the FDA for 
ocular fundus photography and tropicamide 1% eye drops for pupil dilation are an FDA-approved 
drug product that has been demonstrated to have minimal side effects[20]. Ongoing safety 
monitoring will be performed by the Contract Research Organization (CRO), who will review reported 
adverse effects (AEs) or unanticipated adverse device effects (UADEs) received from clinical trial 
sites on a regular basis and report them promptly in communications to the Sponsor. 
VI. 
CLINICAL ASSESSMENTS 
A. 
Demographics  
Demographic information collected from participants as part of this study will include 
birth date, sex, ethnicity and race. Per the consent form and protocol, no additional 
identifiable participant data will be recorded for study purposes.  
B. 
Medical Assessment 
Participants in the study will be assessed at the primary care site for the purpose of 
determining eligibility. This assessment includes a review of medical records and 
questions asked by primary care personnel or clinical study staff. Participants will be 
confirmed for a diagnosis of diabetes by testing or a review of medical history, and 
will be asked whether they have persistent vision loss, blurred vision, or floaters. 
They will also be asked if they are contraindicated for fundus photography on the 
Topcon NW400 on the basis of hypersensitivity to light, recent photodynamic therapy 
(PDT), or taking of medication that causes photosensitivity. These terms will be 
explained as part of the eligibility determination process and in the informed consent 
document. Participants will be asked whether they are diagnosed with macular 
edema, severe non-proliferative retinopathy, proliferative retinopathy, radiation 
retinopathy, or retinal vein occlusion. They will also be asked if they have any history 
of laser treatment of the retina or retinal surgery (including intraocular injections). The 
site may also review the participant’s records for the same information. The initiation, 
continuation or discontinuation of medical therapy will remain at the discretion of the 
Investigator, as this is not expected to be dependent on any aspect of participation in 
this research study.  
 
C. 
Reading Center Assessment and CRO Follow-Up 
The Reading Center will be providing an EDTRS result for each participant in the 
study within 2-10 weeks of their completion of the study protocol.    
To ensure patients are appropriately referred to an eye care professional based on 
Reading Center grades, all adjudicated ETDRS Reading Center results will be 
converted to an ICDR level by the CRO based on the American Academy of 

 
 
Ophthalmology’s (AAO) International Clinical Diabetic Retinopathy (ICDR) Disease 
Severity Scale (http://www.icoph.org/downloads/Diabetic-Retinopathy-
Detail.pdf).  ICDR results provided to sites will also indicate whether the Reading 
Center detected macular edema (ME). 
To support referral determinations based on ICDR results provided to them by the 
CRO, participating clinicians should review the Management Recommendations for 
Patients with Diabetes as contained in the AAO’s Preferred Practice Pattern (AAO 
PPP) Recommendations for Diabetic Retinopathy (See Table 6 
at http://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp-updated-
2016).   
 
In correspondence about Reading Center results, clinicians will also be provided with 
the following notes regarding the PPP: 

 
 
 
The AAO PPP recommends a 12-month follow-up for patients with normal, 
minimal non proliferative diabetic retinopathy (NPDR) or mild NPDR when 
there is no presence of macular edema (ME).  
 
The AAO PPP recommends that it may be appropriate for patients with 
moderate NPDR to receive follow-up examination by an eye care 
professional in an interval less than 12 months.     
 
Based on the AAO PPP, those patients with severe NPDR, Non-high risk PDR, 
or High Risk PDR – as well as those with macular edema – may be indicated 
for treatment based on evaluation by an eye care professional.  These subjects 
should be referred. 
On the basis of Reading Center ICDR results and AAO PPP Recommendations, 
physicians will be able to provide appropriate eye care referrals for participants.   
VII. CLINICAL SITE COMMUNICATION, MANAGEMENT AND MONITORING 
A. 
Site Monitoring 
The CRO will follow standard operating procedures for monitoring this study in 
accordance with Good Clinical Practice (GCP) recommendations and FDA regulatory 
requirements. Any site not meeting the minimum requirements to initiate the trial, or 
that has administrative, procedural or data quality deficiencies that require correction 
in order to comply with regulatory requirements, the protocol, or to meet the 
requirements of the sponsor and the CRO, will be notified in writing of the 
deficiencies and permitted a reasonable opportunity to rectify deficient conditions. 
After study initiation, the inability of the site to rectify seriously deficient conditions in 
a timely manner or to maintain compliance with regulatory requirements may be 
cause for termination of study activities, closure of the investigational site, and 
notification of that decision to the relevant Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) and other regulatory authorities as appropriate. 
Participating sites will have an initial monitoring visit, routine interim monitoring visits 
(at a schedule determined by sponsor or CRO) during the study and a study close-
out visit conducted by experienced monitoring personnel. Additional monitoring visits 
may be performed for cause or if the volume of information to be reviewed cannot be 
easily completed in a single visit. Study visits will normally be scheduled well in 
advance so that necessary site staff and appropriate records will be available during 
the monitoring visit. 
Each monitoring visit will utilize a standardized checklist of elements to be reviewed 
at the site, tailored to the specific requirements of this study. Site monitoring visits will 
routinely review the participating site staff roster; study administrative and financial 
documents; required regulatory documentation; status of IRB/IEC approvals; 
changes or actions taken since any previous visit; participant recruitment status, 
screening, enrollment, and follow-up visit records; documentation of informed 
consent for each participant; review of adverse events; investigational product 
storage conditions; outstanding data clarifications and a review of data elements 
against source documentation. Site visits will follow standard CRO procedures and a 
report will be prepared for study records. 
 

 
 
B. 
Essential Document Management 
The CRO will obtain and maintain essential regulatory documentation for the clinical 
trial investigator sites only to the extent described in the International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines and 21 CFR 
812.140(a), and those Sponsor records listed under 812.140(b) only if they are 
provided to the CRO by the Sponsor. The regulatory documentation does not contain 
clinical records, CRFs or other source documentation regarding individual 
participants.  
The site Principal Investigator is required to maintain this documentation in a suitable 
regulatory binder or similar filing system and make it available for review by 
authorized study monitors, auditors and regulatory authorities. The Sponsor or their 
designee will maintain a master trial file. Both current and outdated study documents 
must be maintained. Older versions of documents may be stored elsewhere in a 
secure location, provided a reference to the actual storage location remains in the 
binder. If the binder contents become voluminous, multiple volumes may be 
maintained. The site Principal Investigator or Study Coordinator/Research Contact 
maintains the Regulatory Binder. Contents of the regulatory binder(s) or master trial 
file must include the following sections (the order of which may vary), which may be 
supplemented with additional dividers/folders if necessary. Any empty or unused 
sections should contain a document acknowledging this status. 
Regulatory Binder/Master Trial File  
a. 
Investigator Agreement 
b. 
Curriculum vitae and other qualification documents (licenses, training) if applicable 
c. 
Financial disclosure and/or Conflict of Interest certifications 
d. 
Regulatory (FDA) authority authorization (where applicable) 
e. 
IRB/IEC approvals 
f. 
IRB roster or Letter of Assurance 
g. 
Approved Clinical Protocol and any amendments 
h. 
Approved Informed Consent  
i. 
Participant recruitment materials and any other written information given to 
Participants (where applicable) 
j. 
Investigator’s Brochure (or relevant product labeling) 
k. 
Safety Reports (from other sites or sponsor) 
l. 
Serious Adverse Event summaries (from this site) 
m. Laboratory certifications and normal reference ranges for any tests required by the 
protocol, unless the test method is CLIA-waived 
n. 
Authorized site staff signature log documenting authorized study responsibilities 
o. 
Site Visit Monitoring Log 
p. 
All monitoring reports including the final trial close-out monitoring report 
q. 
Correspondence 
The CRO will track submission of the study protocol and informed 
consent documents to the IRB/IEC responsible for each site using the Emmes 
Regulatory Tracking System (RTS), and notify the sponsor when documented 
approval or favorable opinion from the IRB/IEC has been obtained for each clinical 
trial site. The CRO will also track signed, dated, and completed Case Report Forms 
(CRF’s) if paper forms are used. Sites are responsible for maintaining signed 
informed consent forms and the participant enrollment log.  

 
 
C. 
Data Management and Transfer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
D. 
Safety Monitoring 
The CRO will provide safety reporting services, including review, 
assessment, documentation, and reporting of AEs or UADEs submitted by clinical 
investigators. Investigators and the Sponsor will be notified if unreported AEs or 
UADEs are observed in study records by the monitors during routine or for cause 
monitoring activities. 
Events considered serious and unexpected by the site staff or the CRO will be 
immediately investigated by the CRO or Sponsor to determine if the event qualifies 
for expedited reporting to regulatory authorities. The CRO will be responsible for 
coordinating the expedited reporting of serious and unexpected AEs or UADEs to 
regulatory authorities within the required timeframes once the determination for 
reporting has been made. The CRO will review summary information on all reports of 
unexpected serious AEs or UADEs submitted by investigators, and will review 
individual events if the situation requires.  
1. 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
Safety will be evaluated during the time the participant is in the study which will 
include from the time of consent through the time of exit which will typically be less 
than one day. Safety will be assessed by frequency and incidence of ADEs and 
UADEs.  
Because this is considered a device study, it is consistent to use the following 
definitions when assessing safety issues:  
 
Adverse device effect (ADE), which means an adverse event related to the 
use of an investigational medical device. 
 
Unanticipated adverse device effect (UADE), which means any serious 
adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with its use that had not been previously identified 
in nature, severity, or degree of incidence. 
 

 
 
2. 
Identification of Events and Timeframe for Reporting  
For the purpose of this study, ADEs and UADEs will only be recorded for the duration 
of the participant’s involvement in the study, which will be less than one day. Many 
participants in this study may have pre-existing medical conditions however, those 
pre-existing conditions will not be considered as ADE/UADEs, unless use of the 
study device elicits a new ADE/UADE or worsens an existing condition in terms of 
frequency or intensity during or immediately after the use of the study device. All 
reportable events as defined above, determined to be an ADE/UADE will be recorded 
in the source documents and entered in the electronic case report form (e-CRF). The 
investigator will provide the date of onset and resolution, intensity, frequency, 
action(s) taken, changes in study device application, relationship to study device, and 
outcome.  
3. 
Follow-up of Adverse Device Effects 
ADEs that occur on the day of the visit will be followed up to adequately evaluate the 
participant’s safety or until the event stabilizes. When the event resolves, a resolution 
date should be documented on the case report form. All UADEs will be followed until 
resolution or until the participant is medically stable. All other events that cannot be 
resolved by 30 days after the last study contact will be considered resolved by 
convention and entered in the electronic data capture (EDC) system.  
4. 
Guidelines for Assessing Intensity of an Adverse Device Effect 
The investigator should use the following definitions when assessing intensity of an 
adverse event: 
 MILD: Participant is aware of symptoms or has minor findings but 
tolerates them well, and no or minimal intervention required 
 MODERATE: Participant experiences enough symptoms or findings to 
require intervention  
 SEVERE: Participant experiences symptoms or findings that require 
significant medical intervention 
5. 
Guidelines for Determining Causality 
The investigator will use the following question when assessing causality of an 
ADE/UADE to study device, where an affirmative answer designates the event as a 
suspected ADE: Is there a reasonable possibility that the device or its use caused the 
event? ‘‘Reasonable possibility’’ means that there is evidence to suggest a causal 
relationship between use of the device and the ADE. 
6. 
Discontinuation Due to ADEs/UADEs 
Participants may be withdrawn from the study at any time. Participants withdrawn 
from the study due to an ADE, whether serious or non-serious, must be followed by 
the investigator until the clinical outcome from the ADE is determined. Any participant 
who experiences an ADE may be withdrawn at any time from the study at the 
discretion of the investigator. The ADE(s) should be noted on the appropriate CRFs, 

 
 
and the participant’s progress should be followed until the ADE is resolved. The 
medical monitor or project manager must be notified. 
7. 
Reporting Procedures 
All recordable ADEs will be entered into the safety data system within 7 days of 
identification. Recordable UADEs will be entered into the data system within 24 
hours of identification. If there are any technical difficulties, the UADE will be reported 
by telephone or fax communication. This data will be entered into the EDC as soon 
as the system is available.  
8. 
Unanticipated Adverse Device Effects 
Any UADE entered in the safety database by a site investigator will generate an 
automatic email notification to the sponsor IDx-DR Medical Monitor. The sponsor is 
obligated to investigate UADE reports promptly to determine reporting requirements 
of the event and assess if the event warrants further action by the sponsor.  
9. 
Regulatory Reporting  
Any event that may be considered a UADE related to the IDx-DR device and 
therefore may require reporting based on federal regulations will be forwarded to the 
sponsor for investigation. After assessing reporting requirements of the event, the 
sponsor or its representative will submit reports to the FDA and other regulatory 
agencies as necessary, and will inform the investigators of such regulatory reports. 
Site investigators must submit safety reports as required by their IRB. Documentation 
of the submission and receipt by the IRB must be retained for each safety report. 
10. 
Type and Duration of Follow-up of Participants after ADEs 
ADEs/UADEs will be followed until resolved or considered stable. Adverse events will 
be followed by the investigator or a clinician member of the study team in person if 
the participant is hospitalized for an ADE or UADE. If the participant is not 
hospitalized, the investigator or a clinician may review the participant’s medical 
record, contact the participant by phone, or contact the participant’s primary care 
physician for follow-up. Participant safety data will be reviewed on an ongoing basis 
by the sponsor.  
 
VIII. ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, the US Code of Federal 
Regulations described for the Protection of Human Subjects (21 CFR 50), Financial Disclosure by 
Clinical Investigators (21 CFR 54), Institutional Review Boards (21 CFR 56), and the abbreviated 
Investigational Device Exemption (IDE) requirements (under 21 CFR 812.2(b)). 
To maintain confidentiality, all records other than consent forms will be identified by a coded number 
only and only the site Principal Investigator or coordinator shall maintain an enrollment log linking 
coded identifiers to personally identifiable information. The Investigator must also comply with all 
applicable national and local privacy regulations (e.g., Health Insurance Portability and 
Accountability Act of 1996 [HIPAA], EU Data Protection Directive 95/46/EC) and the requirements of 
their reviewing IRB/IEC. 

 
 
A. 
Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, 
International Conference on Harmonization (ICH) GCP, 21 CFR 50.25, CFR 50.27, 
and CFR Part 56, Subpart A, HIPAA, if applicable, and local regulations. 
The Sponsor will prepare informed consent forms and HIPAA authorizations for 
approval by the IRB/IEC. The written consent documents will embody the elements 
of informed consent as described in the ICH GCP Guidelines, and also comply with 
FDA and local regulations. IRB/IEC-approved copies of the blank Informed Consent 
Forms will be maintained as part of the study files. 
Study investigators and qualified staff members with consenting privileges will obtain 
informed consent. All participants will receive a verbal explanation in terms suited to 
their comprehension of the purposes, procedures and potential risks of the study. 
The participants must have the ability to understand and sign an informed consent 
form, which must be signed prior to enrollment. A properly executed, written, 
informed consent must be obtained from each participant prior to entering the 
participant into the trial. Information will be given in both oral and written form and 
participants must be given ample opportunity to inquire about details of the study and 
they will be informed that they may withdraw from the study at any time without 
prejudice to themselves or loss of benefits. If a site is participating in the “sub-study” 
for repeatability and reproducibility (see Section XI), participants must “opt-in” to the 
sub-study by signing an additional or supplemental consent form in order to have the 
additional imaging performed, and may decline to be in the sub-study without 
affecting their participation in the main study cohort. If the participant requires the 
consent to be in larger font in order to read it well, this will be provided. If participants 
are visually impaired to the point of being unable to read the consent (but still meet 
inclusion criteria), they can take the consent back with them to read it over with a 
family member or with the use of magnifying devices. If the participant chooses, the 
investigator can also read the consent verbatim to the participant and answer any 
questions that may arise. If a participant is unable to sign the informed consent form 
(ICF) and the HIPAA authorization, a legal representative may sign for the 
participant. A copy of the signed ICF will be given to the participant or legal 
representative of the participant and the original will be maintained by the 
Investigator. The investigator obtaining consent should document the consent 
process in the participant’s medical record. Participants who do not understand the 
ICF due to language or other barriers will not be eligible for the study.  
B. 
Participant Confidentiality 
All medical records will be kept confidential and will only be reviewed by the 
participating investigators. In order to maintain participant confidentiality, only a site 
number and coded participant number will identify all study participants on CRFs and 
other documentation submitted to the Sponsor, FPRC or CRO, in addition to basic 
participant demographic information. The participants’ name will not appear on any of 
the images exported to the Reading Center or any of the data forms reported to the 
CRO. Participants’ personal information will be kept as private as possible. However, 
records can be inspected by organizations for quality assurance and data analysis. 
These include the members of the FDA, IRB and the CRO. 

 
 
C. 
Individual Withdrawal Criteria 
Participants may choose to withdraw from this study, including the repeatability and 
reproducibility sub-study, for any reason at any time without penalty, loss of benefits 
or prohibition from enrolling in other clinical protocols. 
Reasons for participant discontinuation may include, but are not limited to, the 
following: 
 
Investigator determination that study continuation is not in the best medical 
interest of the participant; 
 
 Findings in the course of the trial that may affect willingness to participate; 
 
Study eye requires ocular surgery or ocular injections which cannot safely be 
postponed until after the end of the study; 
 
Inability to keep study visits or to comply with study requirements; 
 
Any other safety concerns. 
 
IX. 
STUDY DESIGN 
This is a multi-center observational study. Study participants will be recruited at 
primary care sites. Evaluation of the study participant inclusion/exclusion criteria must be based on 
the review of clinic medical records and/or documented patient interviews conducted by the 
Investigator or under the direction of the Investigator using qualified study staff (e.g., nursing staff 
or research coordinators) trained by the Investigator in the application of the study inclusion and 
exclusion criteria. 
A. 
Participant Inclusion criteria: 
1. Documented diagnosis of diabetes mellitus, e.g.: 
a. Having met the criteria established by either the World Health Organization 
(WHO) or the American Diabetes Association (ADA) 
b. Hemoglobin A1c (HbA1c) ≥ 6.5% 
c. Fasting Plasma Glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L) 
d. 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 
e. Symptoms of hyperglycemia or hyperglycemic crisis with a random plasma 
glucose (RPG) ≥ 200 mg/dL (11.1 mmol/L)  
2. Age 22 or older 
3. Understand the study and volunteer to sign the informed consent 
 
B. 
Participant Exclusion criteria: 
 
Persistent vision loss, blurred vision, or floaters. 
 
Diagnosed with macular edema, severe non-proliferative retinopathy, proliferative 
retinopathy, radiation retinopathy, or retinal vein occlusion. 
 
History of laser treatment of the retina or injections into either eye, or any history 
of retinal surgery.  

 
 
 
Currently participating in another investigational eye study and actively receiving 
investigational product for DR or DME. 
 
Participant has a condition that, in the opinion of the investigator, would preclude 
participation in the study (e.g., unstable medical status including blood pressure 
or glycemic control, microphthalmia or previous enucleation). 
 
Participant is contraindicated for imaging by fundus imaging system used in the 
study: 
 
Participant is hypersensitive to light 
 
Participant recently underwent photodynamic therapy (PDT) 
 
Participant is taking medication that causes photosensitivity 
 
C. 
Clinical Site Selection  
The coordinating center (CRO), with the agreement of the Sponsor, will select clinical 
sites according to their interest and ability to participate and to sign an appropriate 
investigator agreement with the Sponsor, the ability of the investigational site to be 
reviewed and approved for this study by a qualified IRB/IEC, the presence of staffing 
suitable to conduct protocol-required assessments, the availability to follow this 
protocol and utilize other written procedures or SOPs regarding the conduct of clinical 
research, and with input on geographic diversity and suitable patient populations from 
the study Sponsor. See Qualification of the Sites below.  
 
1. 
Primary Care (PC) Site inclusion criteria 
o 
Frontline care site with an adequate patient population likely to meet the 
inclusion/exclusion criteria 
o 
Ethnic and racial distribution suitable to achieve study overall ethnic and racial 
distribution goal (in combination with other selected sites) 
o 
Availability of space to have ocular fundus and OCT cameras on site, including 
the following to be installed and maintained by the Sponsor, only for the 
purposes of the study 
 
 
 
 
 
 
 
 
o 
Availability of staff to train and take fundus photographs per IDx-DR imaging 
protocol 
o 
Internet connection and computer hardware (supplied) for operation of the IDx-
DR device and eCRF forms 
o 
Willing to administer tropicamide 1.0% eye drops to participants that do not 
provide images suitable for IDx-DR analysis with undilated eyes 
o 
Previous experience with clinical studies preferred or demonstrated aptitude 
for conducting study  
o 
Willingness to allow a FPRC-certified ophthalmic photographer onsite for “Gold 
Standard” reference standard imaging using the Maestro system 
 
2. 
NW400 Camera Operators at Sites 
All personnel who will be taking fundus images and operating 
the IDx-DR device will be documented and trained as per the IDx training 
protocol to become NW400 operators. NW400 operators must attest to the 

 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E. 
Masking Protocol 
IDx has chosen an independent data storage center for the clinical trial. The IDx-DR software 
will be locked prior to initiating the clinical trial. A copy will be placed in escrow prior to the 
start of enrollment for auditing purposes. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 

 
 
 
  
F. 
Configurable Output Testing 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
G. 
Primary Care Imaging Procedure 
1. 
IDx-DR SCREENING PROCEDURE (Topcon TRC-NW400 Imaging 
Platform, by the NW400 operator) 
Imaging and IDx-DR submission activities should follow the instructions included with the 
IDx-DR device..  
2. 
4-W & OCT REFERENCE STANDARD IMAGING (by the FPRC certified 
photographer) 
1. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 

 
 
 
 
X. 
STUDY DESIGN (ENRICHED COHORT) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A. 
Participant Inclusion criteria for enriched cohort: 
1. Diagnosis of diabetes mellitus (as defined above in Section IX.A, except as 
follows): HbA1c and/or FPG level as defined by statistician during enrichment 
period 
2. Age 22 or older 
3. Understand the study and volunteer to sign the informed consent 
 
B. 
Participant Exclusion criteria: 
 
Persistent vision loss, blurred vision, or floaters. 
 
Diagnosed with macular edema, severe non-proliferative retinopathy, proliferative 
retinopathy, radiation retinopathy, or retinal vein occlusion. 
 
History of laser treatment of the retina or injections into either eye, or any history 
of retinal surgery.  
 
Currently participating in another investigational eye study and actively receiving 
investigational product for DR or DME. 
 
Participant has a condition that, in the opinion of the investigator, would preclude 
participation in the study (e.g., unstable medical status including blood pressure 
or glycemic control, microphthalmia or previous enucleation). 
 
Participant is contraindicated for imaging by fundus imaging system used in the 
study: 

 
 
 
Participant is hypersensitive to light 
 
Participant recently underwent photodynamic therapy (PDT) 
 
Participant is taking medication that causes photosensitivity 
 
C. 
Clinical Site Selection  
All sites will participate in enrichment, if implemented, and will be willing to administer 
HbA1c or FPG tests on participants to determine eligibility for enrollment, if the 
participant’s medical record lacks adequate documentation to establish the diagnosis 
of diabetes meeting an enrichment criteria, or for de novo patients being screened for 
study inclusion.  
  
D. 
Primary Care Imaging Procedure 
Other than site selection and HbA1c/FPG testing, the site qualification and imaging 
workflow will be identical to that of the prospective cohort.  
 
XI. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A. 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
1. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
    
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
A. 
  
 
 
 
 
 
 
   
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
XII. 
READING CENTER GRADING PROTOCOL 
A Grading and Imaging Charter has been established to define image grading processes associated 
with the University of Wisconsin Fundus Photography Reading Center’s generation of a “gold 
standard”.  
Participant Identification Codes 
All data and forms will carry a unique identification code. This code will consist of the study site 
number and the participant number at that site. The codes will not reveal the participant’s name, 
any personal health information about the participant, or any indication of the IDx-DR result. 
 
Certification 
The Reading Center will certify any ophthalmic photographers where 
photographers have not previously been certified. The Reading Center may grandfather existing 
certifications if candidates are currently certified for similar procedures in other studies and have 
been actively performing the procedures. 
 
Timeline (Estimated Dates) 
The period for conduct of the study is expected to last 7 months, beginning in 2017. 
 
XIII. 
APPENDIX VI: REFERENCES 
1. 
Klonoff, D.C. and D.M. Schwartz, An economic analysis of interventions for diabetes. Diabetes 
Care, 2000. 23(3): p. 390-404. 
2. 
CDC. Vision Health Initiative. 2015 [cited 2015 August 4, 2015]; Available from: 
http://www.cdc.gov/visionhealth/basic information/eye disorders.htm#a5. 
3. 
Bressler, N.M., et al., Underuse of the health care system by persons with diabetes mellitus 
and diabetic macular edema in the United States. JAMA Ophthalmol, 2014. 132(2): p. 168-73. 
4. 
Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment 
Diabetic Retinopathy Study Research Group. Ophthalmology, 1991. 98(5 Suppl): p. 766-785. 
5. 
Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study 
report number 1. Early Treatment Diabetic Retinopathy Study research group. 
Arch.Ophthalmol., 1985. 103(12): p. 1796-1806. 
6. 
Diabetic Retinopathy Study, G., Photocoagulation treatment of proliferative diabetic 
retinopathy: clinical application of DRS findings: DRS report 8. Ophthalmology, 1981. 88: p. 
583-600. 
7. 
Diabetic Retinopathy Study, G., Indications for photocoagulation treatment of diabetic 
retinopathy: DRS report 14. Int Ophthalmol Clin, 1987. 27: p. 239-253. 
8. 
Helmchen, L.A., H.P. Lehmann, and M.D. Abramoff, Automated Detection of Retinal Disease. 
Am J Manag Care, 2014. 11(17). 
9. 
Abramoff, M.D., et al., Automated analysis of retinal images for detection of referable diabetic 
retinopathy. JAMA Ophthalmol, 2013. 131(3): p. 351-7. 
10. 
National Institute of Diabetes and Digestive and Kidney Diseases. What is the Current State 
of 
Quality 
of 
Care 
in 
Diabetes? 
2013 
[cited 
2015 
02]; 
Available 
from: 
http://www.ncqa.org/PublicationsProducts/OtherProducts/QualityProfiles/FocusonDiabetes/
WhatistheCurrentStateofQualityofCare.aspx. 
11. 
Hazin, R., M.K. Barazi, and M. Summerfield, Challenges to establishing nationwide diabetic 
retinopathy screening programs. Curr Opin Ophthalmol, 2011. 22(3): p. 174-9. 
12. 
Lee, D.J., et al., Dilated eye examination screening guideline compliance among patients with 
diabetes without a diabetic retinopathy diagnosis: the role of geographic access. BMJ Open 
Diabetes Res Care, 2014. 2(1): p. e000031. 
13. 
Liew, G., M. Michaelides, and C. Bunce, A comparison of the causes of blindness certifications 
in England and Wales in working age adults (16-64 years), 1999-2000 with 2009-2010. BMJ 
Open, 2014. 4(2): p. e004015. 

 
 
14. 
Mansberger, S.L., et al., Long-term Comparative Effectiveness of Telemedicine in Providing 
Diabetic Retinopathy Screening Examinations: A Randomized Clinical Trial. JAMA 
Ophthalmol, 2015. 
15. 
Sim, D.A., et al., Automated retinal image analysis for diabetic retinopathy in telemedicine. 
Curr Diab Rep, 2015. 15(3): p. 14. 
16. 
American Diabetes Association. Statistics About Diabetes. 2014 [cited 2016 February 16, 
2016]; 
Available 
from: 
http://www.diabetes.org/diabetes-
basics/statistics/?referrer=https://www.google.com/. 
17. 
Bresnick, G.H., et al., A screening approach to the surveillance of patients with diabetes for 
the presence of vision-threatening retinopathy. Ophthalmology, 2000. 107(1): p. 19-24. 
18. 
Centers for Disease Control and Prevention. Age-Adjusted Percentage of Adults Aged 18 
Years or Older with Diagnosed Diabetes Receiving a Dilated Eye Exam in the Last Year, 
United 
States, 
1994–2010. 
2014; 
Available 
from: 
http://www.cdc.gov/diabetes/statistics/preventive/fX eye.htm. 
19. 
Hazin, R., et al., Revisiting diabetes 2000: challenges in establishing nationwide diabetic 
retinopathy prevention programs. Am J Ophthalmology, 2011. 152(5): p. 723-9. 
20. 
Inan, U.U., F. Ozturk, and S.S. Ermis, Pharmacologic pupil dilation in diabetic patients. Retina, 
2003. 23(2): p. 254-6.