Funding Mechanism - Jaeb

Funding Mechanism - Jaeb

The DRCR Network Past, Present, and Future DRCR.net Overview 1. DRCR Network introduction 2. Network impact on diabetic retinopathy research and clinical care 3. Key aspects of DRCR Network approach and structure 4. Evolving needs in retinal disease and future research goals 5. Council feedback and questions 2 Who are we? DRCR Network 3 We are an open, collaborative network of diverse clinical sites from across North America, dedicated to scientifically rigorous, impactful clinical research of retinal diseases. 4

Mission Perform high quality clinical studies that lead to a better understanding of retinal diseases, advance their treatment, and improve the lives of individuals with retinal pathology 5 DRCR Network Evolution 2002 2003 - 2018 NEI distributes 30 DR Multicenter Studies RFA: create 93 Publications infrastructure to accelerate 155 Clinical Sites development and to conduct 2002in clinical studies

diabetic DRCR.net retinopathy. Created 2017 DRCR Network Expansion to All Retinal Disease Collaborative Network Jennifer K. Sun MD, MPH Sangeeta Bhargava, PhD NEI Network Chairs

Coordinating Center Clinical Sites Adam R. Glassman, MS Daniel F. Martin MD 505 Current Investigators The DRCR Network has ~1800 members including Investigators, Coordinators, Technicians, and

Coordinating Center staff. 7 Prior DRCR Network Leadership Network Chairs: Lloyd Paul Aiello, MD, PhD: 2002 2005 Neil M. Bressler, MD: 2006 2012 Lee M. Jampol, MD: 2013 2017 Coordinating Center Director: Roy W. Beck, MD, PhD: 2002 2009 8 What impact has the DRCR Network made on diabetic retinopathy research and clinical care? 9 Before 2003 Vision Loss Diabetes

Laser photocoagulation wasfrom the primary method used to treat ALL diabetic eye disease Diabetic Macular Edema Central retinal thickening from abnormal vascular permeability Most common cause of moderate vision loss in diabetic patients Proliferative Diabetic Retinopathy Retinal neovascularization Risk for severe vision loss from vitreous hemorrhage or traction retinal detachment Since 2003 The DRCR Network has initiated 30 studies that have transformed the standard of care for diabetic eye disease Efficacy of intravitreous anti-VEGF therapy for DME and PDR Algorithms to guide anti-VEGF treatment of DME and PDR Outcomes of intravitreous steroid therapy for DME Effect of intravitreous steroid and anti-VEGF on DR severity Cost-effectiveness of treatments for DR and DME

Evaluation of DME with optical coherence tomography Reliability of visual acuity measurements in diabetic eyes Completed DRCR Network Protocols 5/03 3/04 12/04 10/05 8/06 6/07 4/08 2/09 12/09 9/10

A - Laser B - IVT C - OCT D - Vitrectomy E - Peribulbar F - PRP G - Subclinical H - Bevacizumab I - LRT for DME J - LRT for DME + PRP K - Laser Response L - Autorefraction M - Metabolic Control N - Vitreous Hemorrhage O - OCT P - Cataract w/Central DME Q - Cataract w/o Central DME R - NSAID S - IRV for PDR T - Anti-VEGF Comparison U - Steroid/ VEGF Combo V - Very Good Vision 7/11

5/12 3/13 1/14 11/14 9/15 6/16 4/17 2/18 12/18 12 Recruitment Followup

DRCR.net Protocols Enrolling or in Follow-up 2/12 8/12 3/13 10/13 4/14 11/14 5/15 12/15 6/16 1/17 8/17 2/18

9/18 TX - Protocol T Extension W - PDR/DME Prevention AA - Ultra-widefield Imaging AB - Vx for VH from PDR AC - Initial A vs B AD - PROMINENT AG - Gas for VMT AH - Gas for MH Genetics Recruitment Followup 13 Major Advances in the Treatment of DME 2008 Protocol B: Steroids for DME1 2001 potential benefits of intravitreal triamcinolone (IVT) to

treat DME first reported.2,3 2002 survey: 52% of retina specialists using IVT4 despite limited data supporting longterm vision benefit. 1. 2. 3. 4. DRCR Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology.2008 Sep;115(9):1447-9.e1-10 Jonas JB, et al. Am J Ophthalmol 2001;132:425-7 Martidis A, et al. Ophthalmology 2002;109:920-7 American Society of Retina Specialists Preferences and Trends Survey 2002 Dramatic subsequent decrease in use of IVT for DME Results confirm the use of laser treatment for [DME] and will have a significant impact on quality of life for tens of

thousands of people being treated for DME in the United States each year," Dr. Sieving 14 Major Advances in the Treatment of DME 2010 Protocol I: Anti-VEGF for DME1 1994- VEGF identified as a mediator of ocular angiogenesis and abnormal permeability.2 Anti-VEGF approved for neovascular AMD, but effect unknown in DME. Macular laser not efficacious for all eyes with DME- clear unmet need for novel therapy. 1. 2. Led to a new standard of care for DME with vision loss This comparativeeffectiveness study

demonstrated that a new treatment can protect and, in many cases, improve the vision of people with diabetic macular edema Dr. Sieving DRCR Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010 June;117(6):1064-1077.e35 15 Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480-7. Major Advances in the Treatment of DME 2015 Protocol T: Comparative Effectiveness of Anti-VEGF Agents for DME1 All 3 agents highly effective Clear mandate for anti-VEGF as first line therapy for DME, but major differences in cost and availability between anti-VEGF agents Public health importance to understanding potential

differences in efficacy between medications 1. DRCR Network. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema. N Engl J Med. 2015 Mar 26; 372(13): 11931203 All 3 agents have similar effect on vision for eyes with starting acuity of 20/32-20/40 Aflibercept considered by many initial treatment for eyes with vision of 20/50 or worse This comparative effectiveness study will help doctors and patients make informed decisions when choosing treatments for [DME] Dr. Sieving 16 Major Advances in the Treatment of PDR 2015 Protocol S: Anti-VEGF

for PDR Intravitreous anti-VEGF known to regress retinal neovascularization, but long-term visual and anatomic outcomes were unknown in eyes with PDR Therapeutic alternatives needed to PRP, which is effective but destructive 1. 2. Ranibizumab resulted in visual acuity that was no worse than PRP Valuable information provided on long-term visual acuity, peripheral visual field, treatment burden and safety outcomes in eyes with PDR .. latest results from the DRCR Network provide crucial evidence for a safe and effective alternative to laser therapy against [PDR] Dr.

Sieving Diabetic Retinopathy Clinical Research Network. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Trial. JAMA. 2015; 314(20):2137-2146 Gross JG, Glassman AR, Liu D, Sun JK, Antoszyk AN, Baker CW, Bressler NM, Elman MJ, Ferris FL, Gardner TW, Jampol LM, Martic DF, Melia M, Stockdale CR, Beck RW, Diabetic Retinopathy Clinical Research Network. Five-year outcomes of panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: A randomized clinical trial. JAMA Ophthalmol. 2018 Jul 24. doi: 10.1001/jamaophthalmol.2018.3255. 17 What key aspects of the Networks approach and structure have enabled this work? 18 Critical Components of the DRCR Network 1. Open, collaborative and transparent process 2. Rigorous scientific review of all studies 3. Efficient, cost-effective, and productive study pipeline 19

1. Open, Collaborative and Transparent Process DRCR is an open Network Welcomes any qualified retina specialist in U.S. and Canada Active Sites (Community & Academic Centers) Community Sites Investigators Other Personnel 155 106 (68%) 505 1223 20 1. Open, Collaborative and Transparent Process DRCR is an open Network Welcomes any qualified retina specialist in U.S. and Canada Active

Sites (Community & Academic Centers) Community Sites Investigators Other Personnel 155 106 (68%) 505 1223 21 1. Open, Collaborative and Transparent Process The DRCR Network engages Investigators in every step of protocol development, implementation, and reporting. 22 Protocol Development and Implementation Investigators comment on studies in development during

in-person meetings and via e-mail Selected investigators on protocol development committees based on Network activity and expertise Provide scientific input Determine feasibility of study procedures/visits Ensure study results will affect clinical practice Concerted effort to involve young investigators Implementation roles: Recruitment, Protocol Chairs, Vice Chairs, Executive Committee 23 Investigator Involvement in Results Reporting All investigators are given the opportunity to comment on manuscript drafts prior to submission Selected investigators participate on writing committees based on study activity and scientific contributions 142 investigators on writing committees 71 investigators have presented results at national or international meetings for DRCR Network 24

1. Open, Collaborative and Transparent Process DRCR.net public website is a community resource Network Publications DRCR.net Presentations Protocols, Policies, and Procedures Participating Clinical Centers Deidentified Study Datasets Available for Download Deidentified Study Images Available Upon Request 25 Data Sharing and Community Resources Study data- available to the public typically 1 year after publication of the studys results 18 datasets posted on DRCR.net 4,356 downloads of study data by >2,150 researchers ~41,950 images have been shared Idx EyeNuk Rochester Institute of Technology & University of Rochester Marquette Computer Lab Joslin Diabetes Center

Illinois Eye and Ear Infirmary Singapore Eye Research Institute University of Louisville Doheney Girls Computing League 26 2. Rigorous Scientific Review of Protocols The DRCR Network multilayered protocol approval process results in robust, welldesigned, clinically relevant studies. 27 Semi-annual solicitation of ideas. Forms publically available online Designated ideas presented to Network Investigators at semiannual

meeting Network Chairs/CC PI conduct initial review for public health importance and potential expedited review Based on Investigator feedback, ideas presented to Executive Committee and prioritized based on Network resources and public health importance Submitter presents idea directly to Operations Group, which reviews proposals for scientific merit and feasibility Protocol Development Committee formed. 28 Initial Protocol Draft

Open review by all Network Investigators Detailed Review by designated EC members Revised Protocol Protocol reviewed/approved by NEI External Protocol Review Committee. Protocol revised based on EPRC comments. Protocol reviewed/approved by Data and Safety Monitoring Committee. Protocol revised based on DSMC comments Final DRCR Network Protocol 29

3. Efficient, Cost-effective and Productive Study Pipeline 30 Clinical Trials in 15 years enabled by robust clinical research infrastructure Jaeb Center for Health Research Coordinating Center highly respected for conducting world-class clinical trials and epidemiologic research in ophthalmology and diabetes for over 25 years Efficiencies enabled by not having to reinvent the wheel for each protocol many common features across all stages of development, implementation, and reporting within DRCR pipeline 30 Efficient and Productive Study Pipeline Protocol Reporting Secondary Manuscripts Primary Manuscript S T

V W Follow-up AA AB Implementation Currently Recruiting AC AD AE Launching AG AH Development Protocol Development

Committees AF AI AJ 31 3. Efficient, Cost-effective and Productive Study Pipeline Leveraging of NIH funding with industry and foundation support DRCR Network Industry Collaboration Guidelines Academic independence maintained oNetwork controls design, implementation, and reporting 7 collaborations with industry on studies that have: o provided scientific evidence of therapeutic efficacy, o generated data to support FDA approval for new indications, 32 o Allowed direct comparison of same-class agents. Network Funding Breakdown without Drug Costs Over the duration of the Network

JDRF 3% Industry 30%* 47% NEI 20% NIDDK * Approximately $40,000,000 since DRCR.net inception 33 Network Funding Breakdown with Drug Costs Over the duration of the Network JDRF

3% 59%* Industry 29%NEI 9% NIDDK * Approximately $117,000,000 since DRCR inception 34 3. Efficient, Cost-effective and Productive Study Pipeline Network Presentations ~220 poster or platform presentations total >100 in this current grant cycle 12 presented in 2018 7 upcoming + AAO Course Presentations given at 17 different national and international society annual meetings.

35 Network Publications by Year 14 96 Total Publications Accepted 11 Being Written 12 10 9 8 6 6 4 7 7 5 13 11

8 10 8 4 4 2 1 0 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 36 Two Company 1st Major Collaboration Advance NEI Grant Review Impact Score: 11 Head to Head Comparison

In PDR treatment in NEI Grant Reviewer 40 Years. of anti-VEGF Treatment U.S. SenatesHouse Appropriations Committee. Protocol I Bill Recognized by Renewal for the Special Diabetes Program of Representatives Appropriations Trial Recognized Among Eight NIHsupport

Funded Studies as a U.S. Senate Appropriations Bill to oppose inLegislation any way for this as asNoted JDRF cites findings an example of NEIDRCR.net and DRCR Research for Recognized

Effectiveness Clinical Trial Clinical Breakthrough clinical trialComparative network would be equivalent to Revolutionizing Standard of Care for DME Tangible Scientific and Clinical Results Innovative Treatments

opposing motherhood, apple pie and the American flag. 2006 2008 2010 2011 2012 2015 2017 2018 37 What are our major goals over the next 5 years? 38 Diabetic Retinopathy

39 AE: Photobiomodulation for DME AB: Vitrectomy vs Anti-VEGF for Vit Genetics of DR Heme from PDR and Treatment Response V: Anti-VEGF vs Laser vs Observation for DME with Good VA 50% of eyes with Optimize Treatments DME do not respond for DR and DME fully to anti-VEGF Improve

Incomplete Understanding understanding of of DR Mechanisms mechanisms limits Underlying DR therapeutic advances Biobanking of Plasma, Vitreous and Aqueous W: Anti-VEGF for Prevention of PDR and DME Looking to the Future Understand Practice Gap between clinical Patterns that trial results and real

Influence Real World world outcomes DR Outcomes DRPreservation Remains a of Vision in Leading Cause All Patients of Vision Loss with Diabetes Worldwide No methods to Find Effective prevent DR or Strategies

foronset DR and early Prevention worsening DME AD: Pemafibrate for Prevention of DR Worsening Tx: Five Year Followup of Protocol T Participants AI:Iris Artificial AJ: Registry Intelligence for DR and DRCR Network Detection and Collaboration Prediction of Outcomes Limited Develop

resources Efficientto deal Methods with expanding for DR Screening global burden and Risk of diabetes Stratification and DR Patients Find Cost-Effective lose vision Treatments due to treatment and New cost, Waysaccess to Provide and

availability Access toissues Care AA: Ultrawide Field Imaging for DR AC: Anti-VEGF Initiation with Aflibercept vs Bevacizumab for DME Protocol V: Anti-VEGF vs Laser vs Observation for Eyes with DME and Good Vision Randomized, multi-center clinical trial At least one eye meeting all of the following criteria: Center-Involved DME on OCT VA letter score 20/25 (Snellen equivalent) or better Minimal or no prior treatment for DME Prompt anti-VEGF Prompt laser + deferred anti-VEGF

Observation + deferred anti-VEGF Primary outcome: Proportion of eyes losing 5 letters VA at 2 years 41 Protocol W: Prevention of PDR and DME with Anti-VEGF To determine safety and efficacy of anti-VEGF versus observation in eyes presenting with severe NPDR and no CI-DME for prevention of vision threatening outcomes (DME or PDR) Observation (sham injections) Intravitreous anti-VEGF Primary outcome: Proportion of eyes developing PDR/PDR-related outcomes or center-involved DME causing visual acuity loss by 2 yrs 42

Protocol AA: Peripheral DR Lesions and Risk of Worsening Prospective, observational longitudinal study Primary objective To assess whether evaluation of the retinal far periphery on UWF images improves our ability to assess DR and predict rates of DR worsening over time as compared with evaluation only of the area within the 7 standard ETDRS fields. Annual Visits for 4 years Primary outcome: Relative risk of 2 or more step worsening of DR severity over 4 years in groups with and without any predominantly peripheral lesions on UWF images at baseline. 43 Protocol AB: Vitrectomy vs. Anti-VEGF for Vitreous Hemorrhage Multi-Center Randomized Clinical Trial sample size 200 eyes At least one eye with vitreous hemorrhage meeting the following criteria:

1. causing vision impairment 2. presumed to be from PDR 3. requiring intervention (vitrectomy or anti-VEGF) Vitrectomy + PRP Anti-VEGF Primary Outcome: Visual Acuity AUC over 6 months Protocol AC: Aflibercept vs. Bevacizumab for DME Multi-Center Randomized Clinical Trial (312 Eyes, 260 Participants) At least 1 eye that meets all of the following criteria : VA letter score 68 and 24 (20/50 to 20/320) Ophthalmoscopic and OCT evidence of center-involved DME No hx of anti-VEGF treatment for DME in past 12 mos and no hx of any other treatment for DME in past 4 mos Aflibercept

Bevacizumab (plus Aflibercept if needed) Primary Outcome: Mean change in VA over 2 yrs Ongoing or Near Future Protocols Potential Impact V Anti-VEGF vs Laser vs Observation for Eyes with DME and Good Vision Will determine if it is important to start anti-VEGF in eyes with DME and good vision vs laser or observe W Prevention of PDR and DME with Anti-VEGF Could establish a new strategy for preventing vision threatening complications in eyes with high risk DR

Tx 5 Year Follow-up of Protocol T Participants Will elucidate long-term outcomes of anti-VEGF for DME after release to standard care treatment AA Ultrawide Field Imaging for DR Standard evaluation of DR may change if peripheral lesions eyes at high risk for worsening Vitrectomy vs Anti-VEGF for Vitreous May influence surgical decision making in eyes with vitreous hemorrhage from PDR Aflibercept vs Bevacizumab and Deferred Could identify a more cost-effective approach to treatment of DME AB Hemorrhage from PDR AC Aflibercept for DME

May identify an oral agent that reduces risk of AD Pemafibrate for Prevention of DR Worsening worsening from early stage DR AE Photobiomodulation for DME Could provide support for a novel, safe, noninvasive and affordable therapy for DME 46 Ongoing or Near Future Network Initiatives Initiative Genetics of DR and DME Potential Impact May identify genetic contributions to DR/DME severity and treatment response Will provide samples for translational work Biobanking of Plasma, Vitreous and Aqueous identifying novel markers or mechanisms for DR/DME severity and treatment response Could identify novel biomarkers of anatomic and

Optical Coherence Tomography Angiography functional outcomes in the diabetic eye from nonin Eyes with DR and DME invasive, high resolution retinal vascular imaging Iris Registry and DRCR Network Collaboration May lead to better understanding of how trial results translate into clinical practice patterns and identify key questions of clinical importance Artificial Intelligence Algorithms for DR Detection and Risk Stratification DRCR.net collaborations with groups with AI expertise could result in automated DR evaluation 47 methods with substantial public health implications Potential Future Studies DRCR Network has a robust, ongoing body of work in diabetic eye disease. There is much work yet to be done! Evaluation of Novel Therapies for DR and DME Relationship between Retinal Neural and Vascular Changes and

Brain Structure and Function in Patients with Diabetes Implementation of Artificial Intelligence Algorithms in DR/DME Clinical Care Regenerative Approaches to Diabetic Eye Disease 48 AMD and Other Retinal Diseases 49 What Other Diseases Might We Study? Neovascular AMD Dry AMD PVL for Vitreomacular Traction (Protocol AG)

PVL for Macular Hole (Protocol AH) Treatments for CSR ROP (in collaboration with PEDIG) Surgical Trials Other Retinal Diseases 50

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