DRCR Retina Network: an Inside Look at the “National Treasure” in Retinal Disease Research

One of the biggest challenges in clinical research is having the infrastructure to do it.

Historically, to conduct a clinical trial sponsored by the National Institutes of Health (NIH), researchers spent six to 12 months completing a grant application and often another year setting up study logistics once funding was approved. As studies began, study groups were formed. As studies were completed, study groups were dissolved, only to be formed again months or years later for another clinical trial.

In 2002 the National Eye Institute introduced a novel way to streamline this process — a permanent infrastructure for performing clinical studies, the Diabetic Retinopathy Clinical Research Network (DRCR.net). Originally focused on diabetic retinopathy, the organization has since expanded its scope to include the study of all retinal diseases and changed its name to the DRCR Retina Network.

There at the beginning was Daniel F. Martin, MD, Chair of Cleveland Clinic’s Cole Eye Institute. A member of the original steering and executive committees, Dr. Martin became one of the chairs of the newly expanded Network in 2018.

To date, the organization has completed 30 multicenter studies, involving 160 clinical sites and spawning more than 100 publications.

“The Network is a national treasure,” says Dr. Martin. “Our mission is to serve the public’s visual health with work that is funded with federal dollars, often in collaboration with the pharmaceutical industry yet independent of it. Our efforts have produced so many meaningful results, not to mention an enormous database of findings and one of the largest repositories of retinal images in the world.”

In this Q&A, Dr. Martin shares an inside look at the Network, his role and upcoming clinical trials.

What led to the Network’s expansion from focusing only on diabetic retinopathy to including all retinal diseases?

Dr. Martin: Diabetic retinopathy was the original focus because it comprises a large part of most retina practices.

I had been involved with DRCR.net early on and then stepped away in 2005 when I began work as study chair of the Comparison of Age-Related Macular Degeneration [AMD] Treatments Trials (CATT). As the need for more AMD clinical trials became apparent, we began asking the NIH to create an AMD network like DRCR.net. Instead of creating a different network, however, the NIH decided to add AMD research into the very successful, well-established DRCR.net model. That’s when I became a Network chair.

Even though the Network now conducts trials for all retinal diseases, we kept the DRCR acronym because of brand recognition. Diabetic retinopathy is still a major priority, but adding other retinal diseases vastly expanded our Network.

Today the DRCR Retina Network is run by two chairs. Jennifer K. Sun, MD, MPH, of Harvard Medical School’s Joslin Diabetes Center oversees all diabetes initiatives. I oversee AMD, retinal vascular disease, and surgical and other retinal diseases.

How many research studies are happening currently in the DRCR Retina Network?

Dr. Martin: Outside the Network, doing one trial can be all-encompassing, a significant lifetime contribution. Inside the Network — which includes about 1,800 investigators, coordinators, technicians and coordinating center staff — we currently have six trials ongoing or about to launch. We also have three other major studies in development that should start within the next year.

In 2003 we began with Protocol A and named subsequent trials in alphabetical order. Now we’re into double letters, most recently preparing for Protocol AN.

Even with COVID-19, 2020 was a very busy year for us with reporting the results of four major randomized controlled trials, including one (Protocol AB) published in JAMAthat evaluated the optimal management of vitreous hemorrhage in diabetic retinopathy. In 2021 we published an important two-year study (Protocol W) in JAMA Ophthalmology on the use of anti-VEGF therapy in diabetic retinopathy. Quite a few more papers will follow later in the year.

One of my favorite recent papers was published in JAMA in 2019. I view it as a landmark study (Protocol V) that showed treatment was not needed for most patients with good vision and center-involved diabetic macular edema (DME). In other words, the presence of mild macular edema in patients who have maintained good vision does not usually lead to long-term visual decline if it is not treated. In many cases, the edema can resolve on its own. It was an important finding for retina specialists and for the whole diabetic community.

How does the Network develop and select trials to pursue?

Dr. Martin: The NIH funds the DRCR Retina Network. We then determine what trials we will conduct and how the money will be spent.

Anyone can put forward a protocol idea, including members of our Network and those outside of it. Many ophthalmologists have questions that arise in their practice, but not every question is answerable in the context of a randomized clinical trial or worth the seven-figure investment often required to answer it.

All ideas are reviewed by the Network’s operations group. The most viable ideas are presented to the entire investigator group, which meets twice a year. At each meeting, numerous new ideas are presented to gauge investigator interest. For those that get the most interest, I will write a first draft of the trial protocol. That draft protocol then goes to an executive committee, which votes whether or not it should move to the next step — a Protocol Design Committee (PDC).

After a full trial has been developed by the PDC, it is then sent for review by an NIH External Protocol Review Committee. If approved, it goes back to the executive committee for final approval. The person who presented the original idea usually ends up as protocol chair.

It is a detailed, tedious but thoughtful process that helps ensure the Network invests its time and money wisely to answer only the most crisp, focused research questions that will provide the greatest value to our specialty and our patients.

When not crafting protocols, I discuss collaborative opportunities with pharmaceutical companies on behalf of the Network, including arrangements for additional funding or supplying test drugs. While the Network works independently from the pharmaceutical industry, it is important to collaborate since almost no new treatments move forward without a pharmaceutical company partner. My work in CATT underscored the importance of independent clinical trials, but pharmaceutical companies are extremely important partners. The monumental achievements of the DRCR Retina Network have reinforced that.

What are some of the most significant studies done by the Network to date?

Dr. Martin: I recently gave a presentation on the top 5 most important findings from Network studies. In that list I mentioned DRCR Protocol I, which first identified anti-VEGF treatment as most effective for DME. DRCR Protocol T was another landmark study, which showed aflibercept was more effective than bevacizumab and ranibizumab at treating DME in select patients. DRCR Protocol S was the first to show that anti-VEGF therapy was effective for proliferative diabetic retinopathy.

New protocols currently in development could potentially lead to the next breakthroughs in retinal care. Upcoming trials will study the prevention of radiation retinopathy, vitreoretinal surgery for epiretinal membranes, and the optimal long-term management of neovascular AMD.