Schepens lecturer traces advent, evolution of ophthalmic trials

Clinical trials are an indispensable ordeal that are the gold standard for assessing risks and benefits of treatments, said Frederick L. Ferris III, MD.

“We give the highest acceptance for interventions that have randomized clinical trial data demonstrating safety and efficacy, but it was not always that way,” said Dr. Ferris, director, Division of Epidemiology and Clinical Applications, National Eye Institute, Bethesda, MD.

In his presentation of The Charles L. Schepens, MD Lecture at the 2017 Retina Subspecialty Day meeting, Dr. Ferris discussed clinical trials’ past, present, and future, highlighting how they have evolved and benefited patient care.

It is a subject that Dr. Ferris knows well, considering he served as project officer of the Diabetic Retinopathy Study (DRS), co-chairman of the Early Treatment Diabetic Retinopathy Study, and chairman of the Age-Related Eye Disease Study.

Dr. Ferris noted he chose this topic because he was sobered by the thought that the majority of today’s practicing ophthalmologists may not be familiar with the history of the development of clinical trials in ophthalmology and treatments for diabetic retinopathy (DR).

“The DRS was the first large, randomized clinical trial in ophthalmology, but when it was launched in the early 1970s, most current ophthalmologists were not in medical school yet and many had not yet been born,” he explained.

A brief history of the DRS

The idea of using photocoagulation to treat DR was introduced by Gerd Meyer-Schwikerath, MD.

After observing macular burns in patients who had looked at the sun during the 1954 total eclipse in Germany, Dr. Meyer-Schwikerath devised equipment for focusing sunlight on areas of neovascularization in eyes of patients with DR. Although it was crude and had many limitations, the intervention caused photocoagulation burns and was shown to cause regression of proliferative DR.  

At the same time, lasers were being developed. The idea of using this new technology to prevent DR was put forth by William Beetham, MD, who identified an association between the presence of chorioretinal scars and absence of proliferative DR in patients with diabetes.

Dr. Beetham’s son-in-law, Lloyd M. Aiello, MD, transferred the idea into the clinic. Despite evidence from case series showing the benefit of “panretinal photocoagulation” or “scatter photocoagulation,” its use was controversial.

Because diabetic retinopathy was a leading cause of blindness in the United States in the late 1960s, the randomized controlled DRS was planned to acquire robust evidence about the efficacy and safety of photocoagulation.

Members of the planning committee had to resolve many methodological issues in developing the protocol, and there was skepticism among practitioners about the feasibility and ethics of the study. Once the study got under way, however, it was terminated early when interim data showed photocoagulation clearly reduced severe vision loss.
But the DRS should not only be credited for preserving vision for millions of people with diabetic retinopathy, Dr. Ferris said.

“Another huge result of this first trial was in getting acceptance of the randomized clinical trial methodology and the development of the infrastructure for such trials,” he said. “The DRS led to an explosion of new clinical trials in ophthalmology and eventually to the concept of a network for doing clinical research in diabetes, the Diabetic Retinopathy Clinical Research Network (DRCR.net).” 

Facilitating clinical research in ophthalmology

The DRCR.net was started in 2003 and currently comprises 137 sites with 432 investigators. Its approach to conducting research through a collaborative network allowed large, multicenter clinical trials to be completed more efficiently and more economically.

Collaborations with industry and foundations also became possible, with 50% of study costs paid for by these partners, Dr. Ferris said.

The alphabetical system used by the DRCR.net to name its protocols provides easy recognition of how active the program has been. Protocols A through U have been completed, and seven protocols are ongoing.

Importantly, the research conducted by the DRCR.net has revolutionized care for patients with DR, leading to a new era where laser treatment has been replaced by anti-VEGF therapy, Dr. Ferris said. 

Continued evolution

The DRCR.net has broadened its scope, undertaking studies of retinal diseases other than DR. The idea of an ophthalmology clinical research network was applied to form the Pediatric Eye Disease Investigator Group in 1997 for the purpose of studying strabismus, amblyopia, and other eye disorders affecting children.

Looking ahead, Dr. Ferris said that full posting of data and images will afford individual investigators increased capability for answering their independent research questions. In addition, healthcare’s entry into the era of electronic medical records (EMRs) will also play a role in the continued evolution of clinical trials.

“Surely, we will see expanded use of EMR-based registries, providing large observational databases,” Dr. Ferris said. “Although they will probably not be useful for clinical trials initially, they will be hypothesis-generating and provide new directions for research.”

He projected that EMRs will probably be used in multicenter clinical trials eventually, but before that happens, there must be harmonization of EMR systems and creation of common data elements for variables under study. 

Dr. Ferris noted that the EMR at the National Eye Institute is linked to a study database maintained by Emmes, a private clinical research company in Rockville, MD.

“Doing this across multiple clinics and across multiple EMRs is theoretically possible, but it is a log unit jump away and will probably be done initially within networks like the DRCR,” he said.