Researchers consider meaningful endpoints in diabetic retinopathy clinical trials

Madison, WI-The visual and morphology measurements used as endpoints in a clinical trial have both advantages and disadvantages that must be balanced by their value in achieving the goals of the study, according to Ronald Danis, MD.

To obtain valid clinical trial data, the endpoints must be meaningful, measurable, and consistent with study goals, said Dr. Danis, professor, Department of Ophthalmology and Visual Sciences, and director of the Fundus Photograph Reading Center, University of Wisconsin, Madison. A measurable endpoint is one that is reliable, and the signal has to be greater than the noise or the biological variation of the disease. A meaningful endpoint is one in which there is a direct relationship or strong association with the relevant functional outcomes of the disease, he said.

Noting how endpoints have changed as technology has advanced, Dr. Danis said that blindness (defined as a visual acuity of ≤5/200) was an endpoint in the Diabetic Retinopathy Study conducted in the 1970s, and the 15-letter threshold for vision loss became established as the primary outcome in the 1980s with the Early Treatment Diabetic Retinopathy Study (ETDRS). And in recent studies, such as the Lilly PK-DMES trial conducted in the 1990s, vision has not been an endpoint at all because the goal is to have an impact on the disease before vision loss occurs.

Visual acuity (VA) has been validated in many studies, and a standardized way of checking it has evolved because the test is subjective and therefore accompanied by a certain amount of noise, Dr. Danis said. The 3-line change in VA has become the traditional threshold accepted by regulatory agencies because less than this amount of change is seen as part of the normal variation within a population of diabetics.

"While it is obviously a very important endpoint, it is noisy enough that there are some problems with it, which means that you have to have a large sample size in order to detect a significant change in visual acuity," Dr. Danis said. "Partly this is because there are other factors that have an impact on the patient's vision that may not have anything to do with the disease, such as corneal dryness, cataract, and subject effort."

Common endpoints for trials

Other commonly used endpoints for clinical trials include color photography for diabetic retinopathy and diabetic macular edema (DME), fluorescein angiography for DME, and OCT3 for retinal thickening and cross-sectional morphology in DME.

Color photography is helpful for classifying the severity of diabetic retinopathy or DME. Fluorescein angiography is useful for describing the features of DME, although it is not generally employed by itself as either a primary or secondary outcome.

"Optical coherence tomography [OCT] has emerged as a very powerful tool for quantifying retinal thickness and so in particular for eyes that have center-involved macular edema, it appears that the OCT3 is very important as a clinical trial tool," Dr. Danis said.

Evaluation of photographs is the only current, detailed methodology for monitoring the severity and progression of diabetic retinopathy, Dr. Danis said, and the gold standard is seven standard fields stereo photography graded according to the ETDRS scale. Two-step progression on the eye scale and three-step progression on the person scale have been validated as outcomes in many studies.

"Reading centers are very good at reproducibly grading retinopathy severity, but the photographic technique is difficult and it requires a lot of bright flashes in the eye," Dr. Danis said. "Many patients do not enjoy this at all."

A system of quantification also exists for DME, although it is more difficult to grade reproducibly.

"With the advent of OCT, there is ongoing debate as to how valuable photographs are versus OCT," he continued. "I think that in a trial of center-involved diabetic macular edema where you're looking for a treatment outcome, the grading of diabetic macular edema from photographs may not be as valuable as the OCT. In the case of eyes that have non-center-involved diabetic macular edema, I think that's an open question right now."