Authored by:

Raymond Cook, MD, Vice President Internal Medicine

Kathleen Gordon, MD, Sr. Medical Director, Ophthalmology Center of Excellence

Mark Herring, Clinical Project Management Director

Introduction

Designing eligibility criteria for ophthalmology clinical trials, especially those focused on retinal conditions can be complex. These criteria are important for optimizing the trials’ ability to meet study endpoints. However, eligibility criteria that are scientifically valid but do not reflect current clinical practice can significantly impact recruitment. Therefore, finding a balance that respects both the study's scientific goals without compromising the ability to recruit patients into the study is essential.

At IQVIA Biotech, we recognize how important these decisions are for achieving meaningful research outcomes. In this post, we will explore factors to consider that can help guide the development of eligibility criteria for retinal studies.

Understanding the Diabetic Retinopathy Severity Scale (DRSS)

In studies that aim to improve or slow progression of diabetic retinopathy, the Diabetic Retinopathy Severity Scale (DRSS) is often included as part of the eligibility criteria. Providing a standardized scale to classify severity of disease helps to decrease variability in the patient population recruited across sites and allows the results of a trial to be compared across different studies. The DRSS scale takes into account the number of abnormal findings in different areas of the retina and include microaneurysms, hemorrhages, vessel irregularities and areas of ischemia. Eligibility criteria for diabetic retinopathy trials often require patients to have moderate, moderately severe, or severe non-proliferative diabetic retinopathy (NPDR), corresponding to a DRSS score of 43, 47 and 53. However, the DRSS is very complex and seldom used in clinical practice since ophthalmologists often rely on different criteria to make clinical decisions. In addition, the DRSS only considers findings found in the areas of the retina depicted in the 7-field fundus photographs. When ophthalmologists evaluate the retina, they often consider the entire retina, including areas outside of the 7 fields. For this reason, estimation of the DRSS score may be contradictory to the central reading centers evaluation leading to higher than expected screen failure rates. When planning for a clinical trial, it is important that investigator training on DRSS grading emphasize that the required retinal findings must be seen within the part of the fundus captured in 7-field fundus photographs since this is what is evaluated by the central image reading center. We also recommend providing the investigators with accessible digital images to be available at the time of the patient evaluation with reminders of the required fundus findings and their location. If demonstrating improvement in DRSS score is not critical for meeting study endpoints, allowing for lower scores for eligibility helps to mitigate the risk of a high screen failure rate due to investigators’ over-estimation of the DRSS score.

Restrictions on Intravitreal Therapy (IVT)

Trials often place limits on the total number of prior intravitreal therapy (IVT) injections a patient has received before enrolling as this can help isolate the effects of the treatment under study. Significant numbers of studies involving neovascular age-related macular degeneration (nAMD) and diabetic retinopathy (DR) require that patients be treatment naïve for inclusion. Diabetic retinopathy is a chronic disease, so patients may be monitored without treatment at the investigative site until the center of the macula becomes involved or they develop high risk disease. Therefore, potentially eligible treatment naïve patients may be present in the investigators’ clinic and approached about interest in the trial. Identifying investigational sites with an established diabetic retinopathy screening program will have a significant benefit in recruiting patients. However, nAMD often presents with acute symptoms and may progress rapidly without treatment. Therefore, patients with nAMD are often treated soon after diagnosis impacting their eligibility for clinical trials. If an nAMD trial’s eligibility criteria excludes previously treated patients, it is important to consider sites with a strong referral network, so that new, treatment naïve patients can be considered prior to the initiation of treatment.

If prior treatment is allowed, it may be limited to 3 or fewer IVT injections within a defined period of time and response to the treatment may be necessary for entry into the study. If there is a limit to the lifetime number of prior treatments, consideration should be given to standard of care clinical practice. Most treatments recommend a number of fixed frequency loading doses, before moving to an extending dosing frequency. Setting the lifetime requirement too low can push the investigator into a treatment naive population which can make recruitment slower.

Aligning visual acuity requirements with regional diagnostic practices

In clinical trials for nAMD, understanding visual acuity thresholds is crucial for site selection and effective patient recruitment. Trials for new compounds often allow for a visual acuity range between 20/40 to 20/320. A baseline visual acuity of 20/40 or worse allows for the trial to demonstrate visual improvement. Trials for biosimilar drugs often cap visual acuity at 20/200 rather than 20/320. Narrowing the visual acuity range in biosimilar trials helps to decrease variability in the patient population. When considering sites for a clinical trial, it is important to discuss with site staff the expected visual acuity at presentation for the patient population in their region. For example, in Japan, patients are often diagnosed with nAMD at earlier stages, presenting with visual acuity better than 20/40. This discrepancy can lead to challenges in enrolling suitable participants. Similarly, patients in regions with limited access to care might present for treatment with vision that is worse than allowed for eligibility.

Pre-existing conditions and their impact

When considering eligibility criteria, it is also important to take into account pre-existing ocular conditions that could confound study outcomes. Patients with a history of high myopia or other conditions associated with macular degeneration should be excluded. Cataracts that could require surgical intervention during the study, may impact data integrity and confound visual acuity related endpoints. Similarly, patients with a history of intraocular inflammation are at risk of recurrences which would be an adverse event of special interest if occurring during the study. Therefore, a history of intraocular inflammation, in addition to active inflammation, should be considered for exclusion when developing the eligibility criteria.

Conclusion

The success of retinal clinical trials is dependent on carefully planned eligibility criteria that balance scientific integrity with selecting the right patients to prove efficacy and safety. By considering factors such as the DRSS, treatment status, allowable visual acuity range, and pre-existing conditions researchers can design trials that can demonstrate efficacy while maximizing enrollment potential.

At IQVIA Biotech, our approach combines deep clinical expertise with a patient-centric focus, for studies that lead to meaningful advancements in ophthalmology and truly improve patient outcomes. Through these thoughtful considerations, we ensure that clinical trials are poised to deliver valuable insights while maintaining the highest ethical standards. This balanced approach not only advances scientific understanding but also supports the development of treatments that make a real difference in patients' lives.

Contact us to learn how we can help support your retinal clinical trials.