Unsuccessful Clinical Trials in Retina: Lessons Learned.

Area of Science:

• Ophthalmology
• Clinical Trial Design
• Retinal Diseases

Background:

• Retinal drug development faces significant challenges in translating early-stage successes to late-phase trials.
• High attrition rates are a persistent issue in interventional retinal clinical trials.

Purpose of the Study:

• To analyze patterns of non-success in US-based phase 2 and 3 interventional retinal clinical trials from 2015-2025.
• Identify recurring design, feasibility, and operational challenges contributing to trial failures.

Main Methods:

• Retrospective analysis of unsuccessful clinical trials (terminated, withdrawn, or failed primary endpoints).
• Evaluation across indications (diabetic macular edema, retinopathy, AMD, geographic atrophy), trial phases, intervention classes, and mechanisms of action.

Main Results:

• High attrition observed in diabetic macular edema, diabetic retinopathy, neovascular AMD, and geographic atrophy.
• Phase 2 trials often discontinued post-interim analysis; Phase 3 trials frequently missed primary efficacy endpoints.
• Later-phase trials showed increased complexity (sample size, duration, burden); endpoint selection and operational factors contributed to failures.

Conclusions:

• Translating early retinal research findings into successful late-stage outcomes remains difficult.
• Enhancing alignment between biological rationale, endpoint selection, and operational feasibility is key to improving trial success rates in ophthalmology.