I read with interest the article by Tran and Chhablani examining the causes of unsuccessful retinal clinical trials. The authors highlight several important contributors to trial failure, including biologic heterogeneity, increasing therapeutic complexity, multidimensional datasets, and unexpected treatment responses.
While these factors are often discussed individually, they may represent manifestations of a common underlying problem, that is, mechanistically distinct diseases continue to be grouped under common phenotypic labels. As retinal therapeutics become increasingly targeted, this disconnect becomes increasingly important. A neutral trial result may not indicate therapeutic failure. Rather, it may indicate that biologically distinct endotypes have been combined within a single study population, obscuring the subgroup in which the targeted pathway is biologically relevant.
This challenge is particularly relevant in diseases such as neovascular age-related macular degeneration, diabetic macular edema, retinal vein occlusion, and geographic atrophy. Although these conditions are defined clinically, they likely encompass multiple biologically distinct subgroups that share similar phenotypic features while differing substantially in their underlying molecular drivers. Consequently, therapies directed at specific pathways may demonstrate meaningful activity in a subset of patients while appearing ineffective when averaged across a heterogeneous population.
One potential solution is to incorporate small, information-rich biologic perturbation studies earlier in development. In this approach, therapeutic interventions function not only as treatments but also as biologic probes. Integration of longitudinal imaging, molecular biomarkers, treatment response, and durability may help identify biologically distinct endotypes before large efficacy studies are undertaken. Such an approach may be particularly valuable for gene therapies, dual-pathway agents, and combination treatments, where development costs are substantial and late-stage failure is especially expensive. Small mechanistic studies may reveal biologic signals that become diluted or obscured once hundreds of heterogeneous patients are enrolled into conventional trials.
The future challenge for retinal drug development may not simply be designing better trials. It may be developing better biologic classification systems. Tran and Chhablani provide a valuable review of why retinal trials fail. The next step may be to identify and measure biologic heterogeneity prospectively so that potentially effective therapies are not discarded before the appropriate patient population is identified.
CRediT authorship contribution statement
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