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This article examines three critical operational challenges in clinical trials for chronic ophthalmic diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR): patient recruitment bottlenecks, retention maintenance, and specialized communication and support measures for visually impaired populations.
Insufficient patient recruitment is the leading cause of failure in ophthalmic clinical trials. In Stargardt disease—a condition with no approved therapy—recruitment delays lead to incomplete study cohorts, extended timelines, and ultimately increased likelihood of trial failure [1]. In the Zoster Eye Disease Study (ZEDS), only 29% of principal investigators agreed that recruiting participants was easy [2]. A retrospective analysis of 87 retinal clinical trials involving 962 patients revealed that up to 51.8% of patients were classified as screen failures due to failure to meet inclusion/exclusion criteria [3].
AMD patients are typically older and often have comorbidities, rendering many ineligible under stringent inclusion/exclusion criteria [4]. Recruitment barriers in DR are equally noteworthy: a survey of 206 Egyptian DR patients found that 29.6% declined trial participation, with 100% of decliners citing “risk of side effects” as the primary barrier, while “fear of blindness” was the foremost motivator among 93.1% of willing participants [5]. In a simulated NPDR clinical trial, 45.5% of patients considered a 4–5 hour on-site visit “too long,” and 50.0% viewed a 72-week trial duration as “excessive”; anxiety surrounding injections was particularly pronounced among patients with no prior intravitreal injection experience [6].
Overly restrictive inclusion/exclusion criteria are a major source of recruitment bottlenecks. In DR trials, for instance, enrollment typically requires patients to have moderate to severe NPDR (DRSS levels 43, 47, and 53), a narrow window that substantially compresses the eligible population [6]. Across 87 retinal trials, imaging findings and visual acuity criteria were the top reasons for exclusion, accounting for 44.5% and 14.7% of screen failures, respectively [3]. Challenges at the site level are equally formidable: in ZEDS, high research coordinator turnover was identified as a significant factor in declining recruitment success by 49% of principal investigators, with 22% stating it made recruitment “more difficult” [2].
Racial and ethnic minority groups have long been underrepresented in ophthalmic clinical trials, despite often bearing a heavier disease burden. In FDA-approved ophthalmic drug trials from 2000 to 2020, White participants were overrepresented, while Black and Hispanic/Latino participants were markedly underrepresented [7]. A 2024 review noted that even in diseases where minority groups constitute the majority of affected individuals, their enrollment in ophthalmic trials often falls below 10% [8]. Barriers to minority participation span institutional obstacles, cultural and linguistic challenges, lack of public awareness, structural barriers, and investigator and physician biases [8]. A geographic analysis of DME clinical trials further confirmed a substantial disconnect between enrollment fractions of underrepresented subgroups and expected enrollment based on U.S. Census data [9].
In response, the FDA issued a draft guidance titled “Diversity Action Plans” in June 2024, requiring sponsors to submit diversity action plans for pivotal clinical studies, specifying enrollment goals with supporting rationale and concrete methods to achieve them [10].
The ZEDS study identified the most effective recruitment strategies as, in descending order: referrals from ophthalmologists within the PI‘s institution (52%), ophthalmology resident referrals (37%), and chart review (37%) [2]. Establishing partnerships with high-performing ophthalmic centers, key opinion leaders, and high-volume retina specialty clinics naturally embeds trial awareness into routine clinical workflows, substantially accelerating patient identification.
In an Australian Phase Ib trial for mild DME, investigators initially targeted only retina specialists, and recruitment progressed extremely slowly. After pivoting to collaboration with patient organizations—partnering with Diabetes Australia (which reaches over 1.5 million people with diabetes nationwide) to disseminate trial information via its weekly newsletter, while simultaneously connecting optometrists with trial sites through the Oculo digital platform—patient identification, screening, and enrollment rates increased by 30% [6].
Verana Health, leveraging its exclusive partnership with the American Academy of Ophthalmology’s IRIS Registry, uses real-world data analytics to optimize inclusion/exclusion criteria. For example, more lenient hemoglobin A1c exclusion criteria in DME trials could facilitate the recruitment of more Black and Hispanic patients [11]. Concurrently, by identifying specific geographic regions and populations with high disease prevalence but low participation rates, sponsors can develop precisely targeted recruitment strategies [11].
Digital recruitment strategies offer scalable reach. Precision targeting tools on platforms such as Facebook, Instagram, and LinkedIn, combined with geolocation and keyword optimization, can markedly improve the efficiency of reaching target populations. Creating dedicated trial landing pages with pre-screening questionnaires, coupled with real-time analytics for iterative optimization, effectively enhances recruitment ROI. Notably, older target populations in many ophthalmic trials may be supplementally reached through traditional media such as local television and radio.
Patient dropout directly compromises the statistical power of a trial. One domestic study found that 62 of 954 outpatient participants dropped out, with personal factors accounting for 66.1%, protocol-related factors for 21.0%, and objective environmental factors for 12.9% [12]. Analyses from the Diabetic Retinopathy Clinical Research Network (DRCR) indicate that among 3,492 enrolled participants, 236 were lost to follow-up before the first data report, 6% formally withdrew, and 5% died [11]. Strengthening informed consent education, fostering positive physician-patient relationships, and proactively managing adverse events have been shown to be key measures in effectively reducing dropout rates [12].
Traditional retention management focuses on site convenience and visit reminders, yet research indicates that patients‘ anxiety levels and personality traits such as neuroticism also play important roles [6]. For highly anxious patients, more detailed explanations may be needed to alleviate fear; for those at high risk of forgetfulness, digital tools such as electronic reminders should be reinforced. Such targeted interventions optimize both the patient experience and the integrity of trial data.
Patient feedback from clinical research simulations has proven to be an effective tool for protocol optimization. In the NPDR trial simulation, patients demonstrated clear misconceptions about sham injections, with some mistakenly believing that sham injections would mimic actual injections, thereby raising concerns about adverse events. Additionally, patients requested practical support measures such as transportation arrangements for participants/caregivers, which were subsequently incorporated into trial protocols [6].
For diseases characterized by visual impairment, such as AMD and inherited retinal diseases (IRD), the informed consent process requires special design. Research indicates that visually impaired participants rely primarily on auditory information for decision-making—visual aids such as charts offer them little value [11]. While screen readers and text-to-speech technologies can provide assistance, they must be accompanied by effective communication methods to ensure information is conveyed clearly [11].
The UCSF Institutional Review Board has issued explicit guidance for enrolling legally blind subjects: IRB-approved informed consent materials should be presented orally, with ample time for questions and answers between the subject and research staff; an impartial witness is recommended to observe the entire informed consent process; and video/audio recording may be considered for documentation of consent [11]. ICH E-6 Section 4.8.9 similarly recognizes this approach, and the FDA has provided guidance on the matter.
In a first-in-human trial of iPSC-derived cell therapy for corneal disease, investigators employed an exploratory approach: providing potential participants with supporting audio materials prior to formal informed consent signing, with a focus on assessing their “readiness.” This practice aligns with the concept of “concise summary of key information” and helps visually impaired patients fully comprehend trial information and make autonomous decisions in the absence of visual aids [11].
For patients with combined hearing and vision loss (dual sensory impairment), relevant reviews recommend that investigators build trusting relationships with participants and caregivers, recognize behavioral cues, and receive specialized communication training [11]. These measures contribute to a more inclusive clinical trial environment.
The successful execution of chronic ophthalmic clinical trials depends not only on cutting-edge scientific design but also on effectively addressing challenges at the “human” level. From precision recruitment to sustained retention management, and from general strategies to specialized support for visually impaired populations, end-to-end patient-centric operations are becoming the decisive factor in the success of ophthalmic clinical research.
With 23 years of industry expertise, GCP ClinPlus leverages its proprietary ClinX intelligent platform—deeply integrated with AI technologies—to deliver efficient, predictable, end-to-end clinical research solutions for global pharmaceutical companies.
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Executed 200+ international multicenter clinical trials (MRCTs), with 4 products receiving FDA/EMA approval
Deep Expertise in Ophthalmology
40+ ophthalmic clinical research projects, building capabilities across the full spectrum of ophthalmic diseases
Disease areas spanning anterior segment conditions (dry eye disease, glaucoma, cataract) and posterior segment conditions (age-related macular degeneration, diabetic retinopathy, retinal vein occlusion)
Extensive real-world study experience supporting evidence generation across the full lifecycle of ophthalmic products
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References
[1] Wang DT, Antonio-Aguirre B, Pan A, et al. Patient, socioeconomic, and clinical influences on clinical trial participation in Stargardt disease. medRxiv. 2025. doi: 10.1101/2025.08.24.25334317.
[2] Sherman MD, Asbell P, Warner D, et al. Recruitment strategies and obstacles during the Zoster Eye Disease Study. Cornea. 2025;44(9):1101-1106. doi: 10.1097/ICO.0000000000003762.
[3] Hasan N, Mehrotra K, Danzig CJ, et al. Screen failures in clinical trials in retina. Ophthalmol Retina. 2024;8(8):738-745. doi: 10.1016/j.oret.2024.05.014.
[4] ICON plc. Complexities of running clinical trials in retinal disorders and ways to overcome them. April 25, 2024. Available at: https://www.iconplc.com/insights/blog/2024/04/25/complexities-running-clinical-trial-retinal-disorders-and-ways-overcome.
[5] Khalil AS, Salama MA, Kotb AN, et al. Willingness and motivation of Egyptian patients with diabetic retinopathy to participate in clinical trials. Delta J Ophthalmol. 2024;25(2):111-116. doi: 10.4103/djo.djo_76_23.
[6] Vujosevic S, Toma C, Ferrulli A, et al. Clinical trial simulation in diabetic retinopathy: insights from patients and site staff. Ophthalmol Ther. 2025;14(8):1773-1787. doi: 10.1007/s40123-025-01164-5.
[7] Bowe T, Richards CJ, Mansour HA, et al. Disparities between clinical trial recruitment and real-world demographics in macular edema secondary to retinal vein occlusion. Am J Ophthalmol. 2025;259:429-434.
[8] Pinal J, Hau VS. Clinical trial recruiting: the problem of diversity. Retina Today. March 2024. Available at: https://retinatoday.com/articles/2024-mar/clinical-trial-recruiting-the-problem-of-diversity.
[9] Soares RR, Bowe T, Mahmoudzadeh R, et al. Geographic access disparities to clinical trials in diabetic eye disease in the United States. Ophthalmol Retina. 2021;5(9):879-887.
[10] FDA. Diversity action plans to improve enrollment of participants from underrepresented populations in clinical studies: guidance for industry (draft). June 26, 2024. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diversity-action-plans-improve-enrollment-participants-underrepresented-populations-clinical-studies.
[11] Verana Health. How real-world data is used to increase diversity and inclusion in clinical trials. September 30, 2024. Available at: https://veranahealth.com/how-real-world-data-is-used-to-increase-diversity-and-inclusion-in-clinical-trials.
Note: The original research underlying the HbA1c example is: Borkar D. HbA1c criteria excludes more Black than White participants with diabetic macular edema. Presented at: American Academy of Ophthalmology (AAO) Annual Meeting; November 3–6, 2023; San Francisco, CA.
[12] Wei CG, Cai Y, Chen DB, et al. Analysis of factors influencing participant dropout in clinical studies. Chinese Journal of Health Statistics. 2021;38(5):752-754.
