There have been enormous challenges leading up to 2023 in ophthalmic clinical development, and more specifically in retinal clinical research. The COVID-19 pandemic has led to significant complications for clinical studies, including setbacks in trial timelines, resulting in overwhelmed sites and investigators, as well as slower patient recruitment due to alterations in how patients engage with health-care professionals. The pandemic also ushered in a virtual workforce, which has led to significant turnover of site staff, as qualified site coordinators accept virtual jobs in the drug development and pharmaceutical industries. These challenges are especially taxing on retinal clinical development given the limited number of clinical sites qualified and sufficiently experienced to perform clinical research.

The need for a holistic, supportive approach to clinical development is ever present, calling on methodology advancements, increases in resource sharing between clinical research organizations (CROs) and sites, and even creative site management solutions in ophthalmic clinical research to secure product development success. Along with this, the importance of developing relationships that support resource sharing between investigative sites and the CRO itself to ensure optimal staffing, training, and technologies for studies is essential to combat present challenges with site resource shortages.

As new trial endpoints are introduced to improve sensitivity and the ability to differentiate patient populations or demonstrate efficacy, the capacity to implement new trial assessment tools at clinical sites and professionally train staff is further impacted by the existing shortcomings in many retina practices. These are only a few of the many challenges facing retinal clinical programs, and CROs need to be diligent in both solving and planning to avoid significant setbacks in product development during a time when potential for and interest in retinal clinical research is great.

COVID-19 RELATED STUDY DELAYS

The COVID-19 pandemic has caused difficulties in all facets of work and life, with retinal clinical research being no exception. During the pandemic, clinical research sites focused on ensuring patient and site staff safety, but new protective policies and procedures resulted in slowed or discontinued screening, enrollment, and patient follow-up. As a result, sites are now inundated with delayed studies still ongoing, as well as a backlog of new clinical studies being initiated, which creates an exponential challenge to site resourcing.

This is especially problematic for investigative sites conducting retinal clinical development programs, because fewer clinical sites and resources are available compared to anterior-segment trials, and therefore many of the same sites are approached for a majority of the ongoing phase 2 and 3 studies. Retina research sites also need specific advanced assessment equipment, and certain studies requiring a full team of masked and unmasked staff to be present at each patient visit, which further restricts the sites that can be selected to participate in the study. With advances being made in gene therapies for posterior-segment disease, like age-related macular degeneration (AMD), diabetic retinopathy (DR), and inherited retinal diseases (IRDs), retina studies are one of the most prominent focuses of therapeutic development today, and therefore providing skilled investigators and experienced sites for these studies must be a top priority.

PRACTICE MANAGEMENT TOOLS

Clinical research organizations and development companies are working closely with sites to find solutions to this challenging situation. Leveraging a research practice management and clinical services company, like ClinEdge, recently acquired by Elligo Health Research, can use novel methods to accelerate clinical trial timelines, thereby enhancing access for patients who are considering involvement in these programs. ClinEdge provides access to patient recruitment, marketing services, staffing, and a network of research sites globally.¹

Along with this, the company Ora combats this demand through OraNet, a global research site enablement solution. OraNet works directly with clinical research sites, providing multiple facets of support to promote success, including methods for more accurate feasibility assessments, focused enrollment times and prescreening that improve site scheduling, and strategically balancing studies across a targeted site network.²

Advanced Clinical is taking a similar approach by providing recruitment experts to ensure that any support required is secured for the clinical trial. This company can tailor their support precisely to the needs of a study, including on-demand resourcing, permanent placements, and payroll support.³ In addition to the examples mentioned above, the Research Hive team strives to discover qualified patients for clinical research trials through their tool that investigators can use to find and refer patients for protocols based on criteria they feel the patient meets.⁴

The importance of rethinking the clinical research model from individual standalone sites to a community of successors working toward a common goal of advancing ophthalmic clinical research for patients globally is essential for product development success. The sharing of resources and consistent communication between investigative sites and the study’s respective CRO is crucial for driving engagement to successfully push studies forward, especially with the many present and upcoming studies focusing on gene therapies for various posterior-segment diseases.

HIGH STAFF TURNOVER RATES

Along with study delays and overwhelmed sites caused by COVID-19 effects, retinal clinical research sites globally are dealing with high staff turnover rates, as they are losing staff to remote roles, and newer replacements with less experience who need to invest time into the learning process of that role. Given current unmet patient needs for posterior-segment diseases like AMD and DR, clinical therapeutic development for potentially life-altering therapies cannot afford to be delayed or have increased risk to quality of data. For extraordinarily complex gene therapy clinical trials, staff with extensive skillsets are required to successfully conduct therapeutic administration and therefore require considerable training. We have seen studies be delayed in startup when sites transition imaging technicians who then take significantly longer to become certified through the central imaging reading centers due to inexperience of the incoming photographer(s).

Developing a community of skilled staff, incorporating experienced investigators, clinical research coordinators, and clinical research associates ensures that investigative sites are well prepared for clinical studies, including the many upcoming gene therapy programs in 2023 and beyond. Providing proper training to the above-mentioned roles and securing skilled and knowledgeable team members, both remote and on the ground, can set up retinal clinical programs for the best chance of success. Some site networks now offer additional staff to loan out to sites as part of a network membership to fill gaps in a clinic when shortages occur. In the ever-changing climate of retinal clinical research, where forecasting staff needs are unpredictable, a CRO should aim to support sites and sponsors by ensuring that internal on-call experts are ready to jump in when needed. This is in line with a more community-based approach where sites can tap into shared resources to create study success.

It is extremely important to assess challenges with staff retention and site turnover, and prepare for them. It is imperative to ensure that sites conducting retinal clinical trials are fully supported by the CRO overseeing the study, so that clients can rest assured that their clinical programs will not be delayed, and patients have a chance to receive investigative therapies that may become the standard of care in the future. Support by the CRO can be given to sites by building staff turnover scenarios into the initial risk assessment and mapping structured trainings, tools, and oversight into the risk mitigation plan when staff turnover arises so that the CRO and trial sponsor can be involved proactively instead of reactively. Tools such as up-to-date incoming staff training materials, checklists for system access/removal, triggered onsite or remote monitoring visits, and centralized repository of historical study materials and instructions should all be effectively provided by a sponsor’s respective CRO to ensure clinical study success.

DIVERSITY IN CLINICAL TRIALS

Representation of diverse patient populations within clinical studies is necessary to ensure that results can be generally applied to all national populations. To that end, providing potentially life-altering retinal therapies to underserved and trial-naïve communities worldwide should be the utmost priority in advancing retinal clinical development.

Therefore, access to underprivileged populations both inside and outside of the United States who have not had the ability to receive clinical research therapies as a care option is essential to meet the needs of retinal clinical trials investigating potentially vision-improving therapeutics. To ensure these processes are successful, support on the ground in these underserved areas is imperative to guarantee consistency of study conduct by both investigators and other staff.

Although it has historically been commonplace to conduct large phase 3 retinal programs globally, there is a trend toward smaller phase 2 programs requiring global conduct due to the limited patient populations, but also in part to hedge against inefficiencies in enrollment based on complexities of the protocol and COVID-19 risk.

The need for diversity and global reach in retinal clinical trials is more evident than ever, with large patient populations that may have limited access to needed therapies. To meet specific needs of retinal clinical trials globally, clinical development companies should welcome these potential research-naïve populations who need care options for various retinal diseases.

ASSESSING QUALITY OF LIFE IMPACT OF INVESTIGATIVE THERAPEUTICS

When it comes to patients with retinal disease, any potential visual improvement can significantly enhance their quality of life. Gene therapy approaches for posterior-segment diseases are being extensively evaluated at this time due to their potential of improving vision in patients who previously had limited options for treatment. With this, the need for methods to assess these drugs in a meaningful way is essential to continual advancement of retinal disease therapies.

Investigative therapy development for less prevalent but visually significant ocular conditions are essential. For example, Spark Therapeutics’ voretigene neparvovec-rzyl (Luxturna) is the first gene therapy for patients with biallelic RPE65 mutation–associated retinal dystrophy, providing retinal dystrophy patients with an option for treatment for the first time.⁵ Spark Therapeutics used their multiluminance mobility test (MLMT), developed with researchers from Children’s Hospital of Philadelphia, as a primary outcome measure and discovered high reproducibility between patient visits and clear differences in performance between patients with retinal disease and normal patients. When comparing this mobility test with other common endpoints, such as visual acuity and visual field tests, high correlations could be found between the results of each. Use of the MLMT as a primary endpoint in the phase 3 trial provided a robust approach to assess visual function at varying light levels.⁵ It is of utmost importance that endpoints in retinal clinical research be sensitive enough to detect enhancements in vision secondary to investigative therapy administration for posterior segment therapies that may provide patients with treatment where there previously were limited or no options.

Similarly, to address the need for more sensitive endpoints to assess changes in visual function in initial stages of AMD, Ora has developed the Ora Dry AMD Endpoint Program, which consists of the Ora-VCF Contrast Test and Ora Vanishing Optotypes and Reading Passages. The Ora-VCF and Ora Vanishing Optotypes and Reading Passages are often used to enrich enrollment to selectively identify subjects with underlying visual dysfunction.⁶ The Ora-VCF measures visual function through the principles of flicker fusion and contrast sensitivity, whereas the Ora Vanishing Optotypes and Reading Passages present words or sentences at various contrast levels to measure the time and efficiency of a patient’s response. Both systems are portable and therefore can be used remotely, and they can be administered to patients with nonproliferative diabetic retinopathy, early AMD, and inherited retinal diseases. Studies conducted with these devices have shown superior performance than conventional tests to differentiate healthy subjects from those with early disease. These tools have been validated from a scientific standpoint, as they can differentiate disease from age-matched and vision-matched controls. It is essential to continue to generate methods to evaluate the true scope of visual dysfunction in patients with retinal disease and use visual function testing when assessing investigative therapies to determine what treatments are most effective and appropriate for these patients.

CONCLUSION

There are many challenges facing retinal clinical research. Some of these barriers consist of continued fallout from the COVID-19 pandemic, resulting in study delays and therefore overwhelmed investigative sites that may be unavailable for upcoming studies. Advanced equipment and highly experienced staff are essential to drive forward a successful retinal clinical trial, along with more sensitive endpoints for retinal disease clinical trial programs.

For gene therapy clinical trials specifically, the demand for advancement in retinal therapies for untreatable blinding disease states is imperative, and both swift and effective action is needed to combat recent barriers to clinical trial success. Clinical research organizations and retina clinical development companies must face these recent challenges with creative solutions that keep the potential for success of a clinical study, as well as the possibility that patients may receive life-altering therapies, top of mind.

An integrated approach to product development between CROs and investigative sites should be a highly sought-out method in 2023, resulting in a holistic and supportive approach to clinical development. This encourages resource sharing, detailed training, and optimal technologies for studies to ensure that CROs, trial sponsors, and investigative sites are collaborating toward a common goal of advancing clinical development for patients who need access to better treatments. RP

REFERENCES

1. Elligo Health Research and ClinEdge join in major expansion. News release. September 22, 2021. Accessed March 16, 2023. https://www.elligohealthresearch.com/news/elligo-health-research-and-clinedge-join-in-major-expansion/
2. OraNet. Ora Clinical. Accessed March 10, 2023. https://www.oraclinical.com/our-services/cro-services/site-and-patient-networks/oranet/
3. Advanced Clinical. Strategic resourcing services: clinical research. Accessed March 10, 2023. https://www.advancedclinical.com/services/strategic-resourcing/
4. Research Hive. About. Accessed March 10, 2023. https://www.researchhive.com/about
5. FDA approves Spark Therapeutics’ Luxturna (voretigene neparvovec-rzyl), a one-time gene therapy for patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Spark Therapeutics. Accessed March 10, 2023. https://sparktx.com/press_releases/fda-approves-spark-therapeutics-luxturna-voretigene-neparvovec-rzyl-a-one-time-gene-therapy-for-patients-with-confirmed-biallelic-rpe65-mutation-associated-retinal-dystrophy/
6. Ora Clinical. Ora-VCF contrast test: dry amd model. Accessed March 10, 2023. https://www.oraclinical.com/our-services/therapeutic-areas/posterior-segment/ora-vcf-contrast-test/