New Opportunities, New Challenges: Emerging Factors Shaping the Future of Clinical Trials in Ophthalmology and Beyond
Clinical trials are the primary tools for evaluating the safety and efficacy of potential new drugs, serving as an essential checkpoint in the process of bringing valuable therapeutics to the patients who need them. In order to expand the treatment landscape, a strong network of sponsors, investigators, supporting staff and patients are needed to ensure that these therapies are thoroughly evaluated for medical intervention.
OcuTerra enrolled an astounding 225 patients, in just over 12 months, into the Phase 2 DR:EAM clinical trial to study OTT166, a novel integrin inhibitor delivered via eye drop, as an earlier, non-invasive treatment for diabetic retinopathy (DR). Our team rigorously designed this trial to ensure that we have a clear picture of OTT166’s clinical profile and impact on patients with early-stage DR ahead of Phase 3 evaluation. We’re thrilled that the trial has gone smoothly to date and has provided us with many valuable insights.
Identifying and navigating potential roadblocks in recruitment
No trial can proceed without enrolling an appropriate number of patients to participate, but certain hurdles may arise in the recruitment process. The most commonly reported concerns patients have about trial participation are the various time demands and uncertainty around consent and clarity of information about the trial1. These findings highlight not only the potential barriers that must be considered when designing a clinical trial, but the importance of ensuring that referring physicians have ample information and ability to clearly communicate these details with patients.
A survey carried out by researchers at the Mayo Clinic assessed patients’ attitudes on clinical trial participation and highlighted the important relationships between patients and their physicians, with a high percentage of patients saying that they were mostly unaware of online information about clinical trials (82%), and that they expected their physicians to inform them about current trials (76%). This led the authors to conclude that receiving more or better information from their physicians may improve patient enrollment2. In addition, an Austrian study surveyed current participants in clinical trials (both healthy volunteers and patients) to determine their motivations for participation. Both groups listed contributing to scientific research (~81% agree or strongly agree) and benefiting future patients (~85%) in their top three motivations, but the number one reason given was that they trusted their attending physician (~86%)3 – again highlighting this important relationship.
In consultation with scientific and medical advisors, appropriate inclusion and exclusion criteria must be applied in clinical trials; this supports both an accurate understanding of the studied candidate’s effects and a participant population that reflects the real-world target patient population as closely as possible. It is essential to avoid the underrepresentation of certain racial and ethnic populations, which in many cases have a disproportionately higher disease burden. DR is one indication where these considerations have been critical. Historically, much of the epidemiologic data for diabetes was based on studies of predominantly white populations in Europe and North America, whereas researchers now have a greater appreciation of the enormity of the global diabetes pandemic, and the differential effects of the disease in people from various socio-economic and ethnic backgrounds5. OcuTerra plans to follow the FDA’s diversity guidelines during our Phase 3 studies in order to recruit a diverse and representative DR patient population.
Maintaining strong relationships with investigators and trial staff
Together, this evidence highlights the importance of selecting the right clinical sites, and the right teams of investigators, in optimizing patient enrollment. Data from Bain & Company show that when investigators have a positive relationship with a study’s sponsor, they are more likely to enroll more patients, resulting in fewer delays for the clinical trial6. The increasing complexity and specialization of clinical trials has also led to a corresponding increase in competition for the limited number of sites available for any given study7. This begs the question, what can be done to improve investigator relations and recruit the best investigators for your study?
The most common concerns noted by potential trial investigators are the burden of trial-associated administrative tasks, and time spent on staff training6. Sponsors can address these concerns in a variety of ways, including the use of digital tools to facilitate data entry, streamlining study-specific training, and prioritizing in-person interactions between investigators and sponsor liaisons to facilitate rapid and effective communication. OcuTerra’s leadership has prioritized strong relationships with our investigators throughout the DR:EAM clinical trial, scheduling time for frequent connections and working collaboratively to address any challenges that have arisen.
The changing face of DR clinical trials
As we’ve previously discussed, intravitreal anti-VEGF injections are one of the few active treatments currently available for the treatment of DR. However, some non-invasive alternatives to intravitreal injection, such as OcuTerra’s topically delivered OTT166, are in development for patients earlier in the course of disease. While anti-VEGFs have established efficacy, their burdensome nature leads to doctors rarely prescribing these injections to patients in the earlier stages of DR – and even if they are prescribed, many patients are averse to such an invasive form of treatment. In order to ensure that patients actually receive therapies that could halt or improve the progression of DR, non-invasive treatment options are critical.
As new therapeutic candidates for DR are evaluated, we expect to see a change to the established paradigm of trial design. While patients with severe non-proliferative or proliferative diabetic retinopathy often experience vision loss, signaling the need for an anti-VEGF intervention, patients who are diagnosed in the early stages of DR often have no symptoms. For these individuals, a non-invasive therapeutic that supports a stable level of vision without progression to a later stage of DR may be far more desirable. In addition, oral drugs that are delivered systemically throughout a patient’s body must be evaluated differently than eye drops like OTT166, which only deliver active agents to the site of disease.
The new therapies in development for DR also bring a host of new opportunities. OTT166 is an integrin inhibitor, expanding beyond the established effects of anti-VEGF therapies. OTT166’s MOA gives it the potential to block multiple disease pathways that are not addressed by anti-VEGF therapy alone, including fibrosis, a long-term complication of retinal disease. As such, endpoints that may have been irrelevant in previous trials focused on anti-VEGF must also be considered as clinical data for novel therapeutics emerge.
The Phase 2 DR:EAM study achieved full enrollment earlier this year, recruiting more patients than originally intended across 65 unique trial sites. The success of the trial so far can be attributed to many of the factors discussed above, as well as the innovative and paradigm shifting nature of the therapeutic itself, which is appealing to both investigators and patients. Carl Regillo, MD, Principal Investigator on the DR:EAM study, had this to say on the study progress so far:
“This has been an incredibly smooth study…Why? Because it’s so appealing to patients. Patients have diabetic retinopathy, and they know there’s a threat for disease progression – even potential to have injections to treat some of the complications. So, when you present the notion – which is a paradigm shift – to treat DR with a topical drop they find that very attractive and I’ve found recruitment into phase 2 to be probably the easiest study I’ve ever enrolled8.”
References
Prescott RJ, Counsell CE, Gillespie WJ, Grant AM, Russell IT, Kiauka S, Colthart IR, Ross S, Shepherd SM, Russell D. Factors that limit the quality, number and progress of randomised controlled trials. Health Technol Assess. 1999;3(20):1-143. PMID: 10683591. https://pubmed.ncbi.nlm.nih.gov/10683591/
Sood A, Prasad K, Chhatwani L, Shinozaki E, Cha SS, Loehrer LL, Wahner-Roedler DL. Patients' attitudes and preferences about participation and recruitment strategies in clinical trials. Mayo Clin Proc. 2009 Mar;84(3):243-7. doi: 10.1016/S0025-6196(11)61141-5. PMID: 19252111; PMCID: PMC2664601. https://pubmed.ncbi.nlm.nih.gov/19252111/
Bergmann F, Matzneller P, Weber M, Yeghiazaryan L, Fuereder T, Weber T, Zeitlinger M. Perception of clinical research among patients and healthy volunteers of clinical trials. Eur J Clin Pharmacol. 2022 Oct;78(10):1647-1655. doi: 10.1007/s00228-022-03366-3. Epub 2022 Jul 27. PMID: 35896802; PMCID: PMC9482583. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9482583/
Abdulhussein D, Yap TE, Manzar H, Miodragovic S, Cordeiro F. Factors impacting participation in research during the COVID-19 pandemic: results from a survey of patients in the ophthalmology outpatient department. Trials. 2022 Sep 30;23(1):823. doi: 10.1186/s13063-022-06748-1. PMID: 36175935; PMCID: PMC9522458. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9522458/
Unnikrishnan R, Pradeepa R, Joshi SR, Mohan V. Type 2 Diabetes: Demystifying the Global Epidemic. Diabetes. 2017 Jun;66(6):1432-1442. doi: 10.2337/db16-0766. PMID: 28533294. https://pubmed.ncbi.nlm.nih.gov/28533294/
George, K., Oldfield, C., Evers, J., & Flanagan, J. (2022, August 11). The Clinical Trial Challenge: To win patients, win over physicians. Bain. https://www.bain.com/insights/the-clinical-trial-challenge-to-win-patients-win-over-physicians/
Flanagan, J., & Evers, J. (2023, April 17). How customer-first clinical trials cut complexity and delays. Bain. https://www.bain.com/insights/how-customer-first-clinical-trials-cut-complexity-and-delays/
Regillo, C. (2023). Observations from phase 2 of the DR:EAM study. Eyetube. https://eyetube.net/spotlight/ocuterra/observations-from-phase-2-of-the-dream-study