Biosimilar development in ophthalmology
Regulatory and Operational Nuances Demand Specialised Support
Bart Chapman, MD
Bart Chapman is a board-certified ophthalmologist for over 35 years in addition to his 30 years experience in the biopharmaceutical industry. He directs clinical ophthalmology trials through all phases. This has included serving as the medical director during the approval of six drugs for DME, three for nAMD, and three for retinal vein occlusion (RVO). He has provided medical oversight for the approval of an anti-VEGF drug for the treatment of DME and nAMD.
Bart Chapman and Shanthi Sundaramoorthy answer common questions about ophthalmology studies, and those relating to biosimilars.
Q. How would you describe the development landscape in ocular diseases right now?
A. It’s extremely active. There are currently hundreds of products in development now, including 27 in the queue at the US Food & Drug Administration (FDA) for dry eye alone. This is in response to a high unmet need in ocular diseases, exacerbated by rising disease prevalence. The population is aging and many eye diseases are more common in the elderly. At the same time, there’s an increase in the diabetes population as well as the hypertensive population – particularly after a change in the threshold for hypertension – and both are high risk factors for eye disease. Many new therapies are relying on advances in monoclonal antibodies, stem cells, and genetics. These, of course, will come at a high price.
Q. What are the current treatment options for neovascular agerelated macular degeneration (nAMD) and diabetic macular edema (DME)?
A. The primary – and gold standard – treatment for both is anti-vascular endothelial growth factor (VEGF) treatment, as it causes neovascular regression as well as stabilisation. Pan retinal photocoagulation is also a common treatment for DME.
Q. What are the pros/cons of developing a biosimilar for DME or AMD?
A. The prevalence of both diseases is already great and continues to grow. There are already a few companies developing biosimilars, and there are also new original therapeutics in the pipeline that promise to be even more effective in addressing disease progression. The question is: how well will a biosimilar be accepted when a branded therapeutic is well established, having been proven highly effective, as well as the cost of the branded therapeutic. Many newer biologic drugs for DME and AMD can easily cost from 10,000 to 20,000 USD per year per patient and it is in the interest of patients that alternative sources of a medicine (including Bart Chapman, MD Medical Director Early Phase Shanthi Sundaramoorthy, PhD Sr.Director, Global Project Management Biosimilars and Biotech ICONplc.com/biosimilars Bart Chapman is a board-certified ophthalmologist for over 35 years in addition to his 30 years experience in the biopharmaceutical industry. He directs clinical ophthalmology trials through all phases. This has included serving as the medical director during the approval of six drugs for DME, three for nAMD, and three for retinal vein occlusion (RVO). He has provided medical oversight for the approval of an anti-VEGF drug for the treatment of DME and nAMD. Shanthi Sundaramoorthy is a Senior Director in Project Management, Biosimilar Group at ICON. She has nearly 20 years of Clinical Research experience. Her background includes experience in pharma working for both large pharmaceutical and biotech companies. Shanthi holds a doctoral degree in Molecular Biology and Biochemistry with a wide therapeutic clinical research experience including Ophthalmology, Endocrine, Infectious Disease, Respiratory System, Rare Diseases, Hematology and Oncology, Gastrointestinal, Immunology and CNS. biosimilars) become available to ensure sustainable patient access to treatment.
Q. How difficult is patient recruitment for ocular studies? Does the fact that there remains a high unmet need make recruitment easier?
A. Actually, patient recruitment is very challenging in this therapeutic area. As mentioned, there’s a crowded field of studies, so competition for patients is intense. Other difficulties arise from the particular aspects of the protocol that do not suit patients’ treatment preferences. A patient’s disease may be present in both eyes, but the study may be designed to treat only one, for instance, so that the second eye becomes the comparator. Or, there may be a waiting period between treating the first and second eye, a deterrent to patients who want both eyes treated simultaneously. Studies may also place a heavy burden on patients, with site visits often lasting four to six hours and the study itself extending over several years. We’re working on one study now that follows patients for five years. Tactics focusing on retaining subjects through appreciation and providing tools that support patient participation, such as study guides, consent tools, convenience items, and assistance, for example would help for studies with long duration.. Additionally, if requested ICON can support sites in developing a robust retention plan including sharing tips and best practices for retention and re-enforcing regular communication between the patient and the site. Large font and colors appropriate for visually impaired will be applied across all patient facing materials. The patient population can also be challenging, as patients tend to be elderly and may have compromised vision. They may need to rely on caregivers for transportation to/from clinic visits. Reimbursing for travel and for meal expenses during lengthy visits can help patients contend with the logistics.
Q. Does patient recruitment differ for biosimilars?
A. Yes, because elderly patients, who may be more fearful of clinical trials to begin with, may be unfamiliar with biosimilars. Providing patients and caregivers with educational materials about their condition, about the study, and biosimilar education tools can support patient consent and engagement. Large font and colors are recommended in all materials for the visually impaired. Plus, recruitment rates can be improved by including countries in which patient access to the originator and/or alternative therapies is low.
Q. What are the challenges with site selection and engagement, particularly for biosimilars?
A. Healthcare professionals, too, may have limited knowledge of biosimilars. Investigators may also be less eager to take part because the publication opportunities will likely be limited. And, in trials for ocular diseases, there may be very specific equipment, software, and image transfer needs at the site. It is helpful to pre-screen sites that have been high enrollers in other studies in the disease area. We’ve also seen sites drop out during the start-up process at a higher rate for biosimilars than for originator treatments. One solution for this is to have a certain percentage of “backup” sites ready to go in that event.
Q. What endpoints are commonly used in ophthalmic therapies? Are the measures straightforward?
A. It depends on the disease, but, in most cases, they are dictated by regulators. The challenge is in figuring out how you will establish them. What do you need to do in operationalizing the trial to get to those endpoints? Often, such as in DME and neovascular macular degeneration, the endpoint can be the patient’s best-corrected visual acuity (BCVA), measured through subjective refraction in a clinical examination. It can be a good idea to employ a third-party vendor to standardize and conduct BCVA training across sites. Sites need a dedicated space for performing BCVA exams. In other cases, such as in dry eye syndrome, the endpoint is very difficult to establish and measure because it must rely on patientreported outcomes. In other areas such as geographic atrophy, the endpoint is based on measurable physical changes in the back of the eye, such as the size of a lesion or degree of neovascular regression.
Q. What is the general development path for ocular treatments that are invasive, such as with anti-VEGF injections?
A. For intravitreal administration of an originator drug, such as for AMD or DME, it is not necessary to perform a Phase I study. Since the treatment is not systemic, the procedure will not produce sound pharmacokinetic and pharmacodynamic data on which to base a scientific conclusion. One route is to conduct a Phase Ib study, proceed to a Phase II (dose escalation) study, and then to a sentinel study in which a small number of patients are enrolled and monitored closely for highly repeatable adverse events and serious adverse events. Only after their safety signals have been evaluated are larger cohorts enrolled. ICONplc.com/biosimilars This provides the safety data needed in advance of a Phase III pivotal study. For a biosimilar product, since intravitreal injection of an anti-VEGF drug cannot be done in healthy eyes, sponsors can proceed straight to a Phase III study, ensuring adequate safety oversight as it will be a First In Human trial. Another complication that must be mentioned in relation to studies of anti-VEGF therapies is the possibility of tachyphylaxis, a sudden onset of drug tolerance. We are starting to see cases of tachyphylaxis in some patients who’ve been on long-term therapy for AMD.
Q. What advice can you offer for developing a “lean, clean” trial for a biosimilar ocular therapy?
A. Well, first, make sure that you understand what regulatory agencies are looking for in terms of demonstrating biosimilarity through the chemistry, manufacturing, and control process. Second, understand what the regulatory agencies are looking for with respect to evidence, and provide only that information. Some developers have a tendency to include a lot of “nice to haves” in the study protocol, rather than adopting a design that simply addresses the main research questions for a biosimilar. For example, they may include assessments and additional visits that are not required in order to demonstrate biosimilarity. Adding in extra data points increases the burden for site staff and patients, negatively impacting the study feasibility. We recommend starting with the very minimum requirements for the Biologics License Application /Marketing Authorization Application approval, adding in only those aspects that could facilitate market access. Another suggestion is to consider adopting innovative statistical designs, such as a Bayesian approach. With a Bayesian design, rather than establishing a one-toone comparison between patients receiving the biosimilar and those receiving the originator, the ratio can be two to one. A Bayesian design can greatly minimise the number of patients required for the trial, which in turn has a major impact on cost and timelines. It is important, of course, to confer with regulators on the acceptability of your plan to use a Bayesian statistical analysis.
Q. Why has ICON established a specific group to support biosimilar development?
A. Biosimilars are complex molecules, and there are nuances in the development and approval process that are different from that of originators. It requires specialise knowledge and expertise. ICON has created an Integrated Biosimilar Services team to help sponsors navigate the evolving regulatory environment and the operational and commercial challenges that arise. Our team has spent decades in delivering the first generation of biologic and biosimilar drugs.