Bench to bedside: Bridging the gap

The trajectory of a novel therapeutic from initial scientific discovery to clinical application (colloquially known as “bench to bedside”) is fraught with intricate challenges. In ophthalmology, a discipline continuously pursuing breakthroughs for blinding diseases ranging from glaucoma and age-related macular degeneration (AMD) to inherited retinal diseases (IRD), this translational pathway can be particularly complex. Despite significant advancements in basic science, a substantial number of promising preclinical candidates fail to reach patients.[1] This article highlights critical hurdles encountered during the translation of potential new ophthalmology treatments, encompassing limitations in preclinical models, regulatory complexities, intellectual property (IP) dilemmas, funding challenges, and global reimbursement disparities.

The Translational Pathway

The path of a new ophthalmic treatment starts in the lab, involving initial discovery research, target identification, and the screening of potential therapeutic compounds to select a lead candidate. This foundational phase typically occurs in academic laboratories or early-stage biotech firms. Promising candidates then advance to preclinical development, which encompasses in vitro studies and in vivo experimentation, initially utilizing smaller animal models to assess efficacy and proof of concept. As a candidate demonstrates promise, studies progress to larger species with rigorously designed studies under good laboratory practices (GLP) to critically assess pharmacokinetics, toxicokinetics, and systemic and ocular safety, which are essential to moving into the clinic.

Upon successful completion of preclinical studies, an Investigational New Drug (IND) application must be submitted to regulatory bodies such as the U.S. Food and Drug Administration (FDA) or its international counterparts. For ocular drugs or combination products, the IND application necessitates comprehensive data, including detailed pharmacology and toxicology profiles, robust chemistry, manufacturing, and controls (CMC) information to ensure product quality and consistency, and meticulously designed clinical protocols for proposed first-in-human trials. The IND approval permits the initiation of human clinical trials, which typically proceed through three distinct phases: Phase I trials tend to be dose ranging, with small cohorts of healthy volunteers to identify safety issues while pushing exposure; Phase II trials evaluate efficacy, dose and regimen, and further characterize safety in a larger patient group; and Phase III trials confirm efficacy, monitor adverse reactions, and compare the new treatment in a well-powered robust controlled manner to an existing standard of care in a large patient population. Successful completion of these phases, coupled with CMC, culminates in a New Drug Application or Biologics License Application submission for regulatory review and potential market approval.

While simple to describe, the translational research pathway can be exceedingly complex and is full of hurdles that must be managed in a timely fashion to maintain timelines and stay on budget. We will dig into some of those hurdles below.

Preclinical Model Limitations and Their Impact on Translation

A foundational challenge in ophthalmology drug development resides in the inherent limitations of preclinical animal models.[2] While these models are indispensable for elucidating disease mechanisms and validating one’s initial hypotheses, they frequently prove inadequate in accurately mimicking the intricate pathology, multifactorial, and progressive nature of human ocular diseases. For instance, numerous retinal degenerations in humans involve multifaceted genetic, systemic, and environmental factors that are arduous to replicate within a singular knockout model. Similarly, while optic nerve crush models are extraordinarily helpful in the identification of potentially neuroprotective compounds for the treatment of glaucoma, this is not the pathophysiology of slowly progressive glaucomatous vision loss in an aging individual.

Another critical concern pertains to the lack of heterogeneity within preclinical models. Animal studies typically use genetically identical or highly inbred strains, leading to highly uniform responses to therapeutic interventions. This is in stark contrast to human patient populations, whose vast genetic, lifestyle, and environmental heterogeneity profoundly influences disease presentation and therapeutic efficacy. While this lack of preclinical heterogeneity is important to keep early drug discovery studies small by requiring fewer animals, and therefore lower in cost, it can result in ostensibly promising outcomes in controlled animal settings that do not effectively translate to diverse clinical populations.

The considerably shortened life span of rodents presents another critical hurdle in the early-stage investigation of age-related diseases such as AMD and glaucoma. While this shortened life span has several benefits, shorter lifespans as well as divergent ocular anatomies and physiologies compared to humans make the accurate modeling of chronic, age-dependent human conditions exceedingly challenging.

Recognizing these limitations, regulatory bodies, including the U.S. FDA, are increasingly exploring and encouraging the use of New Approach Methodologies as alternatives to traditional animal testing.[3] These innovations include human cell culture models, organ-on-a-chip technologies (which mimic organ function on a microfluidic device), and advanced computational models. Such human-relevant in vitro systems can offer valuable insights into how a drug might behave in patients, potentially providing more predictive data, reducing ethical concerns associated with animal use, and speeding up early development. Other international regulatory agencies, particularly in Europe and the UK, have also been at the forefront of accepting data from nonanimal methods where scientifically justified, indicating a global shift toward more human-centric and efficient preclinical assessment.

IP and Publication Dilemmas

Once the initial discovery is made, the academic instinct to “publish or perish” can prove difficult to ignore. Without question, the timely dissemination of research findings through peer-reviewed publications is paramount for professional advancement and securing funding. However, this frequently conflicts with the prerequisites for IP protection, particularly patenting. Public disclosure of an invention prior to the filing of a patent application can jeopardize patentability in numerous jurisdictions.[4]

More specifically, public sharing of an invention, whether through a grant application that becomes publicly accessible, an abstract presented at a conference, or a published manuscript, can be considered prior art.[4] Prior art refers to any evidence that an invention is already known to the public. Most patent systems around the world operate on a “first-to-file” principle, meaning that if an invention is publicly disclosed before a patent application is filed, it can no longer be patented by anyone, as it is no longer considered novel. While the U.S. offers a one-year “grace period” after public disclosure to file a patent application, many other countries do not have such a provision, making any public disclosure a fatal blow to international patent rights.

This presents a critical dilemma for academic scientists: publish early to garner recognition and secure grants, or defer publication to safeguard IP and augment the commercial viability of their discoveries? Dealing with this tension requires careful planning, support from their institutions for IP management, and a shift in thinking toward understanding the business side of research right from the start. It is therefore crucial for researchers who believe their observations are potentially patentable to engage early with their university’s technology transfer office. Without robust IP protection, the incentive for industry partners to invest in a promising academic discovery is significantly diminished.

Funding Landscape Challenges

While early-stage academic research can be conducted using funds procured through government grants (like from the National Institutes of Health (NIH), National Science Foundation (NSF), or Indian Council of Medical Research (ICMR)) and charitable nonprofit organizations, these monies are often insufficient to cover the extensive costs of preclinical development, safety testing, and scaling up CMC manufacturing, all of which are needed before human trials can even begin. This finding gap between the initial promising discovery and the point at which they become attractive investments for venture capital firms or pharmaceutical companies is colloquially referred to as “the valley of death.”[5]

A significant portion of these costs comes from the need for GLP-compliant preclinical studies. GLP refers to a set of strict regulations and quality standards for nonclinical laboratory safety studies, ensuring their integrity, reliability, and validity for regulatory submission. Non-GLP studies, typically conducted in earlier research phases, are more flexible and cost-effective as they do not require the same extensive documentation, quality control, and auditing rigor of GLP work. Any work that must be GLP-compliant is often performed at a Commercial Research Organization, which can be expensive.

The need for GLP compliance markedly increases other costs incurred at this stage, such as extensive GMP-compliant CMC activities to refine the list of candidates down to a single drug formulation, as well as scaling up production of a product that passes sterility, purity, and analytical testing. Additionally, extensive GLP-compliant pharmacokinetic, toxicokinetic, and pharmacodynamic studies in multiple nonrodent species (typically rabbits and dogs) are required by regulatory agencies prior to use in humans to better understand how the drug behaves in the body across different species over the course of several weeks or months.

Beyond GLP, other expenses incurred at this stage are often related to preparing for regulatory submissions (e.g. IND packages), including the use of regulatory consultants and writers to aid in the preparation of these documents. Additional consultants are often used to help write clinical trial protocols, set up trial sites, and manage patient-sensitive data.

To bridge this crucial gap, innovative solutions are emerging, including the establishment of dedicated translational research funds, accelerator programs, and more robust public–private partnerships. These initiatives aim to provide the necessary capital and expertise to derisk early-stage assets, making them more attractive for larger investments and ultimately accelerating their journey to patients.

Regulatory Complexities and the Need for Novel Endpoints

Navigating the global regulatory landscape can present a formidable barrier. Clinical trial prerequisites, ethical guidelines, and approval processes can vary considerably across different nations and regulatory authorities (e.g., the US FDA, the European Medicine Association, or the Central Drugs Standard Control Organisation in India). These variances mean companies need to design bespoke trials specific to each region, which require extensive documentation and often repeat efforts, which adds to the time and cost of developing drugs. Harmonizing global regulatory standards to be more similar remains a lofty goal, and, until that is complete, the global clinical trial process introduces multiple layers of complexity for multinational pharmaceutical companies and academic researchers alike.

Moreover, for ambitious clinical objectives such as neuroprotection in glaucoma or restoration of vision in advanced retinal dystrophies, clinical endpoints may prove insufficient. The development of novel, sensitive, and clinically meaningful regulatory-approved endpoints is imperative. However, this may require additional work, understanding the natural history of the disease in order to determine the impact of an intervention and or therapy. A pertinent example is the development of Luxturna (voretigene neparvovec), a gene therapy for RPE65-mediated IRD. Its approval necessitated the creation of a new multiluminance mobility testing endpoint to objectively demonstrate Luxterna’s capacity to facilitate patient navigation and enhance visual perception in low-light conditions, representing a significant change from the previously accepted standard visual acuity tests.[6] This underscores the importance of innovative endpoint development that genuinely reflects the functional benefits of nascent therapies, particularly for diseases that are considered untreatable, poorly understood, and or still progressive.

Eventual Commercialization and Reimbursement

Another crucial, yet often overlooked, consideration in early-stage development is the future commercial and reimbursement landscape. While researchers may be focused on efficacy and safety, the long-term viability of a novel therapy is also influenced by its ability to compete in a complex, stratified marketplace. If a new therapy is launched into a therapeutic space where genetic variability affects treatment outcomes, this can have profound implications for pricing, positioning, and patient selection.

Beyond scientific innovation, practical issues such as manufacturing scale-up, product stability, shipping logistics, and shelf life—especially for products requiring refrigeration or with limited stability—must be addressed early. These factors contribute to the cost of goods (COGs), which can substantially influence a product’s profitability. High COGs, when combined with modest reimbursement rates, may render an otherwise promising product commercially nonviable.

Market research, therefore, becomes a critical early activity.[7] Understanding the true unmet medical need, the competitive landscape, and the expectations of key stakeholders, including prescribers, payers, and policy makers, can help define a product’s value proposition. Developers must ask: Who will use this therapy? Who are the payers? What is the measurable benefit, particularly if efficacy is only comparable to existing genetic-based alternatives?

Finally, it is important to recognize that pricing and reimbursement dynamics differ significantly across healthcare systems.[7] In single-payer systems, such as those in many European countries, pricing pressures are higher and reimbursement thresholds may be stricter. As a result, even a clinically effective product may not be commercially pursued if projected revenues cannot offset development and manufacturing costs. These economic realities emphasize the need for early alignment between scientific promise and commercial feasibility.

Conclusion

Getting a potential new ophthalmology treatment from the lab to patients is a complex, multifaceted effort with significant challenges, but also significant rewards if these hurdles can be overcome! Challenges with preclinical models, the complexities of global regulations, the need for new ways to measure clinical success, the tricky balance between protecting IP and publishing research, constant struggles to find funding, and reimbursement hurdles have all contributed to many promising treatments failing to reach patients. Overcoming these hurdles requires a coordinated team effort involving basic scientists, doctors, regulatory experts, industry partners, and policymakers. Building collaborative environments, creating better preclinical models, making regulatory pathways more consistent, encouraging early awareness of IP, and setting up strong funding for translational research are key steps to getting sight-saving therapies to patients worldwide faster.