Ten best practices for developing ophthalmic CGTs

Cell and gene therapies are transformative innovations in ophthalmology, offering the possibility of one-and-done interventions to replace monthly injections for chronic conditions and to target diseases once considered untreatable.

Because the eye is an immune-privileged site,¹ these treatments are advancing rapidly, with Luxturna² and Encelto³ approved by the U.S. Food and Drug Administration and many others in development.^4,5 But to bring such therapies to market, sponsors need comprehensive plans that incorporate proven development strategies.

Through years of cross-functional experience, we’ve identified our top 10 best practices that can help drug developers avoid delays, protect data quality and meet regulatory, clinical and manufacturing expectations.

We’re excited to envision this checklist helping innovators to introduce treatments with the power to change practice and improve lives.

1. Lock in product quality early

Early decisions about cell and gene therapy approaches can shape clinical performance, scalability and regulatory success.

In cell therapy, to ensure fitness for purpose and consistency across batches, starting materials should be well-characterized for identity, purity, functional activity and genomic stability. For therapies delivered with induced pluripotent stem cells (iPSCs), sponsors should establish master and working cell banks under current Good Manufacturing Practice (cGMP).

To generate stable and predictable cell therapies — or to enhance durability through immune evasion⁶ — developers should rely on precise, site-specific genome editing technologies, such as CRISPR-Cas9⁷ or recombinase-based technologies such as TARGATT^TM or S-SELeCT^TM.⁸ Editing approaches should be evaluated for off-target effects, insertional mutagenesis risk and long-term genomic stability with analytical methods such as next-generation sequencing-based assays.

Internal characterization packages can support comparability as processes evolve from research to clinical manufacturing, and potency assays developed as companions to specific therapies can bolster approval and long-term product control.

Best practices are similar in gene therapy development, where the use of well-characterized, cGMP-compliant viral vectors that remain potent and maintain quality from batch to batch is key to achieving controlled, cell-specific gene expression.⁴

2. Take cues from disease biology and clinical practicalities when choosing drug delivery methods

Both disease biology and the practicalities of administration routes should help sponsors choose a treatment’s delivery method.

Cell and gene therapies can be injected subretinally, intravitreally, suprachoroidally or intracamerally, but the biology of a disease and the components of its proposed treatment will help pinpoint the most appropriate method.

Sponsors should also consider potential side effects, such as inflammation, that can occur with intravitreal delivery or surgical complications that can arise with subretinal injections. Suprachoroidal administration seems to represent the sweet spot for delivering a retinal therapeutic from a safety perspective, and the good news is that we can get many treatments to the back of the eye through this space.⁹

The treatment setting is worth some reflection too, with subretinal injections typically conducted in the operating suite while the other methods are less invasive. In fact, cultured endothelial cells can now be delivered at the slit lamp to treat corneal diseases like Fuchs dystrophy.

3. Investigate disease natural history before planning a clinical trial

When developing a treatment, sponsors must understand the natural history of the disease they intend to treat and how it’s likely to affect patient eligibility for studies, the selection of endpoints and trial duration.¹⁰

To learn more about how a disease evolves and affects patients, sponsors can conduct meta-analyses of studies about the condition’s natural history. While there is a dearth of studies in this area, the National Eye Institute is funding more.¹¹

4. Design fit-for-purpose informed consent documents

Some cell therapies and all gene therapies raise unique considerations that must be addressed in participant-informed consent documents (ICD) under the supervision of an institutional review board (IRB), which protects the rights, welfare and safety of study participants. An IRB will require that ICDs describe the irreversibility of genetic changes; their potential transmissibility to future generations if gene editing is systemic rather than retina-restricted; and the possibility that investigators will need to monitor participants long term.

Participants must also be warned that gene therapies may cause unexpected effects — as Luxturna did in some patients who experienced atrophy of the retinal pigment epithelium years after the delivery of the therapeutic.¹²

Finally, they must be told whether whole-exome testing is planned, whether they will receive the results, how their genetic information will be reused or commercialized and how their privacy, and that of their relatives, will be protected.

5. Incorporate patient involvement from the start

Drug development is most successful when it incorporates patient insights, and regulators across the globe now require this. There are many examples of patients and patient advocates adding value to drug development by contributing their perspectives to trial design,¹³ endpoints¹⁴ and informed consent forms and by serving on patient advisory and drug safety and monitoring boards.¹⁵

This makes the resulting products more likely to resonate with stakeholders, from the regulators and payers who will decide whether to approve them to the patients who will incorporate the treatments into their daily lives.

6. Support IRB and IBC review — and reap its benefits

In addition to an IRB, the sponsors of cell or gene therapy trials are often required to work with institutional biosafety committees (IBCs), which protect the safety of research staff, close contacts of participants and the community.

To streamline both the IRB and IBC processes, drug developers should share their protocols, investigator’s brochures and pharmacy manuals with those bodies as early as possible. Documentation should describe investigational agents, along with how the drugs should be administered and what training clinic staff will need to accomplish that. IBCs will also need to know where investigational products will be received, stored, prepared and administered at each site and what will happen to any waste produced during the trial — as well as who will handle each of those steps.

When studies have multiple sites, it can be helpful to use a single IRB and an external IBC — even if local IBCs are required at each site. In those cases, a central IBC can review requirements and help sites prepare for inspections by their local IBCs. Using a single IRB and an external IBC can also promote consistency and save time by universally sharing problem-solving strategies that have been successful at individual sites.

7. Consider novel endpoints, but start planning early

There are many novel endpoints that could align elegantly with the natural history of specific diseases and the visual outcomes patients consider meaningful.

For instance, while trials evaluating therapies for inherited retinal diseases (IRDs) usually incorporate functional endpoints such as mobility testing, researchers are exploring measures they consider more accessible, such as best corrected visual acuity, low luminance visual acuity and full field sensitivity light threshold testing.

These efforts are most likely to be successful when sponsors validate their proposed endpoints and share their findings with regulators as early as possible. Ideally, sponsors should seek to use their novel measurements as primary endpoints, as regulators and payers consider these to be the most relevant.

8. Harmonize procedures and training across all clinical sites

To avoid delays and reduce variability across trial sites, sponsors must standardize their procedures.

They should train investigators to administer injections and monitor for side effects, or hire another organization to do so, with methods standardized across all sites. Clinical research teams must also be trained to collect and interpret endpoint data, such as retina optical coherence tomography or fundus photos, or to share them with an independent reading center for objective, standardized and masked review.

Equipment and environmental conditions should be standardized across sites, too. For instance, all eye examination lanes should feature the same level of light illumination, with Early Treatment of Diabetic Retinopathy Study (ETDRS) charts positioned at a standard distance from patients.

9. Plan for scalable expansion in manufacturing

A cell therapy’s delivery strategy informs how it will be manufactured. For instance, subretinal products require small-volume but high-viability preparations, making stability, thaw-to-dose workflows and site training essential. Intravitreal delivery demands different potency and distribution considerations, as it requires large doses and sometimes repeated administration.

Considerations are similar for gene therapies. In subretinal delivery, a well-engineered vector that contains a stable transgene and is surrounded by a pure capsid are key to successful delivery, while intravitreal gene therapies, due to their larger vector doses and higher exposure to the immune system, require careful planning around scalability, potency and purity.

Therapeutic modalities also call for specific processes. For example, autologous cell therapies require robust chain-of-identity and chain-of-custody systems to ensure that all patients receive their own cells safely, while allogeneic therapies benefit from centralized, batch-based production.

To plan for scalable expansion while maintaining product quality, sponsors can use closed systems to reduce contamination risk, supplier management programs to ensure consistency and continuity and stability programs to address shipping, thawing and site preparation.

As programs advance, sponsors should plan for technology transfer to cGMP facilities or contract development manufacturing organizations and implement digital systems to enhance traceability, reduce deviations and support compliance.

10. Think about the end of the process before getting started

For sustained success, sponsors should map out their entire developmental package in advance, ensuring that their plans are realistic and they have recruited the experts they’ll need for guidance. What matters to patients is key, but sponsors must also establish alignment with regulators and payers from the start so they can choose endpoints that will appeal to decision-makers.

Finally, sponsors should anticipate being asked by regulators to launch post-approval safety studies to monitor for unexpected adverse events.

Moving into the future

Luxturna’s approval started a movement that is poised to bring a host of cell and gene therapies to the treatment of ophthalmic diseases. It’s exciting to consider how those advancements will improve quality of life for patients who might otherwise have lost their sight, and for the physicians who treat them.

Our path toward that future is being forged by the companies and institutions developing these innovative cell and gene therapy treatments, and with expert guidance about how to approach that process, their contributions are bound to be revolutionary. 

References

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