Cell And Gene: Regulating Rare Disease Study Design

By Life Science Connect Editorial Staff

A 2023 Cell & Gene Live event welcomed Dr. Adora Ndu, Chief Regulatory Affairs Officer at BridgeBio and Dr. Nina Hunter, Vice President, Corporate Strategy at REGENXBIO, to join host Erin Harris to discuss the top three regulatory issues impacting the cell and gene therapy sector.ⁱ Drawing from that discussion, this article examines how the industry can better leverage existing data and tools toward improving cell and gene (C&G) study design.

More than 7,000 unique rare diseases exist in the United States, and 300 million people worldwide live with a rare disease. Despite the complex nature of studying these diseases and producing therapies, regulatory requirements don't change for demonstrating their safety and efficacy versus, say, a more common small molecule therapy. The FDA has acknowledged the need for additional flexibility in applying these standards to rare diseases, as well as a willingness to rely on less certainty when appropriate.

Pediatric Drug Development Faces Unique Hurdles

Half, if not more, of rare diseases impact pediatric patients. So, C&G therapies provide a potentially transformative option for these children early on. Their conditions may progress quickly, be irreversible, and/or lead to early death in childhood. But pediatric clinical trials are perhaps the most challenging area of treatment because the risk is higher, and difficulties exist around diagnosis and access to patients dispersed around the world.

Additionally, heterogeneity exists even within the pediatric population, especially around neurodegenerative diseases, so even demonstrating the prospect of direct benefit is a significant challenge. Sponsors and researchers also must consider ethical standards relevant to dose selection, when to introduce the treatment to patients, etc. The industry would be well served to explore how technology can make those pediatric patients, studies, and data more accessible when they span a limited number of research centers across a wide geographical area.

Patient Perspective Is Integral To Regulatory Practicality

The incorporation of patient perspective improves the quality, relevance, safety, and efficacy of drug development. It also can help to inform regulatory decision-making. So, it is fundamental to seek out and value patients’ perspectives on the disease they live with every day.  Part of what we learn, even early in development, includes the burdens of the condition and the outcomes patients see as important. This information, in turn, helps inform decisions like selection of study endpoints.

Both qualitatively and quantitatively, it is critical to incorporate patients’ voices — from surveys, focus groups, PROs, or by including them in engagements with health authorities — throughout the development life cycle and even after product approval. A tripartite collaboration between the FDA, sponsors, and patients/patient advocacy organizations helps ensure patients’ challenges and concerns are being heard, understood, and accommodated. Some diseases are so rare that a reviewer may never have treated or even encountered a patient with a particular disease. So, the ability to paint regulators a picture that overflows the four corners of a regulatory submission, detailing what can initially appear as statistically insignificant differences, can be incredibly meaningful in the day-to-day lives of patients.

Overcoming Novel Surrogate Endpoint Challenges

A key part of the challenge when leveraging a surrogate endpoint is that, from a regulatory standpoint, each case represents a unique judgment call for the FDA. So, how much understanding do you need to establish about the relationship between your potential treatment and the disease? That factors into the threshold for use. 

As noted in the previous article in this series, the hope is that agency improvements funded by the U.S.’ 2023 omnibus spending bill will make accelerated approval more accessible to potential treatments.ⁱⁱ Even though a reasonably likely surrogate endpoint doesn't need to be validated, the FDA could request clinical data to support its determination. As the FDA learns more about these biomarkers and how they're being used, those decisions could come together more quickly and with more thoroughly explained rationales.

Animal Models Are Ill-Suited To C&G Therapy

Even when animal models are available, challenges remain in terms of how that those models actually represent what might happen in a clinical study.ⁱⁱⁱ A 2019 FDA meeting focused specifically around fit for purpose, preferred animal model, and thoughtfulness around why a given study is using animal models to pursue its answers. Regardless, even existing animal models cannot provide all the information researchers seek earlier in development.

The FDA's Innovative Science and Technology Approaches for New Drugs (ISTAND) pilot program is designed to encourage the creation of drug development tools that are out of scope for qualification programs (i.e., longer-term biomarker clinical outcome assessment programs). ISTAND’s focus is on areas that show promise for additional application in drug development.

Accordingly, sponsors should turn to novel technologies for answers to the animal model conundrum, especially as their research targets specific mutations. For example, demonstrating the prospect of benefit early for some approaches, microfluidic culture devices (also called “organ on a chip”) are promising in vitro systems that can be used to recapitulate organ-level and even organism-level functions.

Microfluidic devices can recreate organ-level structures with the potential to model organ physiology and disease states for some prospect of benefit demonstration. So, it is vital for sponsors, patient advocates, and the regulators to work together to validate microfluidic device use for clinical development.

Best Practices For A Robust Regulatory Strategy

Many FDA reviewers lack background in rare diseases, so presenting them with a robust scientific foundation, from a clinical perspective, is imperative. Also, being part of broader public-private partnerships not only helps the agency, it helps the industry make progress toward necessary standardization and regulatory harmonization. Bringing external stakeholder voices into the conversation allows us to approach the agency with recommendations and an openness to collaborate.

And the value of leveraging the limited precedent already set in the C&G industry by approved products, incorporating it into your clinical development strategy, cannot be overstated. It is not always possible to obtain strong natural history data for a rare disease. A limited patient population means limited data collection.

Starting from the very first in-human study, how do we extrapolate all data that's useful toward proving safety and efficacy? Well-randomized, concurrent, controlled studies are generally considered ideal standards, but alternative approaches are needed to generate high-quality data when such a strategy is not possible.