Research, Manufacturing, Regulatory, And More: What Are The Challenges With CGTs?
By Roger Palframan, head of U.S. research, UCB
As our scientific knowledge and understanding of disease advances, we are set to enter an era of remarkable medical innovation. A good example is cell and gene therapies (CGT), where we have recently seen several new therapies advance through clinical development and gain approval. This innovative field holds the promise of precision medicine and has the potential to transform healthcare by tackling the root causes of genetic disorders through potentially disease-modifying and curative options for some patients. Yet, along with robust growth and promising prospects, CGT development also presents a unique blend of challenges. From complex manufacturing to the need for greater and more meaningful patient engagement to evolving regulations and reimbursement, these challenges must be traversed for CGT to reach its full potential for patients.
Complex Manufacturing Processes
While small molecules and biologics benefit from well-established manufacturing and quality control practices, manufacturing for CGT clinical trials involves a series of even more intricate processes. Such processes, some of which have similarities to biologics, include cell culture, genetic modification, harvesting, purification, formulation, and fill/finish. These methods currently generate lower-than-optimal productivity and are inherently complex. In addition, they require significant infrastructure and extensive testing to address the unique quality control needs of CGTs.
With complexity comes higher costs. As such, the costs associated with manufacturing CGTs are substantially higher than those of small molecules and biologics. In addition, any changes to processes or products during CGT development can cause significant delays and require additional bridging studies. To manage this, advanced chemistry, manufacturing, and controls (CMC) practices are needed from the start to ensure an integrated, end-to-end approach from research through development and, ultimately, into commercialization.
To ensure that CGTs can deliver a long-term competitive advantage beyond initial approvals, innovation and standardization of manufacturing and quality control processes, supported by robust knowledge and data sets, are needed. As the CGT landscape is fast evolving, establishing technology platforms that can adapt to the increasing complexity of CGT products and evolving regulations to maintain compliance is necessary to stay at the forefront of development.
The supply chain dynamics for CGT clinical trials also differ significantly from those of small molecule and biologics trials. In comparison to these modalities, CGT manufacturing and supply must consider even more thoughtfully the entire treatment journey, from manufacturing to patient administration, while accounting for the specialized storage conditions and, in some cases, limited shelf-life that characterize CGT products. It is, therefore, critical to ensure an adaptive supply chain is in place.
An Evolving Regulatory Landscape
With the intention of most CGT-related programs to treat rare diseases, and the fact that there are few approved CGT products, there is currently limited precedent to guide regulatory strategies. As such, regulatory authorities, like the FDA, are continuously updating guidelines to address their understanding of the increasing complexity of CGTs and the associated regulatory challenges.
While this makes it more challenging for companies to stay up to date with regulatory requirements, there have been significant positive developments. For example, recent guidance from the FDA on platform designation for gene therapies aims to streamline the submission process by allowing the use of data from previously approved products when common elements, like a platform capsid or payload, are used with minimal changes. This initiative aims to reduce both the cost and time burden for both CGT developers and the FDA. The FDA also announced in July 2024 the establishment of a Rare Disease Innovation Hub to enable better navigation and collaboration within the divisions of the FDA to accelerate R&D in rare diseases, often a particular focus for CGT.
Additionally, the FDA is collaborating with other major regulatory bodies in Japan and Europe to harmonize processes, including implementing a common technical document. Early and proactive engagement between regulators and CGT developers, through scientific advice and meetings, is also helping to ensure the efficient design and execution of clinical trials. These efforts reflect a growing recognition of the complexities involved in developing CGTs and a commitment from the broader health community to finding collaborative solutions.
Patient Engagement
Patient engagement is the pivotal element in the successful execution of clinical trials. This is especially true for CGT clinical trials where, unlike more traditional randomized clinical trials that often involve more common conditions with larger patient pools, CGTs target rare diseases, leading to a limited pool of eligible candidates and making it difficult to find study participants. Furthermore, it can be challenging to find patients who are willing to participate in these studies due to a variety of reasons.
A recent study1 by UCB, presented at the American Society of Gene and Cell Therapy’s (ASGCT) 2024 Annual Meeting, looked at the factors that impact patients’ likelihood of participating in gene therapy (GT) trials. The findings showed that, for GTs, patient willingness to participate depended on the progression of their disease and the effectiveness of their current treatments. Patients who perceived their treatment urgency as high and felt the impact of their disease on their quality of life were found to be more likely to participate. Even after patients choose to participate, they may still have questions or concerns and logistical and personal factors also can influence participation. This differs from small molecule trials, where the treatment landscape and patient journey may be more predictable.
Overcoming these challenges requires a multifaceted approach. First of all, we can maximize our ability to identify a greater number of eligible patients by enhancing identification efforts through rigorous screening tests and targeting specific patient groups. Additionally, improving accessibility, streamlining processes, and prioritizing patient support will empower patients throughout their healthcare journey, allowing them to take an active role in their clinical trial experience. This, in turn, fosters a more conducive environment for successful patient recruitment and retention.
Keeping Up With Technological Advances
Today, technology is progressing on so many fronts and driving our ability to innovate in healthcare, and that includes CGT. Recent advancements in vector and capsid technology are enhancing the precision, efficacy, and accessibility of CGT. Innovations in vectors have led to improved targeting specificity, reduced immunogenicity, increased genetic payload capacity, and enhanced stability, ensuring that therapeutic genes reach their intended destinations efficiently and safely. Meanwhile, refined capsid engineering has further honed these capabilities, enabling more precise delivery, greater immune evasion, and the ability to carry larger or multiple genes. This progress not only offers new hope for treating a wider range of diseases with greater efficacy and tolerability but also exemplifies the importance of anticipating and embracing future innovations to ensure the best possible outcomes for all patients.
Overcoming Unique CGT Challenges
CGTs represent a fundamental shift in the healthcare landscape, promising to address the root causes of genetic disorders. However, the development of CGTs is not without its challenges, including complex and expensive manufacturing processes, evolving regulatory landscapes, challenges in patient recruitment, and the need to embrace technological advancements. The industry must standardize manufacturing processes, stay updated on regulatory changes, improve engagement strategies for patients with rare diseases, and keep pace with technological innovations. As the landscape of CGT continues to evolve, leveraging robust technological platforms and implementing a patient-centric approach are key to navigating its complexities and changing the future of medicine.
References:
1.Vandeloo C, Baron O, Gangaramany A, et al. (2024, May 7-11). Understanding Drivers of Patient Acceptance Towards Invasive Gene Therapy Clinical Trials. The American Society of Gene and Cell Therapy’s Annual Meeting, Baltimore, U.S. https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=97921
About The Author:
Roger Palframan is head of U.S. research at UCB. He has held leadership roles in research and external innovation and has led project teams in discovery and global clinical development. Palframan has led the strategy and build of UCB’s U.S. research capability, which included the acquisition and integration of Beryllium Discovery, Element Genomics, Ra Pharmaceuticals, and Zogenix. He has led the strategy and build of the company’s global gene therapy research platform and digital transformation in global research. Palframan received his BSc in pharmacology at King’s College London and his Ph.D. in immunology at Imperial College London. Roger was a Wellcome Trust Postdoctoral Research Fellow at Harvard Medical School.