s of May 2024, there are 36 US-approved cellular and gene therapy products. These products offer unprecedented solutions for diseases where traditional approaches fall short. However, groundbreaking innovations like cell and gene therapies bring unique challenges in their development and commercialization. During a presentation at the DIA/Harvard-MIT Center for Regulatory Science (CRS) Executive Roundtable in January 2024, Director of the FDA Center for Biologics Evaluation and Research (CBER) Peter Marks emphasized that addressing challenges in manufacturing, clinical development timelines, and different global regulatory requirements for these products is one of the center’s main goals in the year ahead: “CBER aims to make 2024 a breakout year addressing key challenges to the development of cell and gene therapies, especially for rare disorders,” Marks said.

CBER Director Peter Marks at Executive Roundtable.

Over the past year, the US FDA has released several guidance documents that highlight the importance of these therapies, providing insights to support their development. Notable among these are Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products (July 2023 draft guidance), Potency Assurance for Cellular and Gene Therapy Products (December 2023 draft guidance), Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products (January 2024 final guidance), and Human Gene Therapy Products Incorporating Human Genome Editing (January 2024 final guidance). But what are the current processes and procedures associated with cell and gene therapy development? Where are the bottlenecks, and why, and can we devise and prioritize solutions to overcome these bottlenecks? This roundtable evaluated these challenges from the regulatory pathway, clinical operations, and manufacturing perspectives.

Regulatory Pathways

Limited Experience in Cell and Gene Therapy

The Issue: One prominent hurdle lies in the limited experience that both developers and regulators have with these innovative therapies. This scientific landscape is relatively new and is rapidly evolving, which means sponsors and health authorities are learning as they go and adjusting study designs and data requirements in real time. This evolving landscape creates uncertainty and amplifies regulatory risk because developers often lack a clear playbook or precedent to follow. Misjudging or inadequately articulating these risks can cause project delays or even jeopardize the viability of projects or companies, particularly those focused on addressing rare diseases where returns on investment are inherently marginal.

Proposed Solution: Training initiatives and knowledge-sharing platforms such as workshops and industry forums could significantly bolster industry and regulator knowledge. Resources like these which facilitate the dissemination of regulatory and industry insights and best practices can help inform clear regulatory requirements for regulators and enhance the efficiency of industry development programs in meeting these requirements.

Regulatory Strategy

The Issue: Early engagement between industry and regulators, along with effective communication across stakeholder groups, is crucial to expediting regulatory strategy. However, these efforts are often hindered by the limits of available guidelines and by novel regulatory strategy models which present unprecedented challenges. In addition, regulatory expectations often remain ambiguous and unclear, leading to a lack of clarity within industry and discrepancy between regulatory authorities and companies attempting to align internal and external requirements. This disconnect underscores the need for an integrated regulatory strategy to bridge the gap between internal and external demands, and for streamlining supplier manufacturing processes to improve engagement.

Proposed Solution: An integrated regulatory strategy playbook that comprises best practices for navigating the journey from development to personalization in cell and gene therapy could be a pivotal tool. Drawing inspiration from existing industry playbooks for medical devices and combination products, such a resource would provide invaluable guidance to industry while ensuring confidentiality.

Regulatory Challenges on Manufacturing Processes

The Issue: Transfer of manufacturing processes poses another major regulatory challenge: process variability between academia and small contract manufacturing organizations (CMOs), for example, in addition to the absence of standardized manufacturing practices, can create barriers in the transition from early-stage development to commercialization. Concerns regarding intellectual property (IP) and exclusivity, which hinder collaboration and information sharing essential for addressing regulatory challenges during application reviews, further complicate this issue.

Proposed Solution: Proactive engagement with regulators to define manufacturing requirements and standards, along with collaborative efforts with various standards committees such as the International Organization for Standardization (ISO), the Association for the Advancement of Medical Instrumentation (AAMI), and the International Electrotechnical Commission (IEC), are essential to facilitate the evolution of standards in this space. This collaborative effort, leveraging existing clinical standard protocols endorsed by the FDA, holds the promise of establishing standardized practices and enhancing regulatory compliance within the dynamic landscape of cell and gene therapy.

CMC Comparability

The Issue: A lack of standards, harmonized guidance, and flexibility complicates chemistry, manufacturing, and controls (CMC) comparability, as does the distinct difference between academic developers’ starting points and commercial manufacturers’ requirements.

Proposed Solution: A Manufacturing Advisory Board could define methods for conducting the comparability exercise, leveraging existing data, and addressing pre- and post-change scenarios when appropriate. For example, a manufacturing advisory board may help define methods for how to conduct the comparability exercise or how to leverage existing or prior data pre-change or post-change, when appropriate. FDA’s draft guidance and the ICH cell and gene therapy discussion group are positive steps forward in developing policy in this area.

Global Regulatory Divergence

The Issue: Significant inconsistencies in regulatory requirements across different health authorities make it difficult to navigate the global landscape of clinical trials and development. Regional variations in clinical trial initiation and design, medical practices and standards of care, and development programs and submission strategies lead to multiple submission strategies and feedback mechanisms. The absence of harmonization and convergence exacerbates these issues and hinders progress. Additionally, resource limitations in industry and agencies further complicate matters and emphasize the need for developers to engage with regulatory authorities.

Proposed Solution: Efforts are underway to foster global harmonization and to streamline feedback processes, but the need for enhanced training and cross-learning opportunities to bridge the gap between stakeholders and facilitate more cohesive regulatory strategies remains critical. Forums like this can offer opportunities to bring together a “state of the industry” on a specific topic to help raise the level of knowledge, since not every sponsor is sophisticated in what they bring to agencies, which strains agency resources.

Divergence Between Health Technology Assessment (HTA) and Regulatory Health Authorities

The Issue: With the emergence of HTA over the last few decades, diverging expectations between HTA bodies and regulatory authorities pose a significant challenge. Differences in acceptable study designs (e.g., single-arm versus randomized controlled trials), reliance on surrogate endpoints and biomarkers versus outcomes data for value assessments, and acceptable study sample sizes all contribute to this divergence. The focus on cost-effectiveness and/or budget impact by HTAs, in addition to the regulators’ benefit-risk analysis, is another important difference that will require supplemental evidence for cell and gene therapies.

Proposed Solution: Guidance that harmonizes global HTA requirements for cell and gene therapies with regulatory health authority expectations could be helpful in navigating the diverging requirements of these two bodies. Additionally, one could consider a tiered approach to value demonstration, with the first tier involving regulatory health authority approval to facilitate patient access, and the second tier focusing on providing longer-term outcomes data and collecting real-world data initiated at the time of first-in-human studies and extended post-access to inform HTA analyses. This approach aims to meet both health authority and HTA expectations while accelerating patient access to promising therapies.

Manufacturing

Inadequate Exposure to Informed Decision-Making for Cell and Gene Therapy

The Issue: The majority of challenges stem from limited experience with and standardization of manufacturing processes involved in cell and gene therapies. Limited regulatory interactions, portfolios, batches, and patient data impede informed decision-making. The main problems revolve around the lack of standardization in manufacturing processes and analytical technologies, shipping and storage logistics, and workforce training. These challenges are compounded by the absence of industry-wide standards and centralized repositories for sharing information.

Additionally, the current state of storage infrastructure and solutions for highly labile, sensitive products is suboptimal. Despite the critical importance of these products, there has been a noticeable lack of prioritization towards enhancing storage capabilities, which stems from limited profitability and investment reluctance, posing significant challenges for both small and large companies. Small businesses often struggle to allocate sufficient resources for the development of robust storage and supply chain solutions due to the uncertain profitability of such investments. Similarly, large corporations face obstacles in committing substantial investments to assets that may not yield immediate returns. These are highly labile, sensitive products. Good infrastructure or good solutions for storage are lacking. There hasn’t been enough priority placed on storage solutions, whether it’s infrastructure or abilities to store product better. Addressing these challenges requires a concerted effort to foster a supportive environment conducive to innovation and investment in storage technology.

Proposed Solution: To address the lack of standardization and experience, disruptive technologies, automation, and data controls, alongside extensive knowledge-sharing initiatives and policy developments, could drive technology and standardization forward.

Improvements to storage infrastructure may require a larger investment in technology, advocating for decentralization (to lessen the dependency of low-temperature shipping/storage of the temperature-sensitive cell and gene therapy products), and drawing inspiration from disruptive technologies in other sectors, such as the solar and energy industries. Moreover, there is an urgent need to obtain funds to train and overcome the talent gap in the cell and gene therapy workforce, educate the public, foster wider acceptance of gene and cell therapies in the general population, and encourage innovation. Parallels to historical precedents like the “Sputnik moment” highlight the transformative potential of comprehensive training programs in propelling innovation and addressing the workforce needs of the future.

Clinical Operations

Quality Management System (QMS) Optimization

The Issue: Optimization of QMS processes faces significant hurdles due to a lack of experience in the specialized field of cell and gene therapy. This lack of experience is exacerbated by industry’s reliance on outdated methodologies derived from traditional pharmaceutical approaches. In addition, there is only limited experience with optimizing QMS for novel therapies and a lack of awareness and education about QMS in the cell and gene therapy domain. Industry’s tendency to utilize existing commercially available products for unmet medical needs rather than opting for a more novel product with less exposure ultimately leaves little room for innovation and optimization.

Proposed Solution: Integrating cell and gene therapy requirements into the overall QMS ecosystem would mirror past successes with incorporating regulations for biologics, drugs, and devices. Industry could draw on their prior experience and ensure successful integration mandated by the FDA in 2013 with 21 CFR Part 4 for combination products, as that approach underscores the necessity for proactive adaptation.

Effective Bidirectional Communication Strategies

The Issue: Regulatory hurdles including communication gaps between regulatory authorities, sponsors, manufacturers, clinicians, and patients have been pinpointed as impeding timely feedback and pathway clarity in the realm of clinical operations.

Proposed Solution: Enhancing communication channels, such as providing more frequent “current thinking” updates, FAQs, and leveraging platforms like professional society and liaison meetings can streamline interactions and crystallize emerging regulatory topics. Additionally, initiatives like joint regulatory and HTA efforts, such as the collaboration between the Medicines and Healthcare products Regulatory Agency (MHRA) and the National Institute for Health and Care Excellence (NICE), can harmonize evidence requirements and assessments across therapies.

Patient Identification

The Issue: Many of the rare diseases targeted by cell and gene therapies are underdiagnosed and often misidentified, leading to delays in diagnosis that can preclude patients from receiving treatment in the appropriate therapeutic window to maximize treatment success.

Proposed Solution: Further initiatives are needed to accelerate early diagnoses through newborn screening programs and the wider use (and funding) of genetic testing in the adult population, coupled with more extensive rare-disease awareness education.

Access for Patients

The Issue: Making cell and gene therapy accessible to patients means overcoming challenges in patient and provider education and implementing innovative care-delivery models.

Proposed Solution: Patient education initiatives that provide comprehensive understanding of the complexities surrounding cell and gene therapies as well as sponsor-supported educational programs, provider training, and so-called hub-and-spoke models could facilitate and expand access to lifesaving therapies. Other critical strategies to enhance patient access include leveraging commercial sponsors and patient advocacy groups for educational resources alongside federal initiatives and value-based reimbursements. Finally, examples from successful collaborations between commercial sponsors and central registries demonstrate the importance of addressing data fragmentation through standardized endpoints, data collection, and national registries. Sustained funding and collaborative efforts across stakeholders to realize these solutions are pivotal to ensure success.

Conclusions

The DIA/Harvard-MIT CRS Cell and Gene Therapy Executive Roundtable served as a crucial forum to address the multifaceted challenges and opportunities within the cell and gene therapy landscape. The roundtable highlighted the transformative potential of these therapies in addressing unmet medical needs while shedding light on the intricate regulatory, manufacturing, and operational complexities that hinder their efficient development and commercialization. These insights emphasized the critical importance of proactive engagement, collaborative partnerships, and continuous education to navigate these challenges effectively. Moving forward, industry is encouraged to leverage existing regulatory guidance, enhance bidirectional communication, emphasize clinical development and evidence-generation strategies to support value demonstration for cell and gene therapies, and streamline manufacturing processes to accelerate the delivery of these life-saving therapies to patients worldwide.