The cell and gene therapy (CGT) clinical trials market is experiencing significant growth, with more than 3,900 products in various stages of development.[i]
This expansion places considerable strain on existing clinical trial infrastructure and regulatory review processes, and the escalating demand for specialized resources, such as manufacturing facilities, highly skilled personnel, and appropriately equipped clinical sites, can quickly outstrip the available supply chain capacity. This imbalance contributes to increased operational costs and potential delays in trial execution, making efficient study delivery paramount.
Even with a well-designed protocol, the successful delivery of a CGT trial hinges on meticulous execution and a robust operational framework. In this blog, we delve into the complexity of operationalizing a CGT study, highlighting the unique challenges and providing best practices to ensure safety, data quality, and a seamless patient experience.
[i] American Society of Gene + Cell Therapy and Citeline. Gene, Cell, and RNA therapy Landscape Report: Q1 2025 Quarterly Data Report. Available at https://www.asgct.org/global/documents/asgct-citeline-q1-2025-report.aspx.
Unique Challenges of Delivering CGT Trials
The biological nature of CGTs creates unique challenges that must be addressed for successful study delivery.
- Manufacturing and quality control. The manufacturing process for CGTs is highly complex, often involving multiple distinct components and patient-specific workflows. This creates unique challenges for ensuring product quality, safety, and stability. To ensure patient safety, regulatory agencies focus on on analytical rigor, including contaminant testing for adventitious agents (AA) such as unintended viruses, bacteria, fungi, or mycoplasma in master or working cell banks as well as replication competent viruses used in the manufacturing of CGTs.
- Storage and transport. Many CGTs require an ultra-cold chain to store and transport products at cryogenic temperatures (-150°C to -196°C), necessitating specialized packaging, real-time monitoring, and precise coordination. Any deviation from this narrow temperature range can render the therapy non-viable.
- Complex administration. Many cell therapies, such as chimeric antigen receptor T-cell (CAR-T) products, are patient-specific and require a carefully coordinated vein-to-vein process that involves sample collection, cell engineering, and reinfusion. This process demands advanced tracking systems to manage temperature-sensitive materials, ensure proper chain of identity, and maintain compliance throughout process and transport.
- Safety oversight. Due to their biological complexity, CGTs carry specific risks such as immune reactions, off-target genetic effects, or delayed side effects.
- Long-term follow-up (LTFU) requirements. CGT trials often require years of LTFU to monitor for potential delayed adverse events and to assess durability of the therapeutic effects. This extended monitoring period places a significant burden on both sites and patients and requires a robust system for data collection and management.
Key Considerations and Best Practices
Successful strategic execution is built upon robust collaboration, rigorous processes, and resilient systems.
Selecting the Right Sites
CGT trials are logistically complex, resource-intensive studies that require highly qualified sites with the capability and capacity to deliver on recruitment timelines, protocol compliance, and data quality. In rare disease studies, it is critical to partner with sites that have key opinion leaders (KOLs), rapid startup timelines, and expansive patient networks. Relevant experience with the mode of administration is particularly important in autologous gene therapy studies and trials that require intracranial, spinal, or ocular procedures.
Other ideal site criteria may include Foundation for the Accreditation of Cellular Therapy (FACT) accreditation, experience with genetically modified organisms (GMOs), minimal GMO regulatory barriers, and access to any specialized facilities that might be needed. These facilities may include one for preparing and administering the investigative medicinal product (IMP), intensive care or bone marrow transplant units, surgical capabilities, genetic testing, and advanced imaging. Existing standard operating procedures (SOPs) for storage, handling and disposal of GMOs are also essential, as IMP receipt and storage, preparation and administration, transport, containment, and destruction or return must all be performed in accordance with applicable requirements. To the extent possible, aligning protocol requirements with existing site workflow and policies will help to minimize site burden and maximize staff engagement.
For studies with complex dosing regimens, endpoints, or equipment requirements, sponsors might consider consolidating expertise and referring patients to a centralized site. While this approach optimizes study efficiency, it is not always practical. A hub and spoke model, where IMP administration occurs at the enrolling site and post-dosing follow up occurs at referral sites, may be an alternative to expanding patient access.
Given that the CGT landscape has become increasingly competitive, sponsors may also want to qualify sites based on the existence and expected impact of competing trials at that location. It may also be useful to consider the feasibility of converting clinical trial sites into commercial treatment centers after IMP approval.
Preparing for Cross-Border Enrollment and Streamlining Study Participation
Cross-border enrollment is common in rare diseases due to the geographic dispersion of these small patient populations. Considerations for cross-border enrollment include submission requirements, insurance, medical records and data protection legislations, and support for passports, visas, transportation, and accommodations for prolonged stays. Ensuring that travel and out-of-pocket expenses are included in the study budget eases the burden on patients and their families and improves the overall clinical trial experience.
If different components of the protocol need to be completed at different locations, it is important to coordinate patient assessments so that they are feasible and not unduly burdensome.
Managing Cohorts
Unlike traditional pharmaceuticals, CGTs often have limited time windows for manufacturing and administration. Cohort availability is less flexible, and IMP administration must be carefully choreographed, so both sites and patients must understand the limitations and expectations of the study. Developing site-specific recruitment plans that carefully coordinate apheresis slots, manufacturing capacity, release testing, and infusion scheduling can help support site enrollment, reduce time to treatment, and minimize frustration.
Ensuring Product Safety and Integrity
A meticulously planned, integrated supply chain that coordinates manufacturing, logistics, and clinical sites is critical for CGT studies. This includes having a clear chain of identity and custody for personalized therapies and the ability to audit every step of the process. Embedding quality-by-design approaches and implementing stringent processes and controls during manufacturing is essential. Early and frequent communication with regulatory agencies is important for aligning analytical methods and ensuring compliance with evolving guidelines.
Advanced technologies, such as real-time temperature and location trackers, can be utilized to monitor products during transport. Contract research organizations (CROs) experienced in CGT trials can bring established relationships with specialized couriers, validated shipping procedures, and contingency plans for temperature excursions, shipping delays, or weather emergencies.
Enhancing Data Quality and Management
The complex and often long-term nature of CGT trials generates a vast amount of data that requires robust training and data management systems. Providing clear and comprehensive training to site staff on the protocol and the relevant technologies is essential for ensuring that data collection is accurate and consistent. Implementing electronic data capture (EDC) systems and electronic patient diaries can streamline data collections, reduce data entry errors, and enable real-time monitoring. This is particularly useful for LTFU, where patient-reported outcomes (PROs) are often a key endpoint.
Centralized data management systems allow sponsors to identify trends and patterns in study data using advanced analytics and machine learning. This not only enhances data quality and integrity but also provides valuable insights into safety signals and therapeutic efficacy.
Optimizing Site Performance
Every CGT study has unique nuances. Even if a site has previous experience, it is important to establish processes for training and supporting all sites to optimize performance. Training should include guidance on addressing questions and concerns that patients and families may have regarding any risks, including those related to GMOs, as well as potential benefits associated with the administration of CGTs, particularly in early-phase studies that are designed primarily to assess safety and determine appropriate dosing rather than efficacy.
It should also include detailed information on handling perishable materials, evaluating immune responses, and overall IMP management. Performing a dry run of the protocol requirements at the site initiation visit may help reduce errors, identify risk mitigation tactics, and increase site staff confidence.
Monitoring Safety
CGTs introduce unique risks, including immunogenicity, off-target effects, and insertional mutagenesis. Establishing safety monitoring systems, including daily safety reviews during the first 28 days post-infusion and other high-risk windows, round-the-clock medical oversight, and coordination of data monitoring committees, is essential. It is also important to standardize pathways and grading scales for management of adverse events such as cytokine release syndrome (CRS) and neurotoxicity.
In CGT trials where critical data points are clearly defined, risk-based quality management (RBQM) and centralized monitoring may work well. Source data verification (SDV) should focus on key elements such as dose preparation and administration, chain of identity documentation, adverse events of special interest, and primary endpoint assessments. Centralized monitoring can detect unexpected infusion timing patterns, biomarker trends suggesting safety concerns, laboratory flags requiring investigation, and other safety signals.
For certain CGTs, particularly those using integrating vectors or genome-editing, regulatory bodies, including the FDA, may mandate LTFU for up to 15 years. Retaining patients for such a long period is a significant challenge and retention strategies must be flexible and adaptive to changes in a patient’s life. Patient engagement technologies such as mobile apps are crucial for maintaining communication and keeping patients connected to the study team. Concierge services for travel and logistics, along with reimbursement for out-of-pocket expenses, are also important for reducing patient burden and preventing dropouts.
Key Takeaways
The nature of CGTs introduces a complex web of operational, logistical, and safety challenges during study delivery. Consequently, the outcome of a CGT trial is dependent not only on the scientific merit of the therapy but also the strategic execution of study operations. Success comes from implementing robust systems and processes that manage complexity while minimizing burden and maintaining relentless focus on the patient experience. Working with a CRO that has deep experience in CGTs, from early development through long-term patient monitoring, can help sponsors translate well-designed protocols into well-executed trials.