Best Practices in Managing CGT From Protocol Design to Data Management

On April 17, 2012, Emily Whitehead made history when she became the first pediatric patient1 to be treated with chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Since then, the fields of immunotherapy and cell and gene therapies (CGT) have exponentially grown, accelerating a new frontier in therapeutics.

According to the Alliance for Regenerative Medicine, there are approximately 1,026 companies engaged in CGT research and more than 1,109 clinical trials underway globally, encompassing therapeutic areas from oncology and neurology to cardiovascular and infectious diseases.

While recent successes have provided excitement among the scientific community, CGT clinical research remains challenging. As such, this research sector presents significant fundamental differences between traditional and CGT clinical trials, requiring exacting methods and protocols to collect, ship, engineer, manufacture and administer “living therapies.”

As a result, managing and executing a CGT trial adds a level of complexity that few sponsors have considered. In fact, with emerging biotechs comprising the majority of the market, many sponsors may be embarking on their first CGT trial. Contract Research Organizations (CROs) play a critical role in the growth and demand for resources for these trials and in capturing best practices, especially in the nascent stages of CGT. Through the diverse experience of working within multiple therapeutic areas, CROs can offer a deeper understanding of the unique nuances of CGT trials. Here, we discuss best practices for CGT clinical trials, whether it's your first, or your 10th.

Understanding the importance of clinical strategy, protocol design and feasibility

While immune-oncology continues to dominate the R&D focus in CGT, the increased focus on unmet needs in other therapeutic areas is contributing to significant growth. According to the Alliance for Regenerative Medicine, there are currently 694 trials ongoing in oncology; 388 trials in prevalent diseases & cancers; 186 trials ongoing in rare monogenetic diseases; and 16 trials ongoing in COVID-19 & complications.

As the market has grown with multiple sponsors proposing research in the same areas or considering multiple therapeutic areas, the clinical strategy and up-front feasibility assessment can help drive the direction of the trial. Fully understanding the patient population and their unmet medical needs, the competitive clinical trials with key sites and investigators, and a commercial assessment and valuation can be a key asset in the overall strategy.

During clinical trial study start-up, roadblocks can surface—delaying timelines before a potential new therapy is even administered to the first patient. Regardless of whether it is a large pharma company or an emerging biotech, writing and rewriting protocols and setting up an array of committees can leave both equally overwhelmed.

Often sponsors may develop a timeline with promises that are impossible to manage in CGT. For example, site activation and recruitment plans can be affected by multiple pauses and starts in the early stages of the study due to protocol amendments and/or safety issues, which are more common in CGT trials. That’s why getting off on the right foot starts with clear and efficient protocol writing.

As reviewing protocols in CGT are more involved and time consuming than a traditional clinical trial (requiring an ethics review in addition to other departments), having a well-written and well-thought-out protocol can prevent delays in project timelines. Further, understanding how to plan timelines correctly allows you to speak to a supervising body or board to manage expectations. One strategy includes grouping CGT trial execution into journeys, such as: (1) regulatory, (2) patient, (3) site, (4) product and (5) data. By organizing a trial in this manner, it allows sponsors to better prepare for unique challenges as they arise. 

Moreover, as most CGT clinical trials are adaptive and first-in-human studies, sponsors and their CRO partners will need to have a strategy for different scenarios that may develop and be prepared to quickly and effectively adjust the design as determined by events.

Managing “living therapy” logistics

In CGT clinical trials, the patient samples and the therapy, itself, are built on living cells, creating a complex supply chain, which requires expert logistics orchestration. These “living therapies,” which are time and temperature sensitive, require special handling, handoffs and scheduling, as well as detailed chain of custody traceability between multiple stakeholders.

For example, in autologous trials where the patient’s own cells are used in the manufacturing process, the cell collection from an enrolled patient must be managed between labs, apheresis centers, specialty courier and clinical supply providers, which is all contingent upon the availability of manufacturing capacity and whether the patient can actually adhere to the schedule. This entire process has multiple codependences, requiring close, hands-on coordination, communication and patience. Key logistics challenges presented during the pandemic included managing reduced flight schedules and canceled flights, retraining site personnel and documenting changes in site access. 

Here, product safety is directly related to patient safety, and, as such, a key focus should be on developing procedures, proprietary tools and resources for managing the chain of condition and chain of custody from end to end. For example, to mitigate risk for site procedures prior to shipment and after delivery, sponsors can conduct mock shipments and validation of the detailed processes captured in the investigational product manuals. Similarly, changes in site access and resources need close management.

Considering a new data strategy     

CGT trial data and regulatory requirements also greatly differ from a typical trial, where patients receive regular doses of the investigational product or a placebo, with the data stream being generated over time. In a CGT trial, the bulk of data comes very early in the trial and all at once, creating challenges in managing large volumes of data. The CGT screening process is much more complicated than “typical” trials. Additionally, almost all of the patients are heavily pre-treated and the lymphodepletion and apheresis processes present even more data capture requirements—all within the first few weeks. After dose administration, the hospitalized patient must be monitored full time as acute toxicities can happen quickly and data are critical for dose safety and evaluation, as well as planning for the next patient, and the communication that follows. Proper planning and training for site resources to manage data is critical. Resource planning and management to handle data volumes became especially important during the pandemic when sites lost resources or reassigned staff due to COVID.

Sponsors will need to manage this data from the beginning and stay on top of the situation before things get out of control and require extensive data cleaning, placing burdens at the site level. Therefore, sponsors should develop tools to help predict data volumes to proactively plan for needed resources. For example, a sponsor may monitor and collect data from the study patients every day after receiving the therapy, increasing the probability of generating clean data, which is the first step in being granted accelerated approval.

Keeping on top of regulatory expertise

Many promising CGT therapies are first-in-class programs addressing unmet needs with fast-track designation. In CGT and orphan trials, the regulatory landscape continues to change, sometimes down to a regional level, so it’s important to have support for regulatory strategy, agency meetings and applications for multiple products. Critical to success is having global experience in CGT drug regulations, submissions, exclusivity requirements, and support of tax credit and grant applications.

CRO’s with a strong expertise in CGT regulatory requirements can help sponsors navigate the complex, often accelerated approval process. Working with genetically modified organisms adds regulatory complexity—and the requirements and pathways are constantly changing and will vary not only by country but down to a regional level.  

Conclusion

As this new frontier of medicine continues to expand and diversify, a growing number of pharmaceutical and biotech companies will delve into CGT clinical trials. Finding solutions to ensuing challenges and complexities to ensure business continuity, supply chain resilience and regulatory expertise requires ongoing innovation and agility.

Tamie Joeckel is the Global Cell and Gene Therapy Business Lead, Clinical Research Service, for

ICON plc.

References

1. https://www.chop.edu/stories/relapsed-leukemia-emilys-story