Clinical trials are becoming increasingly complex due to a range of external factors, including policy and regulatory changes and advances in technology. These challenges are further amplified when dealing with intricate therapeutic areas, such as cell and gene therapy (CAGT), in which nuances like challenging patient recruitment, site identification, asset manufacturing and an uninterrupted supply chain play special roles in drug development success. As a result, clinical trial sponsors, clinical research organizations and other vendor partners must navigate a multifaceted landscape to successfully transition from discovery through clinical development to commercialization. 

Meanwhile, competition in CAGT R&D is rapidly increasing. In 2024, there were 533 CAGT trial starts, more than three times the 171 starts in 2015. CAGT trial sponsors are laser-focused on two key stages of clinical development, often with support from contract research organizations (CROs). The first is determining the early safety and efficacy signals of their therapy and finding its right dose through first-in-human/early phase trials. The second is scaling up at late phase registrational trials to confirm efficacy. But what about the other trial stages in this specialized area and how they can impact progress?

From nuanced challenges of finding and engaging rare patient populations to the logistical challenges of the CAGT asset journey, long-term follow-up study design and more, there is a gate at every step of the process that can have rippling consequences downstream for regulatory approval, commercial viability, market access, etc. Mapping out decisions at the earliest possible point is critical to effectively navigating this complex landscape with precision and insight. Importantly, most of the innovation in the CAGT space stems from emerging biopharmaceuticals. Because these companies typically focus on one or two key assets, they are often in “make it or break it” mode, making it crucial to get it right under unique constraints. 

Regardless, this is not a therapeutic space that drug developers will bow out of due to its complexities. CAGTs simply hold too much promise for transforming how previously untreatable diseases can be addressed. Knowing how important CAGTs can be for patients, the question for sponsors is: “What are some key areas within CAGT development that impact downstream success and require early and informed decision-making?” Within that, let’s also explore where we see changes in CAGT R&D and how they will add to the layers of decisions. 

Core CAGT development decisions 

As innovation in CAGT continues, emerging biopharmaceutical companies (EBPs) and other CAGT developers need to rethink business strategies to go beyond achieving proof of concept to secure an asset acquisition deal and consider the full spectrum of development progression and opportunities. 

CROs can offer guidance to anticipate what’s ahead when sponsors look at the wider scope of CAGT R&D and related commercialization efforts. This is where fleshing out core strategic decisions as early as possible can create a foundation to build on and better determine how a therapy is positioned. Also, as new modalities and regulatory requirements emerge, sponsors will need to account for these changes in planning. For example, gene editing technologies are advancing personalized medicine across a wider range of conditions by addressing specific mutations responsible for diseases or conditions. However, questions emerge when such novel modalities are translated into clinical trials. One salient question relates to the potential reproductive toxicology of off-targeting (editing) germline cells. 

Key early decision: Unique trial design factors and related strategic direction 

Due to the novel and complex mechanisms being studied, CAGT trial design can surface several gray areas for sponsors to navigate. To stay competitive in a rapidly changing landscape th00at is also cost-intensive, key strategic decisions made during trial planning can help set the stage for what may come post-approval. 

First, it’s vital to establish the therapy’s safety and efficacy, a dosing range that generates therapeutic effect within the safety profile, and overall value to the market. 

To do so, establishing the right patient population is key. For example, areas with a higher unmet need, such as some rare diseases, may be eligible for regulatory fast-tracking. Alternatively, if a sponsor chooses a patient subgroup within a broader disease population, it may lead to stronger efficacy outcomes despite complicating recruitment. This can translate into restricted labels for commercialization. 

When targeting specific genetic mutations, sponsors will need to determine eligibility criteria based on what stage of disease and patient subgroups are appropriate. It helps to see what’s necessary in terms of: 

• Patient screening, including genetic screening to confirm specific mutations.
• How the investigational therapy may fit sites’ current care paradigms. 
• Accessibility to cell collection facilities and manufacturing capabilities.
• Access to targeted patient populations.
• Capacity to manage often complex coordination and management of trials requiring a large number of patient visits and complete procedures. 

Key early decision: Stronger patient participation 

Patient identification and recruitment can be difficult and slow for CAGT trials. First, genetic screening or use of non-routine biomarkers for rare diseases contributes to high screening failure rates. Sponsors might invest in patient registries and pre-screening protocols or biomarker datasets and work with patient advocacy groups to reach potential participants. There is also a higher patient burden associated with these trials due to the complex nature of CAGTs, required procedures (e.g., invasive administration or required assessments), potential adverse events and the irreversible nature of most therapies, all contributing to delays. 

Key early decision: Country and site selection 

Country and site selection play an integral role in improving participation in CAGT trials. 

Ideally, it’s key to identify countries with harmonized regulatory frameworks for CAGTs. There, sponsors and CROs will need to work with sites able to house specific facilities and with staffs able to conduct CAGT studies efficiently. Currently, data-driven site identification and relationships through established site networks are helping to identify adequate sites. 

Early on, it is important to consider the logistical implications of manufacturing sites that are far from trial sites. As the candidate therapy advances, the countries and sites selected will become the launch pad for commercialization. Early investment in site start-up in areas with significant target patient populations can be important for market success.

Key early decision: Specialized CAGT manufacturing and related logistics 

Every logistical aspect of a CAGT asset, from manufacturing through delivery and administration to patients, can pose a significant barrier and risk. The intricacies of the asset journey may be as unique as the patients CAGTs aim to treat. Within a single trial, each patient’s treatment requires a complex web of interdependent operations comprehensively orchestrated between collection sites, manufacturing facilities, treatment locations and patients. 

Early in trial planning, sponsors, CROs and qualified sites must account for layers of variability and a host of “what if” scenarios to avoid impacting patient dosing in the allotted timeframe or risking the contamination, inconsistency or loss of cell batches, including: 

• Tight timelines for treatment pickup and delivery from manufacturing location to site. For example, in autologous gene-modified cell therapy, which involves extracting cells from a patient, the length of time from apheresis to administration is critical. 
• Maintaining cell viability during transit.
• Import and export regulations and the therapy’s specific requirements, such as designated temperatures, related cold-chain storage and chain of identity. 
• How to scale up asset production. 
• Additional handoffs created by highly targeted delivery and administration methods (e.g., surgical delivery), which may require multi-disciplinary teams at sites. 

Manufacturing locations and timely capabilities are often dictated by therapeutic focus, therapy type (e.g., gene-modified cell therapy versus RNA therapy), site selection and number of patients, so it’s essential to factor them in during trial design. 

Because CAGT manufacturing is extraordinarily complex, early in planning, sponsors may consider partnering with an experienced contract development and manufacturing organization that understands CAGT intricacies and has specialized facilities to carry out development from initial needs through scaling up for commercial purposes.

In fact, as multiple CAGTs for oncology and other therapeutic focuses reach market, the global market for CAGT CDMOs is estimated at more than $8 billion this year and forecasted to reach $74 billion by 2034. The increase includes 19% for CAGT-specific manufacturing in 2023, as well as drug developers integrating in-house CDMOs via acquisitions.  

Key early decision: Long-term follow up studies—integrating real-world changes 

Given the uncertainties associated with the long-term effects of some CAGTs, sponsors are required to evaluate extended safety following administration of the therapy. Guidance from the U.S. Food and Drug Administration and European Medicines Agency requires sponsors to monitor adverse events 5 to 15 years post-trial, depending on the type of therapy. This can be costly and difficult as patients’ lives change. Within those years, pediatric participants may go to college or move to different cities, or aging or debilitated adults may rely on caregivers, who must be instructed about LTFU needs. 

To effectively consider real-world conditions, LTFU design must have a proper balance of extended safety data, which is the primary focus, and efficacy/durability data. Beyond that, strategic approaches will need to account for design variables. Sponsors may turn to a CRO to map out LTFU and address questions regarding design nuances, such as:

• Should there be a single protocol for the trial and LTFU or a separate LTFU protocol? 
• For companies with multiple assets in similar indications or therapeutic focuses, what are the benefits of a single, dedicated LTFU study with a centralized principal investigator to roll over patients from multiple trials? The PI designation is important, because in some cases, such as rare diseases, these providers have useful experience establishing long-term relationships with patients and their families.
• What provider is ideal for LTFU (e.g., main trial sites, a physician near the patient(s) using remote monitoring, or a combined approach)? 
• What sampling and clinical assessments are needed during LTFU and how often? This is where telehealth, remote monitoring, connected devices, etc., can reduce burdens by gathering vital data with minimal patient and caregiver interaction. 

One of the biggest questions for sponsors regarding CAGT LTFU is, “When is the right time to begin planning?” This may depend on their current position and future direction, including corporate business goals. A smaller EBP interested in asset development and acquiring or securing a strategic partnership with another life sciences company may disregard early LTFU planning to save money and resources. But an established sponsor might invest resources for earlier planning to save time and effort downstream. 

Indicators of progress in CAGT development

The potential for expansion and movement in CAGT R&D emphasizes the need to regularly monitor for changes that can impact sponsors’ plans and to stay agile to adjust and leverage opportunities. This includes:

Globalization of trials 

Because of their complexities, CAGT trials tend to have smaller footprints in a few countries or just one, such as in the U.S. For example, while China is growing exponentially in clinical trial activity with 804 trials started in the last five years, 96% of these trials are taking place only in China. Yet, there is a growing representation from the industry. 

Asia-Pacific countries have recently begun to take a share of multinational trial starts from the U.S. and Europe due to incentives and world class health care infrastructure (see Figure 1).

Despite fewer trials, Korea’s and Japan’s proportions of single-country trials are similar to the U.S.’s at 70% and 64%, respectively. Australia, Brazil, Israel and Western European countries round out where multinational studies are more frequently conducted. Global interest in conducting trials in countries like Korea and Japan is partially due to their larger populations but also their regulatory differences. For example, in Japan, the Ministry of Health, Labour and Welfare initiated an expedited regulatory review process called the Sakigake designation in 2019 equivalent to the FDA breakthrough therapy designation and EMA Priority Medicine designation.

Along with its well-developed infrastructure, experienced investigators and data acceptance from regulators worldwide, Australia may draw greater interest in CAGT R&D currently due to the Research and Development Tax Incentive, a tax offset for eligible R&D activities. 

Therapeutic pivoting 

Novel modalities, including antibody-drug conjugates, multispecific antibodies and CAGTs, accounted for 32% of oncology trial starts in 2024, with CAGT trials having tripled in the last decade. However, in recent years, various types of sponsors and companies are investigating CAGTs for a range of diseases. Over the last five years, trial activity has shown notable differences in focus between modality and therapy area, as well as between modality and sponsor size/type.

Two percent of cell-based immunotherapy trials in recent years have targeted autoimmune diseases. This may not seem significant, but when we consider the number of newly submitted Investigational New Drug Applications and recent study findings that patients were able to discontinue immunosuppressive treatments upon being treated with CD19-targeting chimeric antigen receptor (CAR) T cells, it indicates a potential to shift the care paradigm for those with such diseases. 

Among gene therapies, neurological, metabolic, endocrine, cardiovascular and ophthalmic diseases are all significant areas of focus (see Figure 2). Also worth noting is that women’s health makes up a small but important portion of CAGT research, with 34 trials started in the past five years primarily focused on treating infertility. 

Making earlier decisions for post-approval phases: shifting from promise to reality 

R&D stakeholders are investing in transformative, scientific innovation for patients in need regardless of how complex development gets. As more drug developers recognize the value of making critical decisions earlier in the R&D process, we are seeing in real-time the fruits of their labor and investments with the expanding availability and use of novel CAGTs. 

As studies continue to prove efficacy beyond safety, it’s time for those invested in CAGTs to also crack the riddle of patient access challenges post-approval. For example, though the use of CAR-T therapies for third-line or later multiple myeloma creates excitement, only 6% of treatments in the U.S. were these therapies. This may be due to the complex logistics and delivery for CAR-Ts but it’s also about patient and physician preferences. Often, use of these novel therapies is related to payer reimbursement issues due to costs and complex therapy manufacturing and delivery. 

How can CAGT stakeholders better ensure these therapies are not only developed but made available for patients in need? 

For one, it is necessary to account for access challenges early in development. Having commercial team experts involved and engaged from the start of clinical development will help to align planning with what is occurring in real-world patient populations. Engaging in earlier discussions can help drug developers gauge the fortunes of similar therapies already available, determine potential distribution channels to maximize access upon approval and begin discussions with the payer community about a pricing strategy. 

Also, just as these therapies are novel in mechanism and nuances for development and approval, drug developers won’t necessarily follow traditional commercialization frameworks. They may opt for a mix of models that better fits the unique field and smaller patient populations served. This may include earlier engagement and stronger collaboration with patient advocacy organizations, academia and nonprofit organizations. 

As the industry further fine-tunes R&D efforts and related best practices to address the nuances of this innovative focus area, we will continue to see progress, and perhaps expansion, of where CAGTs can offer hope to patients. Regardless of how complex and expansive CAGT R&D may become, the core decisions necessary to map out discovery, trial design, therapy manufacturing, logistics and treatment access will be at the heart of all efforts.

Dr. Diego Correa is Vice President and Global Head, Cell and Gene Therapy Center of Excellence, at IQVIA. Bringing more than two decades of basic and translational research experience in cell therapy, tissue engineering and regenerative medicine to his current role at IQVIA, Dr. Correa provides clinical trial sponsors and study teams with scientific, clinical and operational guidance to apply innovative, data-driven and patient-centered solutions for CAGT studies. Dr. Correa has more than 60 publications in peer-reviewed journals and is an active member of steering committees for international scientific organizations, including the International Society for Cell & Gene Therapy. 

As Vice President of Immuno-Oncology & CAGT at IQVIA Biotech, Erin Finot, MS, MBA, is responsible for leading strategic direction to help sponsors meet their goals with high quality and delivery of innovative services, solutions and expertise. As advancements in immuno-oncology and cell and gene therapies continue to transform patient care, Erin helps guide sponsors through a dynamic landscape with strong therapeutic expertise and more than two decades of experience in global clinical research and drug development processes.