Cell and gene therapies (CGTs) offer the revolutionary potential of curative treatments for previously intractable diseases.
The pipeline of investigative products, particularly in oncology and rare diseases, is rapidly expanding, but translating this potential into successful clinical trials requires a strategic approach to study design that addresses the unique complexities of these novel therapeutics. In this blog, we explore key considerations for designing CGT trials, with a focus on optimizing the likelihood of success from the start.
Unique Challenges of Designing CGT Trials
Unlike small molecule drugs, CGTs involve living cells or genetic material and novel mechanisms of action, creating a distinct set of hurdles that impact the design of clinical trials, from the protocol and logistics to safety and regulatory considerations. Complexity is inherent to the product and manufacturing is intricate, often involving personalized, patient-specific processes. This intricacy can lead to supply chain challenges, including a lack of standardization and scalability, which can significantly impact timelines and costs. Safety is of prime concern for CGT products, which pose risk to patients due to potential immunogenicity, and, in certain instances, the invasiveness of the procedures involved in administration.
For rare diseases, understanding of the pathophysiology, clinical manifestations, and natural history of the condition is often poor or incomplete, making it challenging to identify or develop animal models that exhibit clinically important manifestations of the disease. Consequently, the preclinical data generated for CGT products may not be as informative as it is for small molecules. Further, regulatory guidelines are still evolving, particularly for novel technologies like Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR) gene editing, which can create uncertainty for sponsors.
To help address these challenges, sponsors are increasingly relying on contract research organizations (CROs) at early stages of development to support stronger applications for clinical trial authorization or investigational medicinal product (IMP) approval.
Key Considerations and Strategic Approaches
A well-designed trial that addresses the unique challenges of CGTs is the cornerstone of success.
Establishing a Preclinical Foundation and Chemistry, Manufacturing, and Controls Framework
Comprehensive preclinical studies are a critical upstream factor in preventing costly and time-consuming delays in the clinical development phase. These studies must provide adequate data concerning product distribution, persistence, and potential off-target effects.
Inadequate chemistry, manufacturing, and controls (CMC) is a leading cause of regulatory delays, with more than 20% of clinical holds attributed to CMC concerns.[i] Robust CMC strategies ensure consistent product production, adherence to strict quality standards, and regulatory compliance throughout the development lifecycle, keeping in mind that any change in manufacturing requires demonstration of comparability.
Navigating Ethical Imperatives
In drafting informed consent, the unique nature of CGTs must be taken into account by providing clear, non-technical explanations of the purpose of the trial, the potentially irreversible nature of the therapy, and the foreseeable risks, including insertional mutagenesis, carcinogenesis, infection, and even germline transfer. Participants must be fully informed about the expected participation, procedures, and long-term follow-up (LTFU) requirements, which can extend up to 15 years for certain gene therapy products.
When LTFU is needed, informed consent cannot be a static, one-time event. Instead, it must evolve into a dynamic, ongoing partnership that can adapt to both changes in a patient’s life circumstances and emerging data about the therapy’s long-term effects. This continuous engagement ensures sustained ethical oversight and participant autonomy throughout the entire follow-up duration.
In addition, CGT trials frequently involve vulnerable populations, including children. For minors, careful consideration of their capacity to provide assent is essential, along with obtaining full parental consent.
Selecting the Right Study Design
CGT trials often target rare diseases, where inherently small populations make traditional randomized, placebo-controlled trials challenging or even ethically unfeasible, especially for life-threatening conditions where no approved therapies currently exist. Moreover, many CGT studies are designed as single-dose interventions due to the curative potential and complexity of the investigative product. Thus, alternative trial methodologies are needed, including utilizing standard of care (SOC) as a comparator, incorporating innovative designs, or leveraging natural history data or real-world evidence to generate sufficient and scientifically compelling data for regulatory agencies.
Adaptive trial designs offer flexibility, allowing for predetermined protocol modifications in response to emerging data and enabling researchers to make real-time adjustments based on interim results. Adjustments can include changes to dose, patient selection criteria, and even endpoints. Basket trials evaluate multiple diseases or subpopulations that share a common genetic marker or biological pathway within a single study. This trial approach can significantly improve efficiency and reduce development costs by reducing the overall number of participants required and allowing early termination or modification of the study if interim results are not promising.
Real-world evidence (RWE) derived from diverse real-world data (RWD) sources such as electronic health records (EHRs), claims databases, and patient registries is increasingly crucial for CGT trials. RWE can provide valuable insights into disease natural history, serve as an external control arm, and support the design and interpretation of post-approval studies. RWE is also critical for demonstrating sustained clinical benefit and cost-effectiveness, both of which are integral to demonstrating long-term value to payers and securing reimbursement.
Choosing appropriate clinical endpoints is crucial for demonstrating efficacy and securing regulatory approval. For CGTs, where traditional endpoints might be difficult to measure over short trial durations due to the long-term nature of the therapeutic effect, regulators may be receptive to the use of surrogate endpoints such as biomarker response, gene expression level, or treatment durability. These surrogate endpoints must be validated to reliably predict long-term clinical benefit, providing a measurable proxy for therapeutic outcomes.
Developing a Recruitment Strategy
Recruiting the right patients for a CGT trial can be a major bottleneck, especially for rare diseases where the patient population is small and geographically dispersed. Strategies for streamlining recruitment include:
- Leveraging data and analytics. Rich datasets from EHRs and claims data, supplemented by AI-driven models, can help to predict which sites are most likely to enroll patients quickly and effectively.
- Engaging patient advocacy groups. These groups can help raise awareness of the trial and build trust within the target population, while also providing valuable insights into the patient experience, which can inform protocol design and selection of endpoints that truly matter to patients and their families.
- Utilizing diverse communication channels. Targeted social media campaigns, online advertising, and partnerships with condition-specific online communities allow sponsors to reach a broader and more engaged audience.
Minimizing Site and Patient Burden
CGT trials are demanding on both sites and patients, with complex protocols, frequent assessments, and long-term follow-up (LTFU) requirements. To minimize burden:
- Design patient-centric protocols. Involving patients, caregivers, and patient advocacy groups in protocol design enables sponsors to gain insight into trial feasibility and to optimize the number and timing of assessments, thus reducing the logistical and emotional toll of study participation. Incorporating decentralized elements such as remote monitoring and home visits also reduces burden.
- Standardize and streamline operations. Where possible, sponsors should leverage technology already in place at sites rather than requiring the adoption of new systems for every trial. This minimizes administrative headaches and the time needed for study startup.
- Simplify the contracting and budgeting process. By using master clinical trial agreements (CTAs) and country- or site-specific contract templates, sponsors can significantly reduce the time and effort sites spend on administrative tasks, allowing them to focus on patient care.
Engaging with Regulators
In an evolving regulatory landscape with specialized pathways for CGTs, early and frequent dialogue with regulatory agencies is imperative. Proactive communication helps inform development strategies and anticipate potential issues, ultimately accelerating the path to approval. Both the US Food and Drug Administration (FDA), and European Medicines Agency (EMA) offer expedited pathways for products that address substantial unmet needs, and regulatory engagement facilitates determination of program eligibility. Moreover, for sponsors seeking global market access, interactions with regulators are critical for the development of strategies that align with region-specific requirements while avoiding redundant efforts.
[i] Wills CA, Drago D, Pietrusko RG. Clinical holds for cell and gene therapy trials: Risks, impact, and lessons learned. Mol Ther Methods Clin Dev. 2023;31:101125.
Key Takeaways
CGTs are ushering in a new era of therapies that address the root causes of illness at the cell or gene level, offering the potential to precisely detect and destroy diseased tissues or correct specific genetic errors. The biological origin of CGTs requires a nuanced approach to clinical development that differs from traditional pharmaceutical trials. CROs with experience in CGTs are critical partners in managing the unique scientific, regulatory, and logistical demands of these trials, from early development through long-term patient monitoring.