Three key decisions cell and gene therapy trial sponsors need to make early into drug development

It’s no wonder the cell and gene therapy (CAGT) market is piquing interest from the broader healthcare ecosystem by offering hope to patients where traditional treatments may have fallen short. In 2023 alone, the global CAGT market was estimated at nearly $23 billion and forecasted to grow annually. To successfully, safely, and quickly bring life-changing therapies to patients requires a deep dive into the multitude of unique clinical and laboratory considerations that impact complex CAGT development.

Making pivotal decisions at the earliest possible point in CAGT development can be critical. This includes everything from how to best reach rare patient populations to efficient implementation of complex protocols with higher levels of patient and site burdens, management of costly and often irreplaceable assets, and long-term approaches to safety monitoring. Mapping out key decisions, including those noted below, early and precisely can help determine the likelihood of development success, especially considering the ripple effect they can have on regulatory approval and market access.

Complexities of patient identification

Identifying and securing interest from target patient populations for CAGT trials can be challenging for several reasons.

For one, CAGTs are primarily evaluated for difficult-to-treat malignancies, rare diseases, and indications with unmet clinical needs. Unlike other therapeutic spaces, this often requires genetic screening and confirmation or use of non-routine biomarkers for discrete mutations in each patient prior to trial enrolment. While choosing a patient subgroup within a broader disease population may increase the chance of proving efficacy, based on the trials’ inclusion/exclusion criteria, participant eligibility can narrow quickly and slow enrolment.

As importantly, it is critical for sponsors to consider patients and caregivers’ journeys with a debilitating and potentially life-threatening condition. Especially when a standard of care is available, closely examining how much is required of patients to participate in the trial of an experimental CAGT, in terms of prognosis, potential adverse effects, and efficacy uncertainties, is essential when enrolling.

To reduce trial delays due to unique patient identification and engagement challenges, CAGT trial sponsors are increasingly investing in:

• Creating and expanding dedicated patient registries to match patients to trials quicker.
• Planning for comprehensive pre-screening protocols and gathering biomarker-specific data insights.
• Strengthening collaboration with patient advocacy groups.
• Deploying tailored solutions to educate patients and caregivers about therapies and to minimise patients’ burden to enhance retention throughout the trial.

End-to-end clinical development laboratory assessments

When taking a holistic view of what is needed to support CAGT clinical data insights and estimate a therapy’s safety and efficacy, the series of complex lab assessments required throughout the product lifecycle — from preclinical research through post-approval/use — can be a highly intricate process to effectively manage. But the assessments are necessary because every CAGT varies in genetic sequencing, and validation of assays is critical to gauge safety and efficacy.

Sponsors are recognising the value of integrating a comprehensive plan of action, including assessment timelines, into the overall clinical development strategy to ensure all required measurements and testing are done in a timely and efficient manner. Partnership between the central lab and clinical research organisation during early engagement with the therapeutic sponsor helps ensure the appropriate lab assessments at the correct timepoints with the correct sample type are made. Early validation of often bespoke assays may help circumvent potential trial delays.

While some assessments are only needed at specific times, others may be repeated throughout the study and afterward. Examples of lab assessments potentially required at various CAGT trial phases include:

• At pre-clinical stages, the potential off-target effects of genome editing assets through whole genome sequencing.
• During the trial, pharmacokinetic/pharmacodynamic and immunogenicity of the administered asset.
• Post-market, biomarker-based assessments of the therapy’s durability.

Sponsors may rely on CROs and specialty lab partners to oversee end-to-end assessment planning and management. Currently, some expert lab teams can leverage advanced lab technologies, such as flow cytometry and droplet digital polymerase chain reaction tests, to measure the genetic vector over time, including how a therapy is impacting the body on a cellular level.

Additionally, when accounting for patients across geographical locations, it is important to ensure assessments can be scheduled, conducted, and analysed at designated times at trial and lab sites that can provide support regionally or locally, as needed. This level of movement requires tight coordination and collaboration between experienced researchers, lab experts, study teams, and project managers for seamless oversight and fewer delays in development.

Evolving regulatory guidance

Given the rapid pace of innovation in CAGTs, regulators worldwide are increasing focus and commitment to providing development guidance, which sponsors need to closely monitor. Since 2022, the US Food and Drug Administration (FDA) has provided six new or updated drafts and final guidance for CAGT development, including how to manage manufacturing changes for CAGTs and CAR-T-specific recommendations.

After a late-2023 FDA investigation of the safety of CAR-Ts, the agency published finalised guidance in January 2024 with key considerations for developing these therapies (e.g., safety and manufacturing). Specifically, the guidance emphasises how “well-designed early-phase clinical studies are critical” to establishing product safety, dose-response relationship, optimal dose differences, and manufacturing feasibility.

In March, the agency established the Center for Biologics and Research’s Office of Therapeutic Products, with dedicated staff highly experienced in CAGTs to help support safe and effective CAGT development and review processes. This new office recently hosted a webinar and Q&A session to support those developing CAR-Ts under the FDA’s guidance. OTP leadership recommended evaluating product design early in development, describing tangible considerations, such as “when multiple CARs are expressed, the CAR construct design should reduce the risk of recombination events, if feasible.”

The OTP is also working with industry stakeholders, including healthcare consulting companies, as the number of CAGT-related emerging technologies will only increase and how to ensure regulators are agile and ready to effectively update regulatory paradigms that may impact beneficial innovations and related review is critical. For example, in vivo CAR-T cell engineering technology helps to avoid the need for CAR-T cell isolation from patients or donors. As such, it does require regulators to think about recommendations for producing these cells in an ex vivo setting, including safety, efficacy, and toxicity studies.

Harmonising global regulatory review

In 2023, eight CAGTs launched globally due to expediated development and regulatory review times, which is encouraging. However, given CAGT is a vastly growing, but still emerging field, regulatory guidance and frameworks across regions are still being developed and/or changing, which sponsors need to keep in mind when seeking regulatory approval in multiple countries. In established markets, including the US and Europe, regulations, such as drug classifications, pathways, and requirements, can vary as is. Then, in accounting for countries with little experience in CAGTs, such as Vietnam or Indonesia, and the growing R&D efforts in China, an industry-wide need to improve regulatory harmonisation globally becomes apparent. And stakeholders are taking steps towards bringing regulators across geographies together.

Last year, the International Council for Harmonization created a Cell and Gene Therapies Discussion Group to help develop a pathway for better harmonisation among countries. Also, to ensure gene therapy applications are reviewed in parallel to accelerate development of rare disease therapies, the FDA recently announced the Collaboration on Gene Therapies Global Pilot (CoGenT Global) pilot programme, in collaboration with the World Health Organization (WHO) and ICH member countries, including Japan, Switzerland, and Canada. The European Medicines Agency (EMA) included CoGenT Global as a discussion topic in a recent meeting for its Committee for Advanced Therapies.

Long-term safety evaluation

As the industry gathers scientific insights on the expanding collection of CAGTs, it also builds upon what it learns to determine how best to monitor for delayed adverse events associated with these treatments. Long-term follow-up studies to capture safety data are a significant regulatory requirement unique to CAGTs. The FDA and EMA have both issued guidelines in the past six years for the design and key data elements of LTFU studies, which can last between five and 15 years, based on product characteristics.

To effectively monitor long-term safety and meet regulations in an already complex development space, sponsors and CROs need to account for how to navigate long-term data collection over multiple years and via a spectrum of sources, while considering patients’ real-world conditions caused by ageing, relocation; a reduced interest in participation once symptom-free; lack of site accessibility, etc. Also, over the span of five to 15 years of required follow-up, sponsors will see varying regulatory and technology updates to respond to.

Unlike traditional clinical trials, where protocol amendments are to be minimised, accepting that change will happen during the span of a LTFU study and staying flexible to evolve with it will be beneficial. Effective CAGT LTFU strategy components are discussed in this previous pharmaphorum article.

Continued decision-making early in development

CAGT development can be make-or-break for many sponsors, especially smaller biotech companies. However, as the industry collectively builds upon innovations in cell and gene therapy, stakeholders will have a stronger collection of knowledge and best practices to rely on for innovative drug development.

The foundation to effectively navigating such a complex space will still lie in the earliest phases of development. Accounting for the wide-ranging unique needs of CAGT development will allow sponsors to plan more efficient and cost-effective programmes, accelerate clinical development and get these important new therapies to patients faster, and most importantly, safely.

About the authors

Patrick Brady, PharmD, is global head of therapeutic innovation & regulatory science at IQVIA. With more than two decades of experience in regulatory affairs in the biopharmaceutical industry, Dr Brady regularly advises R&D leadership and project teams on global drug development strategies, emerging technologies, and the changing regulatory landscape and policies to help inform strategies and decision-making.

Dr Diego Correa is global head of the 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-centred 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 organisations, including the International Society for Cell & Gene Therapy.

Alan Wookey is global head, of companion diagnostics at Q2 Solutions. As an oncology subject-matter expert in biomarkers and precision medicine, Wookey has helped oversee the implementation of the immuno-oncology and cell & gene therapy central laboratory services at Q2 Solutions, a clinical laboratory services organisation. For more than 20 years, he has held senior scientific leadership positions for lab services organisations and pharmaceutical companies. This includes his role as head of the Oncology Biomarker Group at AstraZeneca, where he helped to implement company-wide considerations for personalised medicine and pharmacogenetics from translational science through commercialisation of therapies.