Amy Glekas, Head of Field Development and Interim Head of Sales at Solvias, explores the opportunities that analytical testing can offer cell and gene therapy developers. 

Cell and gene therapies (CGTs) have commanded public attention for decades. There are the big milestones, for example, the major gene therapy approvals, a decade of CAR T-induced cancer remission and the first patient-specific, in vivo gene editing treatment. However, in a more guarded investment climate, obstacles like adverse events and deaths with AAV-based gene therapies, manufacturing bottlenecks, quality failures, and commercial and reimbursement challenges have slowed CGT development as cautious investors gravitate toward more predictable, lower risk approaches.  

These headlines capture key inflection points in the industry, but they rarely reflect the full story. Upstream of clinical development, important progress continues to be made on the analytical tools that support CGT development. Among these tools, potency assays remain the most important, and most challenging, component. Advancements in analytical testing capabilities and specialised testing expertise are reshaping what is possible, enabling developers to generate more reliable potency data earlier in the development process. Importantly, this helps de-risk programmes before they reach regulatory review. This progress should ultimately help restore confidence in a field defined by its transformative potential.

CGTs are overrepresented in clinical holds 

Potency assays consistently rank among the most difficult elements in the regulatory pathway for CGTs. These cell-based bioassays serve as critical indicators of whether a therapy is performing as expected, and regulators expect clear, defensible evidence of biological activity.  While expression assays may provide a minimum level of confirmation of activity, potency-indicating assays are not only required in later phases of development but they also ensure many key factors are accounted for in early development. With a strong potency testing strategy, drug developers can have a more streamlined approach to regulatory submissions, reducing risk and reassuring investors that a programme is on a viable trajectory.  

Conversely, when potency strategies are inadequate, the resulting development challenges are well documented. As former Center for Biologics Evaluation and Research (CBER) Director Peter Marks noted, “one of the key things that has delayed a fair number of approvals has been issues related to potency”. 

The data reflect this challenge: while CGTs account for only 2% of NIH-listed clinical trials, they make up approximately 40% of all clinical holds (1). Approximately one in five of these holds is due to chemistry, manufacturing, and controls (CMC) deficiencies, including potency. These delays are not insignificant. An initial clinical hold lasts a minimum of 60 days, but CMC-related holds often take much longer as drug developers work to generate or re-generate the essential data. These delays can erode investor confidence and force difficult strategic decisions. 

Why potency remains difficult 

Potency is challenging in CGT not simply because assays use living cells, but because developers are often asked to quantify complex biological functions that do not neatly translate into an in vitro model. For many CGTs, the mechanism of action is multifactorial, indication-dependent, or only partially understood. Designing a single assay, or in some cases, a set of multiple assays, to capture that biology with reproducibility and regulatory robustness is inherently difficult. 

Living-cell systems introduce additional variability. Cell-based bioassays can respond to subtle differences in culture conditions, donor biology, assay timing, stimulation settings and more.  Even under tight control, small shifts in these variables can alter assay performance in ways that are difficult to fully standardise.  

Allogeneic cell therapies begin with a renewable, uniform starting material. This enables greater batch-to-batch consistency and supports the generation of larger datasets for assay development and validation. While allogeneic systems still contend with the inherent complexity of functional assays, their standardised starting material generally makes potency assay design more tractable.  

By contrast, these challenges become especially pronounced in autologous therapies such as CAR-T, where every batch begins with a different patient’s cells. Limited material availability and patient-to-patient heterogeneity constrain how much testing can be performed and make it difficult to establish consistent reference ranges.  

Because each product is manufactured from unique starting material, potency assays must closely mirror the manufacturing conditions to ensure the in vitro readout reflects the physiologically relevant functional activity of the therapy. Reproducing these conditions with precision requires meticulous assay development and deep cell therapy expertise, making potency one of the most technically demanding aspects of CGT development. It is work that depends on true subject-matter expertise, not generic laboratory proficiency, to produce data that regulators, developers and investors can trust.

Building a comprehensive potency testing strategy 

A reliable potency strategy often cannot rely on a single assay. Because biological activity is multifaceted, a panel of assays is often required to capture the mechanisms most relevant to a therapy’s mode of action. These design efforts need to begin early, well ahead of IND submission, so that teams have time to explore different assay formats, evaluate stability and reproducibility and conduct correlation studies where appropriate.   

A robust potency programme allows developers to: 

• Characterise key functional attributes of a therapy 

• Define and confirm critical quality attributes (CQAs) 

• Generate reliable, regulator-ready datasets 

• Identify and eliminate assays that lack discriminatory power 

This work requires advanced scientific expertise, extensive assay design experience, and access to a diverse set of analytical technologies. It also requires the kind of judgement that comes only from working across many programmes and understanding how regulators evaluate potency strategies in practice. Many developers benefit from partnering with contract research organisations (CROs) that specialise in CGT potency assay development, optimisation and validation. The right partner can guide developers through evolving regulatory expectations.  Importantly, established CROs are also equipped to scale workflows under compliant conditions, ensuring that potency assays remain reliable as programmes scale up their manufacture while advancing through the phases of drug development to commercialisation.

Reducing risk and strengthening confidence 

All drug development carries inherent risk, but CGTs need not be disproportionately vulnerable to costly delays. Improving the reliability, interpretability and robustness of cell-based bioassays is one of the most powerful ways to reduce regulatory uncertainty and strengthen the likelihood of success. Doing so requires more than expertise. It demands early investment in assay design, careful control of assay conditions, clear definition of readouts and consistent execution supported by quality systems that hold up during review.  

As the field advances, CGTs continue to offer promising solutions for complex, difficult-to-treat diseases. By leveraging modern analytical tools and partnering with experts who understand the nuances of cell-based bioassay development, drug developers can build stronger data packages, avoid preventable regulatory setbacks and give investors renewed confidence in the next generation of potentially curative therapies.  

References 

1. Wills CA, et al.Clinical holds for cell and gene therapy trials: Risks, impact, and lessons learned. Molecular Therapy Methods & Clinical Development, Volume 31. 

From DDW Volume 27 – Issue 1, Winter 2025/2026 – Read the digital issue here