Smart Trial Design In Cell Therapy: Fast-Tracking Without Compromising
By Sanjeev Luther, president and CEO, Ernexa Therapeutics
Cell therapy has transformed many areas of medicine, filling gaps that drugs could not. But the path from bench to bedside in medicine is notoriously slow, with the development of cell therapy products taking even longer than drugs. The process can take years or even decades. What if we could accelerate the process without compromising safety, bringing lifesaving drugs into the hands of patients sooner?
A well-crafted clinical trial design and strategy can accelerate the process while maximizing effectiveness and ensuring safety, minimizing development bottlenecks, and streamlining approvals.
Single-Arm Clinical Trials Are The Most Common
The gold standard for most drug trial designs is the randomized clinical trial (RCT) model. However, there are unique complexities in cell therapy – including delivery mechanisms, dosing schedules, and specialized patient populations – that make it difficult to use the traditional model. Alternative trial designs often provide the flexibility needed for cell therapy products.
A single-arm trial, for example, in which all participants receive the same treatment being studied, is the most common model in cell therapy. Safety, efficacy, and other endpoints are assessed by comparing results against historical data, real-world evidence, or prespecified benchmarks. Since all participants receive the treatment, enrollment is quicker. Additionally, the study requires fewer patients than traditional trial designs. This model is also ethically advantageous, as it allows treatment access to the patients who need it most and enables real-time safety monitoring that ensures rigorous oversight.
When a single-arm trial is investigator-sponsored, even more flexibilities and efficiencies are enabled. Since an academic institution is leading the trial, not a pharmaceutical or biotech company, the trials do not require large sponsors and allow for more streamlined protocols. This helps speed up the process.
For these reasons, the clinical trial for ERNA-101 — our lead cell therapy product being studied for the treatment of ovarian cancer — will be an investigator-sponsored, single-arm trial, led by one of the most well-known cancer institutes in the United States.
More Adaptive Clinical Trials To Balance Speed And Safety
Additional trial designs include basket, umbrella, and platform trials, which can all be adaptive.
Adaptive trials allow modifications during the trial based on interim data — from dose adjustments and sample size changes to treatment arm additions. This improves efficiency by allowing flexibility without compromising scientific rigor.
A basket trial tests how a single therapy works across multiple diseases or patient populations that share a common characteristic. For example, patients with a specific biomarker or genetic mutation — across various diseases — may be enrolled in the trial. Based on the data during the trial, investigators may decide to expand successful cohorts or close ineffective ones. This approach can accelerate drug development and regulatory approval.
Kymriah (tisagenlecleucel) is a CAR T cell therapy originally approved for B-cell acute lymphoblastic leukemia (ALL) but was later studied in other B-cell malignancies using basket-like approaches. Another example is Carvykti (ciltacabtagene autoleucel), which was approved for multiple myeloma and later evaluated in broader plasma cell disorders using a basket trial design.
Conversely, umbrella trials focus on treating a single disease with multiple therapies. Investigators establish cohorts based on specific genetic mutations or biomarkers within the same disease and determine which therapy they believe will be most effective. This design, too, allows for adjustments during the trial and enables efficiencies.
Tumor-infiltrating lymphocyte therapy Lifileucel (LN-144) is a prime example of an umbrella trial design in cell therapy. Originally developed for metastatic melanoma, this therapy has been tested across multiple biomarker-driven patient cohorts, including those with non-small cell lung cancer (NSCLC). The trial is structured with different arms to evaluate the effectiveness of the therapy both as a monotherapy and in combination with checkpoint inhibitors. Additionally, it explores treatment responses in patients with distinct genetic profiles, allowing for a more personalized approach to cell therapy. This umbrella trial design enables researchers to simultaneously assess Lifileucel’s efficacy across various subpopulations within a single disease category, optimizing patient selection and treatment strategies.
Platform trials are the most flexible and adaptive. The trial simultaneously tests multiple treatments for one or multiple diseases. The trial functions within a continuously evolving framework, in which treatments are added, modified, or dropped based on ongoing trials. It also uses a shared control group, tapping a single group of patients who serve as the comparison group for multiple experimental treatments within the same trial.
The I-SPY 2 trial is a pioneering example of a platform trial in oncology, specifically designed to accelerate the development of new treatments for breast cancer. This adaptive platform trial evaluates multiple investigational therapies simultaneously, allowing for the rapid assessment of new drugs or drug combinations across various subgroups of breast cancer patients. By using real-time data and biomarkers, the trial can modify its design, dropping ineffective treatments and adding new ones as they become available. The I-SPY 2 trial exemplifies how platform trials can efficiently test multiple therapies in parallel, maximizing the chances of success in clinical trials.
Other Ways To Accelerate A Cell Therapy Trial
Combining trial phases, when possible, is also a way to accelerate a trial. For example, a Phase 1b/2 clinical trial accelerates approval by seamlessly transitioning from safety and dose optimization to efficacy evaluation, reducing delays between trial phases. Strong early efficacy signals can qualify a treatment for Breakthrough Therapy or Fast Track designation, expediting regulatory review. Additionally, early proof of concept attracts funding and partnerships, supporting later-stage development. In some cases, promising results may allow direct expansion into a pivotal Phase 2/3 study, further shortening the approval timeline. This approach is particularly beneficial in oncology, rare diseases, and high-need therapeutic areas.
In addition to determining the most effective and efficient trial model, other strategies can safely accelerate a trial. Investigators can incorporate real-world evidence to supplement trial data, including data from expanded access programs, compassionate use cases, and patient registries. Such real-world data does not have to be limited to single-arm studies. For example, synthetic control groups — a type of external control group used in clinical trials that leverages real-world data or historical trial data instead of a traditional placebo or control group — have many benefits. They can enhance ethical considerations for diseases where withholding treatment is not feasible. They can also accelerate drug development by avoiding the need to recruit actual patients.
Investigators can also minimize patient burden by enabling remote monitoring, at-home sample collection, and local treatment centers. In general, standardizing protocols across multiple trials is important to streamline regulatory approval and reduce redundancies.
Finally, a thoughtful strategy for patient identification and enrollment can also eliminate unnecessary delays. For example, using predictive biomarkers to identify responders early reduces the trial size to focus only on the patients who would potentially benefit most. A smart biomarker strategy is not only important in specific trial designs like basket or umbrella trials but also across most trials. This will not only reduce the duration of the trial but also increase its chances for success. There are many trials that have failed due to a lack of a strong biomarker strategy.
Additional strategies to enhance patient recruitment and engagement include leveraging AI-driven analytics to identify eligible candidates within electronic health records (EHRs) and genomic databases, streamlining the matching process for clinical trials. Additionally, cell therapy companies can strengthen partnerships with community hospitals and patient advocacy groups to expand outreach, build trust, and ensure more diverse and representative enrollment. These collaborations help address disparities in clinical research participation, improve access to cutting-edge treatments, and foster long-term patient engagement.
Final Thoughts On Fast, Effective And Safe Trials
With patients urgently awaiting lifesaving treatments and research and development costs continuing to rise, minimizing unnecessary delays is essential. Through thoughtful and strategic planning, we can ensure the rigorous testing required for effective therapies while eliminating inefficiencies that create bottlenecks. After all, people's lives depend on it.
About The Author:
Sanjeev Luther is president and CEO of Ernexa Therapeutics and a member of the Board of Directors. Sanjeev is a pharmaceutical executive with over 30 years in leadership roles at organizations including Cornerstone Pharmaceuticals, Bristol Myers Squibb, Novartis, Bausch and Lomb, and GE Healthcare. Ernexa Therapeutics is developing innovative cell therapies for the treatment of advanced cancer and autoimmune disease. Its lead cell therapy product, ERNA-101, is being developed for the treatment of ovarian cancer.