11/09/2026  |  Marla Broadfoot, Ph.D.  |  Mayo Clinic

https://newsnetwork.mayoclinic.org/discussion/could-the-clinical-trial-of-the-future-begin-before-the-patient-takes-the-drug/ 

About a decade ago, Charles Howe, Ph.D., a Mayo Clinic neuroimmunologist, reached a frustrating point in his research on multiple sclerosis. 

Much of his earlier work had relied on traditional preclinical models, to study how the immune system damages neurons. Those models could answer important questions, but they did not fully capture the complexities of human biology he was trying to understand. 

"Our preclinical models were coming up against a wall," Dr. Howe says. "They just could not capture the right biology."  

That realization pushed him to look for better ways to model human disease. His team began collecting patient blood and skin samples and using those cells to grow three-dimensional neural organoids, miniature models of human tissue that Dr. Howe sometimes calls "brains in a dish." These models can preserve important features of an individual patient's biology and give researchers a way to test ideas that could not be explored directly in a person. 

As that work evolved, Dr. Howe began thinking beyond individual laboratory models and toward a new way of testing treatments before they ever reach a patient. 

His concept, called an ex vivo clinical trial, would move part of the testing outside the patient's body. It would pair living human cell-based models, or "biological avatars," with computer-based "digital twins." Results from laboratory experiments would be used to refine the computer model, and the model's predictions would help guide what researchers test next. The process would continue in a feedback loop, with each round of testing adding new information. 

The goal is to learn as much as possible about how a treatment might work and whether it could cause harm before a patient receives it. 

How biological avatars and digital twins work together
The term "biological avatar" may sound futuristic, but many of its components already exist. "What's powerful about these models is that they can preserve important aspects of an individual patient's biology,” says Brooke Druliner, Ph.D., director of Mayo Clinic's Human Model Systems Core. "They don't recreate the entire patient, but as we make these systems more complex, we can capture more of the biology that matters in human disease." 

Researchers also can place cells in engineered devices known as organ-on-a-chip or microphysiological systems, which can recreate conditions such as blood flow, mechanical forces and interactions among different cell types. 

These models give researchers access to living human biology that can be studied and manipulated repeatedly. 

A digital twin contributes something different. It is a computer-based model that represents aspects of the patient's biology and physiology using molecular measurements, clinical data and other information. These models can be used to simulate or forecast how the patient might respond to a particular intervention or treatment. 

Mayo researchers have already tested that idea in critical care. In one study, they built digital-twin models of patients with sepsis and prospectively compared the models' predicted responses to treatment with what actually happened during the patients' first 24 hours in the intensive care unit.  

The power, Dr. Howe says, comes from putting the two together. Researchers can expose the biological avatar to a drug and measure how the cells or tissue respond, including signs of effectiveness or toxicity. Those results are fed into the digital twin along with other information about the patient. The twin can then simulate what might happen under different doses or treatments and help guide what researchers test next.  

Each new experiment generates more data, allowing the model to be updated and refined. That continuous updating is what distinguishes a true digital twin from a static computer model. 

Could treatments be tested before patients receive them? 
Consider a patient with inflammatory bowel disease. Numerous medications are available to treat the condition, but finding the right one can involve a long process of trial and error. 

"Start with one. It fails. You give them another one. It fails. You give them another one. It fails," Dr. Howe says. 

He imagines a different future. A biopsy taken from the patient could be used to grow intestinal organoids, allowing researchers to test many potential therapies and combinations at the same time. 

"You can treat them with every available drug all at once in order to identify one that is likely to work," he says.

Researchers are beginning to build toward that possibility. Mayo researchers routinely grow colonic organoids from tissue donated by patients with ulcerative colitis and have used them to study how the intestinal lining responds to inflammatory signals. But these models capture only part of a patient's biology. 

Why drugs fail 
The idea could prove useful even before individualized ex vivo trials become part of routine clinical care. 

Drug development remains extraordinarily difficult. Fewer than 10% of drugs entering phase 1 clinical trials ultimately reach regulatory approval, and many late-stage failures result from lack of effectiveness or safety concerns.  

That gap between traditional preclinical testing and what happens in patients helped motivate Dr. Howe's work. Biological avatars potentially allow researchers to test therapies directly in human-derived tissues earlier in development. Digital twins add the ability to integrate those experimental findings with other data and make predictions about dose, response and toxicity. 

Dr. Howe says the repeated back-and-forth between biological avatars and digital twins could help researchers identify weak drug candidates earlier, improve promising ones more quickly and reduce reliance on animal testing. Some of the strongest early evidence comes from cancer, cystic fibrosis and liver toxicity, though the technology is not equally mature across diseases or applications. 

The regulatory landscape is evolving as well. The Food and Drug Administration Modernization Act 2.0 of 2022 expanded pathways for using non-animal approaches,  including validated human-cell and computational methods, to support drug development.  

The trial of the future 
The research supports Mayo Clinic's Clinical Impact initiative that aims to reimagine clinical trials so discoveries can reach patients faster. Mayo is pursuing strategies that include simplifying trial operations and using digital technologies, data and platforms to expand and accelerate innovative studies. 

Dr. Howe's work also connects with Mayo's broader efforts to build biological and data resources that can be shared across the organization. Those efforts are creating pathways to move patient tissue into organoid and other research workflows, while linking the resulting data with Mayo's Research Data Atlas ecosystem. 

But significant hurdles remain. Organoids must be reproducible from one laboratory to another and from one patient to another. Digital twins must be transparent, validated and able to express uncertainty in their predictions. And the entire process must become fast enough to fit the window in which clinicians need to make treatment decisions. 

Dr. Howe stresses that these are early days. These systems are not yet ready to guide routine patient care, but he can envision where the field could lead. 

In the future, he says, clinical trials could begin by screening a therapy against an avatar that reflects the patient's biology. Researchers could look for signs that the treatment will work, as well as potential toxicities, before the therapy is given. 

"Clinical trials are never going to go away," Dr. Howe says. "But the more we can learn before a therapy reaches the patient, the better chance we have of choosing something that will work."