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Special Considerations for an Investigator’s First Stem Cell Protocol


Mayo Clinic researchers have co-authored a review to serve as a primer for physicians worldwide who want to translate their laboratory-based discoveries in stem cell therapy into clinical trials. Stem cell therapy has enormous potential to alleviate human suffering. Instead of using small-molecule drugs and devices to ameliorate the symptoms of disease, clinicians can harness the therapeutic power of cells to regenerate and cure diseases. The hitch? Translating basic research findings into human therapy has not been straightforward and has presented many scientific, clinical, and regulatory challenges for scientists and clinicians.

Thus, the review, published in Stem Cell Research & Therapy, provides a guidance framework for the design of early-phase clinical studies using stem cell-based therapeutics. It especially encourages investigators to consult with regulatory agencies from the earliest stage of the translational process.

Anthony Windebank, M.D.

“It’s worth engaging the regulators because you’ll get their perspective on the best way to go about your particular trial,” says Anthony Windebank, M.D., neurobiologist with Mayo Clinic’s Cellular Neurobiology Laboratory and co-author of the paper. “Sometimes, people see regulatory agencies as barriers. That’s really the wrong way to think about it. Their primary concern is patient safety, and they’ll direct you and help you establish the best way to make your proposed new treatment safe.”

Consulting with such agencies early in the research process can save significant time and cost in the long run. Dr. Windebank discovered this firsthand when starting out: “When we were thinking about stem cell treatment for ALS, the first trial we began is what’s called a ‘dose escalation trial,’” he says. “This means, we start with a very small dose and treat a group of patients, and then we increase the dose and treat another group of patients, and we keep increasing to the top dose.”

However, before starting a human trial, Dr. Windebank’s team consulted with the FDA on its plans. The agency was encouraging and suggested some streamlining ideas the team had not thought of. “They were wonderful,” says Dr. Windebank. “Consulting with the FDA probably saved us a year’s time.”

Thinking about the regulatory side is critical when translating science because there is a difference between how one does research in a laboratory versus what one does to prepare for a clinical trial. When starting to move toward a clinical trial, an investigator should be thinking about what he or she may need from a regulatory point of view, which can be gained from a study in the laboratory. This particularly applies to the way data is managed and kept.

Take, for example, a study on mice with ALS, using cell therapies: the investigators should document that “not only did the mice get better from their ALS symptoms, but they also didn’t develop kidney problems, hematology blood problems, or liver problems,” says Dr. Windebank. “As you get closer to the clinic, you need to be doing your research studies in a way that will generate data that’s valuable to support your application to the FDA. Most people don’t even think about that.”

Since stem cells are used in the same way as drugs in investigator-initiated protocols, they are required to follow the regulatory pathway of pharmaceuticals into the clinic.

Furthermore, the nature of cells as drugs is more complex, and the translational pathway to development requires special considerations. Cells, being living organisms, behave in many different ways and can do a myriad of things a single-molecule drug cannot do.

“You’re dealing with a whole population of cells, and a population of cells in a dish is like a population of people in a city,” says Dr. Windebank. “So there’s variability. And one of the characteristics you want in a drug is consistency. With a small-molecule drug, that’s very easy to do. But every cell and every population of cells that grow up from each patient has a potential to be different.”

This could mean variability in a cell’s ability to produce side effects, for example, or variability in the cell’s capacity to produce the desired effect. Which is why, when designing ALS trials, Dr. Windebank’s team puts an emphasis on understanding the individual response of each patient. “You have to study what is different about the cells in one patient versus another patient and their diseases,” he says. “So you have to be thinking very comprehensively.”

The key takeaway for investigators? Think ahead. As in, think about what you need to do to translate your cell therapy to a patient right from the beginning of your research study. And remember, the FDA is not the enemy. The agency, as with all regulatory entities, is there to help you. Finally, says Dr. Windebank: “Seek advice, collaboration, or consultation with someone who has been there before, even if it’s someone from another institution.”

Christoph Bahn

Christoph Bahn

Christoph Bahn covers emerging research and discovery for Mayo Clinic Laboratories. His writing has also appeared in The New York Times, Los Angeles Times, and Smithsonian Air & Space. He divides his time between Southern California and Northwest Ohio.