Jordan Schultz has an idea that might improve the lives of people who have Huntington’s disease.
The University of Iowa pharmacist wants to see if a drug designed to lower cholesterol levels can also be used to slow the deterioration of the brain in Huntington’s patients. First, though, he needs to design and run a clinical trial to see if it will work.
So, the doctor and assistant professor of psychiatry and neurology in the Roy J. and Lucille A. Carver College of Medicine designed a clinical trial in 2017 and wrote a grant application for funding. Before submitting it, he decided first to participate in a program that trains young neurology researchers in the art and science of clinical trial design and grant writing. The program is offered jointly by the UI; University of Michigan; University of California, Los Angeles; and National Institute for Neurological Disorders and Stroke.
Schultz’s experience during the nine-month course was sobering.
“I looked back on the original application after I’d gone through the program and realized it was not where it needed to be,” Schultz says. “It was really unpolished, but I didn’t know any better at the time.”
He revised the plan based on the input he received during the class and submitted it to a nonprofit funding agency a year later. It wasn’t accepted, but it wasn’t rejected either, and he was encouraged to re-submit. At the same time, Schultz used what he learned in the class to write two more grants for a clinical trial to repurpose another medication to help people with Parkinson’s Disease. Both of those proposals are now under consideration by the National Institutes of Health (NIH) and the Michael J. Fox Foundation.
Without the class, Schultz says, his research would not be nearly as far along.
“I hit a point where I didn’t know how to move my research forward, and this experience opened my eyes to a lot of opportunities,” he says.
Clinical trials are the foundation on which treatments and cures are built. But Christopher Coffey, professor and director of the Clinical Trials Statistical Data Management Center in the College of Public Health, says a poorly designed and executed trial can be wasteful and does not help people who have neurological disorders.
The Iowa–Michigan partnership is an annual training program for junior neurology faculty and fellows from institutions across the country that teaches participants how to design stronger trials that are more apt to be funded and completed. It not only increases the number of trials that could lead to treatments and cures, it encourages young faculty to pursue research.
“We want to make sure there’s a pipeline of young investigators interested in clinical research,” says Laurie Gutmann, clinical professor of neurology in the Carver College of Medicine who co-directs the program with Coffey and three others. “It shortens the pathway from designing feasible clinical studies and getting them done, so we want to give them those skills early in their careers.”
Clinical trials are research studies in which new drugs, techniques, and other therapies are tested on human subjects to determine their effectiveness as they move from the lab to the clinic. They are scientifically rigorous, highly regulated, and expensive, which means potential funding agencies want to make sure the investigators have a well-designed trial before approving any grants.
The Iowa–Michigan program, called the Clinical Trials Methodology Course, is designed to reduce the number of trial proposals for neurology and the brain sciences that are rejected either because the trial is poorly designed or the grant application is poorly written. Participants submit a proposal for a small clinical trial and a grant as part of their application to the program. The proposal is then reviewed by small groups of senior faculty, biostatisticians, and NIH experts that meet online every week for about six months starting in April.
“That’s when we rip it apart,” says Coffey. “But in a good way.”
The faculty also participate in an intense, four-day summer conference that alternates between Iowa City and Ann Arbor, Michigan. In July, the UI hosted 22 doctors from medical schools across the country who work in an array of brain science disciplines, including neurology, psychiatry, pharmacy, emergency medicine, and surgery.
The schedule also allows plenty of time for networking.
The program is the only one of its kind in the country, as no single institution offers such extensive training to junior researchers. Ted Abel, director of the Iowa Neuroscience Institute, says that hosting so many of the best and brightest builds Iowa’s reputation as a leader in neurological research and brain science, and the outcome of more and better designed clinical trials is important for researchers, clinicians, and patients.
“Clinical trials are how new drugs go from the research lab to the pharmacy and new procedures and therapies go from theory to reality,” says Abel, who is also interim chair of the Department of Pharmacology and Carver Chair in Neuroscience. “Teaching bright and talented young researchers how to design and implement better trials is key to finding the cures and therapies that will improve countless lives.”
The lesson plans address broad issues relating to clinical trials, such as what questions should be asked, what is the most appropriate design to answer them, and what the subject pool should look like. It teaches nuts-and-bolts issues, too, such as budgeting; software systems; data management; work-family balance; and the importance of diversity, equity, and inclusion considerations in trial design and execution.
Coffey says an important lesson of the program is that researchers have to start small and make slow, incremental progress.
“You have to build. You can’t start with a trial that expects to prove a drug or a procedure works and is ready to cure a disease,” he says.
Another lesson is the importance of adding a biostatistician to the trial team at the beginning. Clinical trial biostatisticians are health care professionals who typically work closely with clinical colleagues to provide support for the design, conduct, and analysis of multisite trials. They can help determine appropriate sample size, develop summary reports, implement analysis plans, and help write reports, presentations, and papers.
Gutmann says biostatisticians also bring another viewpoint that often offers clarity to a clinical researcher who may be overwhelmed by all the moving parts.
“It’s not just a benefit to have a statistician on the team, it’s a necessity,” says Schultz. “You may think you have a great idea, but if the trial isn’t designed properly, it’s not going anywhere. It’s easy to get tunnel vision, but a biostatistician can help see things more clearly. It was great to realize there are professional and well-intentioned people at the university who want to help you not just get your trial designed, but want to help your career too.”
Edgar Samaniego, a clinical professor of neurology in the Carver College of Medicine, says he hopes biostatisticians will help him improve the design of a trial to improve treatments for people with brain aneurysms. Too often, he says, doctors aren’t sure how to treat patients with brain aneurysms because there’s not much information on what makes an aneurysm dangerous. Some people can live for years with a fairly large aneurysm, while much smaller aneurysms fatally rupture.
Treatment decisions are urgent because 30% of ruptured aneurysms lead to immediate death, and 50% of patients die later. But what makes an aneurysm rupture? Does size, shape, or position matter? Doctors aren’t sure because previous studies have been inconclusive.
“We ask ourselves, should I treat or not? At this point, we don’t have an answer because we don’t know which are more prone to rupture,” he says. His proposal is a multisite trial that uses MRI images to characterize aneurysms so doctors can make better-informed treatment decisions for people with aneurysms.
Samaniego says the clinical trials program has helped him develop better questions, and he’s made changes in the trial design based on pointed, unbiased feedback from experts.
“That one-on-one feedback has been very important, and we don’t normally get that,” he says.
Nick Trapp, assistant professor of psychiatry in the UI Carver College of Medicine, participated in this year’s program with a trial proposal to compare the effects of transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT) in treating people with depression. He says he quickly realized the value of the class when he considered the caliber of the people who were helping him.
“There were all these genius minds in the room with us in a one-to-one ratio of mentors to mentees, and that doesn’t happen anywhere else,” says Trapp, who plans to reach out to the experts in the coming months as he polishes his proposal. “It was more like a family in a lot of ways. We had fun outside of class and really came to support each other.”