Community feedback: plotting the future of pediatric IBD research

Michael Kappelman sought to understand what kind of research on pediatric inflammatory bowel disease was important to patients and clinicians.

A diagnosis of inflammatory bowel disease, or "IBD," can upend a person's life. IBD—an umbrella term covering a range of gastrointestinal diseases such as ulcerative colitis and Crohn's disease—can manifest as a variety of symptoms, including stomach pain, diarrhea, weight loss, and fatigue. Every version of IBD is chronic, and people often receive a diagnosis in childhood or young adulthood, meaning many will have to manage the disease for most of their life.

Luckily, there's been plenty of research into therapies to help patients manage IBD and reduce the inflammation that causes symptoms. But there's one group of patients who have been left out of much of this research on new therapies: children.

Many of the treatments now approved for adults haven't been formally approved for use in children, and there's little data on how, or how well, these medications might work for treating pediatric IBD. Without this information, many patients may not be getting the optimal treatment, potentially increasing their risk of long-term complications.

Michael Kappelman, a pediatric gastroenterologist at the UNC School of Medicine, has helped many of his own patients navigate this uncertain landscape—and recently, he kicked off a study to finally get some data on the comparative safety and effectiveness of various IBD treatments in children with the disease. But before he could begin that study, Kappelman wanted to make sure he was asking the right questions.

To do so, he organized a series of community feedback sessions through the Patient and Community Engagement in Research (PaCER) program at the North Carolina Translational and Clinical Sciences (NC TraCS) Institute. Kappelman, who also serves as the director of PaCER, says the goal of these sessions was to "pressure-test" his ideas. And by conferring with patients, parents, and other clinicians dealing with this challenging disease, he could make sure his study would be meaningful, important, and accessible to the people who matter most.

"If I'm going to spend my time putting together a large proposal and even more time conducting that study once it's funded, I wanted to make sure that we were addressing one of the most pressing questions in the field," Kappelman says. "I wanted to make sure that we were going after the biggest fish there is. And the only way to do that is to pool together people with a vested interest."

For children with moderate to severe IBD, treatment often includes what are called anti-tumor necrosis factor (anti-TNF) therapies, which can calm inflammation. Anti-TNF drugs are one of the few FDA-approved medications for pediatric IBD—and for many people, these medications can help keep their disease in check. But for other patients, even some who see initial success with the drugs, anti-TNF drugs don't work so well. Kappelman notes that in one clinical trial, about 30% of children with Crohn's disease saw these drugs stop working within two years.

When anti-TNF therapies stop working in adults, clinicians can adjust course with one of the many other medications now approved to treat IBD in adults. But when those drugs stop working for children, figuring out what to do next can be a lot more complicated because researchers haven't yet conducted rigorous studies of many of the alternatives to anti-TNF drugs in children.

Kappelman says this research has lagged for a few reasons. New IBD drugs are generally first tested in adults—like drugs for many other diseases—because there are simply more adults with the disease than there are children with the disease. Officially, those trials can only lead to drug approval for adults. But once those medications are on the market, Kappelman says, many doctors end up prescribing them off-label to their pediatric patients, making enrollment in a traditional placebo-controlled study challenging.

"If I were to ask you: 'Would you like to be part of the study and you might get a placebo, or would you like me to just write you a prescription?'—generally speaking, you'd say let's just write a prescription," Kappelman says.

"So, these studies required for FDA approval in children become really, really hard to do—and the amount of time prior to approval is eternity."

In addition, the lack of studies means there's little understanding of exactly how well these drugs work in pediatric patients, let alone how they interact with other drugs, what side-effects they might bring, or what an optimal course of treatment looks like. There is even less research comparing these treatment options.

Knowing this, Kappelman perceived the need for a study to directly compare the safety and effectiveness of some of the alternatives to anti-TNF drugs in children. His community feedback sessions asked clinicians, parents of children with IBD, and adults with IBD whether that research felt relevant and necessary, and how they thought such a study should be structured.

When a researcher enlists the help of NC TraCS to facilitate a community feedback session, the TraCS team will offer guidance to the researcher on preparing for the session and create a plan for how to gather feedback on the questions at hand. That includes developing discussion prompts, facilitating the actual session, taking notes on what participants offer, and providing a comprehensive follow-up report after the session has concluded. These sessions can focus on a variety of communities, from patient groups to caregivers to clinicians—and they can go a long way toward helping a research team ensure their work lines up with community needs.

In Kappelman's feedback sessions, most participants agreed with the idea that studying alternatives to anti-TNF drugs was important to the field of pediatric IBD research. And they noted some compelling reasons why. For example, some participants noted that families can face a lot of anxiety about choosing the right course of treatment. Others noted that they've seen their children respond well to medications that had only been approved in adults.

The sessions also asked participants their opinions on the proposed study design. Kappelman laid out three possible options for how to study the safety and effectiveness of these drugs in pediatric patients, noting the pros and cons of each.

The first option was investigating the drugs through data on patients who had already taken them. This kind of study would be relatively simple to do, but because any data on these patients would have been gathered outside the auspices of a unified research program, a lot of important information might be missing. The second option was a randomized trial, generally considered the gold standard for clinical research. Data from this kind of study would be very robust, since researchers could compare the drugs in a tightly controlled group of people. But it would also take a long time, and a lot of money, to recruit enough patients into this kind of study—especially since, as Kappelman noted, many patients are already prescribed these drugs off-label.

The work that we had done with those community feedback sessions for sure made the proposal more attractive... They loved the fact that we designed a patient-centered study...

The final option—which both Kappelman and the feedback session participants agreed was the best option—took on some of the best features of the other two options. In this study, the researchers would identify patients who were beginning a treatment, gather the necessary data, and monitor them over time. While this study design wouldn't be as ironclad as a randomized trial, it would be much faster, as well as more controlled than a retrospective study.

Finally, the team wanted to know what participants would like to see as the endpoints of the study—what kind of changes in the disease and the patient's life would be useful to measure? Most of the participants said that patient-reported symptoms and disease status should be either the primary or secondary indicator used in the study, with mixed opinions on how various other measurements, such as clinical assessments and labs, should factor into the assessment. As a result, Kappelman and his team concluded that patient-reported outcomes, as well as some clinically assessed outcomes, would be used to measure the results of their study.

Kappelman incorporated all this feedback into a grant proposal to the Patient-Centered Outcomes Research Institute (PCORI), which specializes in patient-focused clinical effectiveness research. This past fall, Kappelman and his colleagues at Duke University received the grant—for a total of $14.4 million—and he says the community feedback sessions definitely helped improve the grant application.

"The work that we had done with those community feedback sessions for sure made the proposal more attractive to the funder," Kappelman says. "They loved the fact that we designed a patient-centered study based directly on input from patients, parents, and first-line clinicians."

Now, Kappelman and his colleagues have a unique chance to change the future of pediatric IBD care. For patients, there's still a long road ahead before this research might address some of their biggest questions. But by hearing and responding to those questions ahead of time, Kappelman's team set the stage for a research program that could deliver some long-awaited answers.

"I firmly believe that community and patient engagement and involvement from the earliest phases of the design of a study lead to a better study," Kappelman says. "It's more likely to get a result that, at the end of the day, someone cares about. It's more likely to work because the design is optimized for patients."