Inflammatory bowel disease clinical trials are facing headwinds, with challenges in recruitment and trial design. The field is a victim of its own success, according to experts: People can forgo participation in a clinical trial in which they receive a placebo or a novel therapy that might not work and opt for treatment with an approved therapy instead.
“Clinical trial recruitment in IBD is in crisis, and crisis requires reevaluation of the status quo,” said David T. Rubin, MD, a professor of medicine and the director of the IBD Center at the University of Chicago. In Dr. Rubin’s experience, when he tells patients about the existence of the placebo effect, or that they can receive a novel therapy during open-label extensions, it is a hard sell.
In addition to these problems with recruitment, there are other stumbling blocks, such as inclusion criteria that don’t reflect the real world, Dr. Rubin said.
He and other experts spoke with Gastroenterology & Endoscopy News about the hurdles facing IBD clinical trials.
He stressed the significance of the problem, pointing out that “we have reached what is widely acknowledged as a therapeutic ceiling,” with approved therapies sometimes only working in 30% to 50% of the people who receive them.
(Non-)Enticing Participation
Recruitment is particularly tough if the trial design is the classic approach of testing a novel therapy against placebo, or of withdrawing the active treatment during the maintenance phase.
People might be willing to join such trials if the need and the mechanism are compelling enough. For example, Dr. Rubin said, the pivotal trial for vedolizumab (Entyvio, Takeda) had great enrollment despite its placebo arm because many people had failed tumor necrosis factor (TNF) inhibitor therapies, and vedolizumab was the first non–anti-TNF therapy available.
Despite the success with vedolizumab, Dr. Rubin said IBD trials should reduce or eliminate the role of placebos going forward. Approaches could include head-to-head trials of approved therapies, basket trials in which the same drug is tested in multiple diseases and umbrella trials in which multiple drugs are compared with the same placebo arm or an active comparator arm with an approved medication.
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“You have to design trials that are accessible to patients and innovative in their approach,” Dr. Rubin said.
Inclusive Trials for Adults And Children
“The day a drug is approved, the individuals who were included in the trial don’t necessarily reflect the real-world patient,” said Marla Dubinsky, MD, the chief of the Division of Pediatric Gastroenterology at Mount Sinai Kravis Children’s Hospital and the co-director of the Susan and Leonard Feinstein IBD Clinical Center at the Icahn School of Medicine at Mount Sinai, in New York City.
For example, Dr. Dubinsky noted that clinical trials often require long periods of washout of existing medications before someone receives a novel therapy, even though in everyday clinical practice, providers don’t wait to start a new therapy.
“We’re left to extrapolate because the exclusion criteria are so limiting,” Dr. Dubinsky said.
Another enrollment challenge is screening failure, particularly with Crohn’s disease in which patient-reported symptoms may not match Simple Endoscopic Score criteria. “Screen failure rates are extremely high,” Dr. Dubinsky said, noting that inclusion of intestinal ultrasound readings may reduce screen failure rates, as seen in some of her own research (Am J Gastroenterol 2024;119[5]:930-936).
Dr. Dubinsky has led research examining clinical trial design. She is senior author of another 2024 paper calling for more inclusive inclusion criteria for IBD trials so that trial populations better match real-world patients (J Crohns Colitis 2024 Jun 22. doi:10.1093/ecco-jcc/jjae097).
Clinical trials should be designed to more closely match clinical practice, Dr. Dubinsky said. “In the real world, we never take someone who is doing well and re-randomize them to nothing,” Dr. Dubinsky said, although this is a common clinical trial design. She called for greater use of treat-through designs, in which patients maintain use of therapies that are working.
In pediatrics, IBD medication approvals lag far behind those for adults, Dr. Dubinsky noted, with only adalimumab and infliximab indicated for children. One way to hasten pediatric drug development is to build on what already happened with adults.
“To date, IBD therapies approved for adults aged 18 years and older have not proven to perform in the clinic any different in children, especially those weighing above 40 kilos or aged 12 and above,” Dr. Dubinsky said, calling for full extrapolation of efficacy data from well-powered placebo-controlled studies in adults to children, as is done in other pediatric immune diseases. And if well-designed, dose-finding studies occur in phase 2 of adult trials, Dr. Dubinsky added, pharmacokinetic and pharmacodynamic studies in children can begin soon after.
Active Comparators, Not Placebos
“We can continue head-to-head trials, but it should be head-to-head against something that works,” said Peter Higgins, MD, PhD, MSc, a professor of internal medicine at the University of Michigan, in Ann Arbor. Going forward, all IBD trials of investigational agents should use approved, low-cost biosimilar agents such as adalimumab or infliximab as active comparators rather than placebos, Dr. Higgins said, just as methotrexate is used in rheumatology trials.
“We don’t want to see more ‘pretty good’ drugs. We want to see breakthroughs,” Dr. Higgins said, and one way to do that is to subject the investigational agents to tougher competition than placebos. The current model of comparison with placebo leads to a glut of medications with similar levels of efficacy, Dr. Higgins said, such as the many interleukin-23 inhibitors now approved for IBD treatment.
Reliance on placebo can harm patients, Dr. Higgins noted. “There are a lot of consequences to placebo that we tend to blow off,” Dr. Higgins said, such as a severe flare that could require hospitalization or result in missed work.
“Active comparators will really help with recruitment,” Dr. Higgins said, because in this case, trial participants always know they are receiving treatment. Dr. Dubinsky said she believes that adult data could still be extrapolated to children, even if placebos are no longer used.
Active comparators and shorter washout periods can be used in head-to-head trials that only compare two medications, Dr. Higgins said, or in umbrella trials in which people are cycled through different induction medications until finding the treatment regimen that results in the best response. Each intervention in an umbrella trial might have some different drugs, dosages and treatment times, Dr. Higgins said, adding that this iterative approach should seem familiar. “Umbrella trials are a lot more like clinical practice.”
Dr. Dubinsky reported financial relationships with AbbVie, Abivax, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Genentech/Roche, Gilead, Janssen, Johnson & Johnson, Lilly, Merck, Pfizer, Prometheus, Spyre, Takeda and Target PharmaSolutions. Drs. Higgins and Rubin reported no relevant financial disclosures.
This article is from the October 2024 print issue.