The last two years have seen dramatic changes in how researchers determine the efficacy of new therapies for Crohn’s disease. We’re now seeing findings from the first clinical trials to measure a therapy’s effectiveness through a combination of objective measures of the disease and patients’ evaluations of their own results.
Dr. William Sandborn, Professor of Medicine and Chief, Division of Gastroenterology and Director, University of California San Diego Inflammatory Bowel Disease Center, explains how this combination approach for Crohn’s disease trials is raising the bar for new treatment options.
What are the unmet needs for the treatment of Crohn’s disease?
While current treatment options for Crohn’s disease have demonstrated efficacy, their use may be limited due to multiple factors, including initial lack of response, loss of response over time or safety concerns. For instance, steroids have safety risks which increase if they are used for long periods of time, and the commonly used anti-TNF therapies can become less effective over time and can have serious side effects.
How have the endpoints for Crohn’s clinical trials been changing, and why?
Previously, we relied on a tool that did not accurately reflect the underlying biology of disease. That measurement, called the Crohn’s Disease Activity Index (CDAI), provided a score based on diaries that patients kept regarding their abdominal pain, stool frequency and how they felt overall (well-being). But those symptoms do not reliably correlate with the inflammation and sores in a patient’s bowels called ulcers.
To determine if a treatment is reducing the inflammation and ulceration of the gastrointestinal tract, doctors perform a colonoscopy, a diagnostic procedure used to examine a person’s digestive tract with a camera. As the Food and Drug Administration has sought to improve clinical trials in Crohn’s disease over the past two years, the field has been moving toward looking at both patient reported outcomes (how the patient feels) and the biological improvement that we can see in the intestine, which we call endoscopic improvement.
How does this combination of endpoints compare with those used for clinical trials in other diseases?
Clinicians have been incorporating the patient’s experience and an assessment of the physical aspects of other autoimmune diseases for years. In multiple sclerosis, they look at patients’ descriptions of how they feel and function along with MRI of the brain that measures damage to the brain and nervous system. In arthritis, patients’ reports are combined with a physician examining the patient for joint damage, and for psoriasis physicians examine the patient’s skin inflammation. Crohn’s disease is now catching up with these conditions.
What are some of the challenges of looking at endoscopic changes?
The approach is still evolving, but we’ve done a lot in the past two years. We developed ways to measure endoscopic improvements and are using them in clinical trials for the first time now. While it’s not a perfect tool just yet, we are refining it based on our experience. You need a lot of training to interpret the data from a colonoscopy because it’s somewhat difficult to measure damage with a two-dimensional image. So we’ve been improving that training, and we’re also improving the system by video recording the procedures and having Crohn’s disease experts independently score the severity of the Crohn’s disease.
Ten years from now, I think that we will look back and realize that this was a seminal moment where we began to expect treatments to address the root causes of the disease.
Do you expect endoscopic improvements come before or after patients start feeling better? Why is that?
In general, there is a lag between when the patient feels better and when the bowel begins to heal in response to treatment, so we are learning that we have to wait longer to see those improvements. The emerging data from trials that have used endoscopic improvements suggest somewhere between four to six months might be the right time to evaluate intestinal healing. This evidence is causing us to rethink how we design clinical trials for Crohn’s and how we interpret results.
Aside from endoscopic effects, what are some other factors that are important to consider when analyzing potential new therapies?
Physicians are always looking at a drug’s balance of safety and efficacy. An effective treatment with an acceptable balance of side effects would be considered a step in the right direction. And if two therapies are otherwise similar, most physicians and patients would consider therapies that are taken by mouth, like a pill or tablet, over those given intravenously or through an injection.
Are you optimistic about future treatment options for patients with Crohn’s disease?
The evolution of clinical trial endpoints has been very exciting and is already having a significant impact on our search for new therapies. Ten years from now, I think that we will look back and realize that this was a seminal moment where we began to expect treatments to address the root causes of the disease.