ORLANDO (FRONTLINE MEDICAL NEWS) – Independent investigators eager to author studies that have notable impact on the field of inflammatory bowel disease have plenty of important paths to pursue, according to Dr. Jean-Frederic Colombel, a professor of gastroenterology at Mt. Sinai Hospital in New York.

“Over the next 3-5 years, we will have a lot of new drugs, which is nice, but we don’t yet know how to use them, or which ones to use,” Dr. Colombel said during a presentation on the future of the field at this year’s meeting of the annual Advances in Inflammatory Bowel Disease, sponsored by the Crohn’s and Colitis Foundation of America.

A host of biologics including vedolizumab, recently indicated by the U.S. Food and Drug Administration for ulcerative colitis and Crohn’s disease, and ustekinumab, currently in phase III studies for Crohn’s disease, are set to revolutionize treatment at a time when the field is already undergoing great change, according to Dr. Colombel. The result, he says, is that despite “formidable” challenges in recruitment and funding, “huge opportunities” exist for investigators willing to collaborate and be creative.

Studies that elucidate the natural history of Crohn’s disease and colitis offer insight into the efficacy of various treatment strategies, help determine whether to target symptoms or biomarkers, and answer whether combination therapies are safe and effective in certain patients, among others, are what Dr. Colombel says he hopes will help improve the field as the drug pipeline continues to grow.

He stipulated a caveat, however, “I strongly believe we need some new study designs.” Although he noted that trials needn’t be complicated, they should be long enough to collect sorely needed prospective data. “These can only be done in investigator-initiated trials because of the time frames,” Dr. Colombel urged the audience of young investigators and their colleagues.

A fieldwide shift in thinking about ulcerative colitis and Crohn’s disease as chronic, progressive diseases, rather than intermittent afflictions has already helped generate new study endpoints such as the L é mann Score , an index of progressive bowel damage that allows researchers to better track the history of IBD in patients, and thus provide a window of opportunity for interventions, said Dr. Colombel.

To wit, the CURE study, conducted by the French IBD society GITAID, is a 5-year, prospective study of patients whose early Crohn’s disease is treated with the biologic adalimumab. The Lémann Score is used to screen patients at the end of each successive year, in order to adjust their treatment to reach the final endpoint of deep remission by year 5 when several indicators are measured, including bowel image, level of disability, and whether there was the need for surgery. Dr. Colombel said the novel design of the study, which has already recruited 60 patients, with successive endpoints to evaluate new drugs and strategies over longer periods of time shows it is “feasible” to collect longitudinal data.

The field also has a responsibility to conduct randomly assigned controlled trials to demonstrate the comparative effectiveness, safety, immunogenicity, and cost benefits of the rapidly emerging spate of biosimilars, particularly since there is not global agreement about their use, according to Dr. Colombel. Their approval for IBD in Europe is “highly disputable … I think this could be a very nice topic for an investigator-initiated trial, in Canada and the U.S.”

Head-to-head trials that are well designed will help answer “very important questions” about which treatment strategies, including the use of biosimilars, have the best outcomes, but doing so requires fortitude, according to Dr. Colombel. “The Dutch have the guts to conduct the LIRIC trial ,” he said. In it, patients with Crohn’s disease in the terminal ileum, who have failed steroids or immune therapy, will be assigned randomly to either laparoscopic ileocolic resection or infliximab, the first available biosimilar. Sixty participants have enrolled to date, he said.

These types of studies could also help delineate how best to employ combination therapies. “What I propose for this kind of study is an intensive therapy combining biologics very early in patients with bad prognoses, and looking at the long-term outcome using bowel image,” Dr. Colombel said. These data, and others indicating the most appropriate length of treatment in patients with varying states of disease, are Dr. Colombel’s personal “top choice” for investigation.

The excitement that personalized medicine has engendered across the specialities has so far not resulted in specific, validated treatments for IBD patients. However, the question of how to use personal characteristics, serologic and genetic markers to create predictive models for which patients will need either step-up or top-down therapies, accounting for their individual risk of complication, is what he said is among the most “important [question] we need to answer because the choice of early therapy will depend on this predictor,” according to Dr. Colombel.

The question of which treatment targets are best remains unclear but is important to decipher, according to Dr. Colombel, who said simple studies comparing outcomes when patients are treated to symptoms vs. treated to biomarker measurements are needed. Whether to treat to certain medication trough levels vs. symptom relief is also a pressing need, as well as is the importance of mucosal healing vs. symptoms. “This is important because there is discordance between endoscopy and histology,” said Dr. Colombel. “Persistent histologic inflammation is frequently associated with bad outcomes.”

However, endoscopic scoring itself is another area Dr. Colombel said is worth investigating, especially when it comes to validating endpoints such as those in the Crohn’s Disease Index of Severity ( CDEIS ), and Simple Endoscopic Score for Crohn’s Disease ( SES-CD ), which will help determine remission cut offs. Also, using endoscopic scores in comparison with live video and imaging still need standardized approaches. “When you see how it is done in the U.S., it is generally very poor,” Dr. Colombel said.

The biggest obstacles of all when it comes to independent investigation in the United States, according to Frenchman Dr. Colombel, is heavy regulation and cost. “In France, [conducting trials] was considered part of my job. I was not compensated. It is different here.”

Despite that, he said successful studies are a matter of desire. “You have to have dedicated people who want to run these studies and who can meet often and drive the process, and be ready to recruit patients.”

Dr. Colombel has numerous financial ties to the pharmaceutical industry, including AB Science, Amgen, Baxter, Bristol-Meyers Squibb, Merck, Nutrition Science Partners, Teva, and Vertex, among several others.

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