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Challenges facing IBD clinical trials.
Many promising compounds for inflammatory bowel disease (IBD) are lost during the complex development process, and it is vital to find out why and discover some solutions to prevent further leakage from the clinical trials pipeline. Translating basic science into clinical practice is proving difficult in IBD, partly because of the immunological problems suffered by trial subjects and partly because no good experimental model exists, particularly for Crohn's disease.
These are the views of Jean Frédéric Colombel, MD, Professor of Hepatogastroenterology at Centre Hospitalier Régional Universitaire, Lille, France. He gave the closing plenary lecture at the 6th Congress of the European Crohn's and Colitis Organization, held in Dublin in late February.
"Keeping drugs in the clinical trials pipeline is often a difficult challenge," he said. "The placebo effect is a killer of drugs."
To optimize the chances of success, he recommends a reduction of concomitant medication, selecting a robust identifiable endpoint, only entering patients with active disease into clinical trials, a short duration for induction studies, and the minimization of clinic visits. Focusing on patients with active disease is the most important of these factors, but another important issue is the length of the evaluation, noted Colombel, who is a visiting professor at the Inflammatory Bowel Disease Center, Mount Sinai School of Medicine, New York. He argued that a longer evaluation time also raises the possibility of increasing the placebo effect. It is best to opt for an open point of six weeks clinical remission in IBD trials, but this may be too short a time, particularly for those subjects who enter a trial with severe active disease, and it might be prudent to wait longer to observe a clinical effect.
Better endpoints are also needed, he noted. In many IBD trials, the chosen endpoint is mucosal healing (the absence of ulcers is used as a marker to indicate healing). This simple endpoint is easy to identify, especially in Crohn's disease, and is a strong indication of a drug's effectiveness. However, it does have limitations, not least because there is no full validation of what exactly an ulcer is. Colombel thinks qualitative studies of this aspect are necessary, and queries whether one small ulcer is evidence of non-mucosal healing.
The Crohn's Disease Endoscopic Index of Severity (CDEIS) may be a much more sensitive score when assessing mucosal healing, even though many physicians appear reluctant to use the index because they regard it as a complex tool. Using the CDEIS helps to define the endpoints, and therefore is a useful instrument in IBD trials, he pointed out. When considering that the gold standard of healing in patients with IBD is "minor lesions," the endpoint of definition of mucosal healing on the CDEIS should be six. If clinicians are looking for a more stringent endpoint of "no lesions," then the CDEIS should be three.
Currently physicians are assessing the limitations of endpoints on very short-term periods, he stated. Short-term studies are "the black box of clinical trials," and therapeutic strategies are of value for assessing a greater proportion of the patient's life. Induction studies are currently being undertaken up to a maximum of two years. Colombel made a plea that during this time, physicians ought not to define patients' lives in terms of flare-ups and remissions. New endpoints are needed in IBD trials to accurately assess digestive damage. He anticipates that future work will involve the use of a new index of digestive damage, and this may help to provide clinicians with a clearer definition of early Crohn's disease.
This new index is known as the Lémann Score. The score was developed to understand cumulative bowel damage and the impact of early intervention, and it is based on a comprehensive assessment of structural bowel damage. This score is based on damage, not disease activity, and it will take into account damage location, extent, and severity. The Lémann Score will allow physicians to assess the cumulative and progressive damage and to study the effects of early intervention on damage progression.
When only looking at clinical disease activity in patients, physicians may miss the progressive accumulation of digestive damage. The current endpoints of the clinical picture, histology, and endoscopy can no longer be used to assess digestive damage and the impact of drugs on the long-term natural history of IBD, he said. Following the path of rheumatologists when assessing endpoints, he supports using the "Sharp Index," which is an index of bone destruction and is used in many clinical trials as a primary endpoint.
The challenge for future clinical trials in IBD is to look at large studies with robust endpoints and to begin thinking about non inferiority trials. Access to patients in the early stages of the disease is vital when designing IBD trials, and also of interest are long-term studies looking at disease modification with new endpoints, innovative strategies (tight control, dose reduction, and discontinuation), and personalized medicine.
— Edna Astbury-Ward, PhD