Executive Summary

CROHN's DISEASE PHASE II TRIALS should investigate a variety of indications, FDA draft guidelines for the clinical evaluation of drugs for Crohn's disease state. In the section on Phase II studies, the guideline states: "a wide range of indications should be explored at this stage to gain experience with the potential clinical utility of the drug." The guidelines, which are a second draft, were distributed and discussed at the July 25 meeting of FDA's Gastrointestinal Drugs Advisory Committee. The guidelines explain that potential Crohn's Disease agents should be considered for as many indications as possible at the Phase II level of development because Crohn's disease has no clearly defined manifestations and is an inflammatory bowel disease that can involve any layer of the digestive tract from the mouth to the anus. "There is no pathognomic feature of Crohn's disease, and in the absence of a recognized etiology or definitive marker the diagnosis is based upon composite clinical and pathologic features and the exclusion of alternative disease states," the guidelines say. Currently the only approved treatment for Crohn's disease is steroids. General indications for Crohn's disease therapy include treatment of the acute disease, induction of remission, and maintenance of remission. The guidelines state that a treatment endpoint for acute disease would be reduction in the inflammatory symptoms. "Due to the protean manifestations and the broad spectrum of clinical features, symptomatic treatment of acute disease may be based on improvement in a specific, prespecified symptom or conglomerate symptom complex." The guidelines define induction of remission as "the resolution of clinical symptoms and signs of Crohn's disease and documentation of mucosal healing." The definition of maintenance of remission is "the absence of clinical symptoms and mucosal features of acute inflammation." In Phase II trials, "the new drug should be compared to placebo or an appropriately evaluated [or FDA approval] comparative agent such as steroids, mesalamine or 6-mercaptopurine in a well-defined cohort of patients with Crohn's disease," the guidelines say. "If an active comparator is used, the new drug should be demonstrably superior." The studies should be randomized, double-blind and parallel. The studies should be of different lengths depending on the indications. "Studies evaluating symptom response may require 2-8 weeks of treatment, remission may require 8-52 weeks of treatment, whereas maintenance studies should continue for 12-24 months," the guidelines say. After completion of Phase II trials, the guidelines recommend that a company begin studies in pediatric patients. The guidance also strongly endorses the scheduling of an end of Phase II conference with FDA "to assess the information gathered thus far and the detailed plan for Phase III studies." The guidelines recommend that a multicenter, double-blind, placebo or active controlled, Phase III trial be conducted for each indication sought by a sponsor. "The study of more than one dose, dose regimen, or drug concentration is recommended." The guidelines also note that during the juncture between completion of Phase III trials and NDA approval, a company can request a Treatment IND for its drug. One firm that has a potential Crohn's disease treatment in development is Marion Merrell Dow with its mesalamine product Pentasa for which an NDA is pending for treatment of ulcerative colitis. Reid-Rowell's mesalamine Rowasa is already approved for treating active mild to moderate distal ulcerative colitis, proctosigmoiditis or proctitis.