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Executive Summary

FDA ULCERATIVE COLITIS DRUG DRAFT GUIDELINES INCLUDE ACUTE DISEASE treatment as an indication for which drugs in development may be approved. The guidelines were reviewed by FDA's Gastrointestinal Drugs Advisory Committee at its Oct. 23 meeting. Drafted by Stephen Hanauer, MD, University of Chicago, the guidelines state that "the treatment of) acute disease may pertain to an improvement in symptoms, endoscopic changes, or pathologic changes when appropriately defined in a subgroup of patients (in which case the indication will be limited to that subgroup), or to induction of remission." Hanauer noted in the guidelines that he would "like to eliminate treatment of acute disease as an indication" because it is too subjective, but said he included the indication to encourage industry to develop new therapies for ulcerative colitis. The objective is "specifically to not limit development of therapeutics for those [responses] that will improve remission," Hanauer said. Though the guidelines permit the broader indication of acute disease, Hanauer stressed that the primary goal is induction of remission. While "allowing the development [of therapies] for other parts of active disease," Hanauer remarked, "I don't want to allow a drug that has improvement in symptoms [to] be equated with a drug that induces remission." Hanauer added that he wanted to "make it clear that there are two major endpoints that the FDA and the clinical physician are interested in, and those endpoints are induction of remission and maintenance of remission." FDA Division of Gastrointestinal and Coagulation Drug Products Director Stephen Fredd, MD, agreed with Hanauer's approach, stating: "We don't want to lose any drugs that are beneficial for ulcerative colitis patients; the armamentarium is very poor." Fredd suggested that there could be a "gradation of benefit" accorded drugs that are found to fall short of inducing complete remission of the disease. However, Fredd commented that data supporting an indication for acute disease would need to show not only an improvement in symptoms but "some objective improvement in the underlying disease" such as an improvement as measured by sigmoidoscopy. "Without any objective signs that you are dealing with the underlying disease . . . can we really say this is a drug that is indicated in ulcerative colitis, rather than for [a symptom] of nonspecific reason?" Fredd asked. Hanauer said that a drug in clinical development should target a specific subgroup of patients with ulcerative colitis. "Unless you are looking for an endpoint of remission, meaning mucosal healing and absence of symptoms relate to colitis, you are going to have to be specific for the subgroups, the indications, and the endpoint." The major endpoint of induction of remission is defined as "the resolution of clinical symptoms attributed to ulcerative colitis and endoscopically documented mucosal healing." Such healing is defined by "the regeneration of an intact mucosa without ulceration, granularity, or friability [bleeding of the mucosa upon rubbing]." Maintenance of remission can be shown by the "absence of clinical, endoscopic, or histologic features of acute ulcerative colitis." Regarding clinical parameters to be measured in Phase I studies, Hanauer said that "blood in stool and diarrhea are the two most important symptoms." He suggested that rectal urgency, incontinence in certain populations and abdominal cramping also could be used. Other clinical parameters include patient assessment by sigmoidoscopy, biopsy, and global evaluation. During the meeting, the committee discussed the possibility of also requiring video endoscopy, however FDA's Fredd said that the agency "certainly encourage[s] video endoscopy, but it is not a regulatory requirement." According to the draft, Phase II studies must include a placebo control or a positive control "in a well-defined cohort of patients with ulcerative colitis." Hanauer cited mesalamine enemas (Reid-Rowell's Rowasa) and sulfasalazine (Pharmacia's Azulfidine) as examples of positive controls that could be used in the trials. Different doses of the drug under study may also be used for comparison, Fredd noted. Clinical parameters to be observed in Phase II are similar to those for Phase I with the addition of the patient's global self-assessment. Studies should include more than 20 patients per center. "Treatment-naive patients, as well as patients on a stable dose of anti-inflammatory drugs, may be entered," the guidelines state, "but patients must be stratified for treatment status and analyzed separately." The length of Phase II studies "should be determined according to the anticipated time to response for the indication," the guidelines state. They note that "studies evaluating remission will generally require four to 12 weeks of treatment, whereas maintenance studies should continue for six to 24 months." The primary efficacy variable in Phase III studies would be induction of remission as determined by physicians' global evaluation. Secondary symptomatic response variables would be analyzed and used as supportive to the primary data. The safety database for all the studies should total 750-1,000 patients, the guidelines advise.



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