MOTILITY-MODIFYING DRUG REVISED GUIDELINES REQUIRE SYMPTOM RELIEF " GREATER THAN 50%

MOTILITY-MODIFYING DRUG REVISED GUIDELINES REQUIRE SYMPTOM RELIEF " GREATER THAN 50% or complete relief of previously defined specific symptoms . . . [as] evidence of effectiveness." The drug development guidelines, revised for the first time since 1977, were discussed at the FDA Gastrointestinal Drugs Advisory Committee's Oct. 22 meeting. FDA Gastrointestinal & Coagulation Drug Products Division Director Stephen Fredd, MD, questioned the "greater than 50%" requirement, pointing out that if a drug shows "a one or two percent statistical benefit that is clinically meaningful, but not [by] much, then I think you have to say, 'Well here's the benefit, now what's the down side of that,' and come to a benefit/risk"calculation. He added: "If there's an absolute that if you get greater than 50% relief from baseline no matter what . . . that would be a wrong signal to send." Some committee members were concerned that the guidelines state that "it is not necessary" for Phase III studies "to demonstrate modification of gastrointestinal motility in patients with specific clinical entities." The guidelines specify instead that "appropriate methods of clinical evaluation, including physical examinations and laboratory tests, should be utilized to detect evidence of toxicity." Appropriate "clinical studies should be designed and performed to demonstrate significant evidence of effectiveness in reducing or eliminating subjective symptoms." Explaining the rationale for the statement, Fredd said: "If the modification of the motility parameter is your pharmacodynamic endpoint and you have . . . found correlation between pharmacokinetic levels and the pharmacodynamic endpoint, and you have in Phase II shown the relationship in a well-controlled study . . . you don't have to re-demonstrate [in Phase III] that which has already been demonstrated." David Earnest, MD, University of Arizona, expressed a concern indicated also by other committee members about how to make the guidelines flexible yet also specific enough to provide for high quality studies. For example, Earnest cited the "Purpose" subsection of the "Phase II Studies" portion of the guidelines. It lists a "group of conditions which you set out as being examples of motility disorders and I think many people would agree with most of those, some people would not agree with any of those and some people would want to put additional ones in there -- so I'm not sure how useful that is." Earnest suggested an alternative approach of providing a "general boilerplate statement" that would require the study sponsors "to propose some studies that will investigate both physiological abnormalities [and] clinical abnormalities." The committee did not reach a consensus on whether or how to revise the list of clinical conditions. Conditions cited include esophageal motility disorders associated with dysphagia; reflux esophagitis; "functional" upper gastrointestinal syndromes "(e.g. non-ulcer dyspepsia)"; irritable bowel syndrome; and acute nonspecific diarrhea.