Problems and challenges in the design of irritable bowel syndrome clinical trials: experience from published trials.

The last two decades have seen many studies that are of inadequate design and power. This report focuses on what we have learned from the 25 randomized, controlled studies that included at least 30 patients during the period 1976-1998. The most important finding has been that the median placebo response was 47% (range, 0-84%), which is approximately three times the size of the difference between placebo and drug response, median 16% (range, -17-64%). This tells us the importance of reassurance and the powerful nonspecific therapeutic effects of entering patients into clinical trials in irritable bowel syndrome (IBS). Patients should be stratified according to the dominant symptoms that are relevant to the drug's intended effect. A randomized, double-blind, controlled, parallel group study appears the most robust design. Minimizing the placebo response reduces the numbers needed to detect a significant difference. The optimum length of trial is probably >3 months, because the placebo effect takes approximately 12 weeks to start to recede. Dose titration should maximize the chance of detecting a benefit.