Adopting new enrollment criteria for pharmaceutical trials in constipation: look before leaping

Abstract

In this issue Dr Camilleri provides an important critique of the use of the Rome III criteria for functional constipation as inclusion criteria for clinical trials of new drugs or other therapies for chronic constipation. He points out that the Rome criteria for functional constipation require the presence of any two of six symptoms, some of which are suggestive of slow transit (e.g. less than three stools per week, hard or lumpy stools) and some of which are suggestive of evacuatory dysfunction (e.g. straining, sensation of anorectal blockage, and manual maneuvers to facilitate defecation). He reminds us that recent studies suggest that patients with evacuation disorders show a poor response to laxatives and suggests that, consequently, the use of inclusion/exclusion criteria that do not distinguish among subtypes of constipation may lead to an underestimation of the efficacy of new therapeutic agents with a mechanism of action similar to laxatives and to an overestimation of the sample sizes required to adequately power clinical trials. He ends by proposing alternative symptom criteria for clinical trials based on the presence of key symptoms of infrequent stools and hard or lumpy stool consistency, combined with the absence of excessive straining and manual maneuvers to facilitate defecation. This is a valid concern: inclusion criteria based only on the Rome III criteria for functional constipation will inevitably result in the inclusion of a heterogeneous group of patients with constipation. However, one should be cautious about embracing new symptom criteria before evaluating their sensitivity and specificity for discriminating patients with disordered defecatio from patients with other types of chronic constipation. The comments below begin with an explanation of the rationale behind the Rome III symptom criteria for functional constipation, including comments on why the Rome criteria for functional constipation are different for children and adolescents compared with adults. Then we summarize published evidence suggesting that the new symptom criteria proposed by Dr Camilleri have only modest sensitivity and specificity and may require further testing to make sure they will achieve the objective of reducing the heterogeneity of study populations in clinical trials.