Finally, experience of trying to develop novel therapeutic brokers for these patients (see previous sections) leads to the conclusion that targeting one or even a few of the late-stage mediators is likely to deliver, at best, a therapeutic with limited efficacy, in a defined subpopulation of these patients. Table 1. Summary of numerous potential etiologies and pathophysiological mechanisms underlying the spectrum of symptoms in functional bowel disorders. to first demonstrate efficacy in a non-FGID group of patients (where there is a well-defined clinical endpoint that is directly relevant to the mechanism under study), before exploring the efficacy of that compound in a subgroup of FGID patients (e.g. for new drugs affecting GI motility [Sanger and Alpers, 2008]). These troubles have been discussed in detail in previous reviews [Camilleri and Chang, 2008; Mayer 2008], but a brief description of some of the troubles is usually given in the following. Patient-reported outcomes Patient-reported outcomes are used in clinical trials due to a lack of a reliable biomarker in FGIDs, such as IBS and FD. Previously used primary endpoints such as binary or global improvement endpoints have recently fallen out of favor due to the belief by regulatory agencies that they lack content validity and have not been tested adequately in the target population. There are ongoing collaborative efforts to develop and validate outcome measures to be used in human clinical studies as mandated by the US Food and Drug Administration (FDA) in their Patient Reported Outcome (PRO) Guidance Document released in 2006 [Talley, 2009; US Department of Health and Human Services FDA Center for Drug Evaluation and Research; US Department of Health and Human Services FDA Center for Biologics Evaluation and Research; US Department of Health and Human Services FDA Center for Devices and Radiological Health, 2006]. Patient-derived outcome steps which capture the patients experience are currently being explored, but the hope in the future is usually to determine objective steps which can reliably diagnose and measure treatment response in FGID patients. For a detailed discussion, see Camilleri and Chang [2008]. Physiologic subgroups in patients There is increasing evidence that FGIDs are complex conditions with multiple factors contributing to their pathophysiology. In patients with IBS, for example, genetic predisposition, contamination, and early adverse life events may each predispose individuals to developing the disorder [Spiller and Garsed, 2009; Chitkara 2008; Saito and Talley, 2008]. In addition, chronic stress, psychological symptoms, and maladaptive coping mechanisms can increase symptom exacerbations, illness severity and adverse outcomes in affected individuals [Levy 2006]. Such a diversity of possible contributing factors suggests diversity in the pathways that generate symptoms and, hence, a low probability that treatments which target only one pathway will find widespread clinical benefit. A number of studies conducted in different laboratories, again in patients with IBS, have demonstrated enhanced visceral belief but this is not a finding that is usually replicated by all [Camilleri and Chang, 2008]. There are also troubles in interpreting visceral sensitivity studies, which deploy different techniques and do not distinguish between affective, cognitive and CB-839 true peripheral and/or central mechanisms of increased visceral belief. For example, studies have found that only 40C60% of IBS patients have lowered pain thresholds [Posserud 2007; Whitehead and Palsson1998] and only 16C37% have increased sensory ratings [Camilleri 2008a; Posserud 2007] to balloon distension. In addition, whilst recent studies have shown DES that pain and bloating are highly correlated CB-839 with steps of sensory ratings [Posserud 2007], there is only a modest correlation with perceptual thresholds and symptom ratings [Mayer CB-839 2008]. Moreover, symptom severity in a single patient does not reliably predict whether they will be hypersensitive or not. Thus, assessment of potential visceral analgesics in patients defined on symptomatology or bowel habit predominance alone, in which a significant proportion will not be hypersensitive, may be unlikely to show beneficial effects on visceral sensitivity. This is supported by the observations that hypnotherapy improves abdominal pain in association with CB-839 an improvement in rectal sensitivity in patients who are rectally hypersensitive prior to treatment, but not those who are not [Lea 2003]. Thus, there is potential for such assessments to be able to identify patients with hypersensitivity who may then respond more favorably to visceral analgesics, but further research is required. Colonic transit is usually normal in most patients, with one comprehensive study showing abnormal transit times in only 16% of IBS patients with constipation (IBS-C), 17% of IBS patients with mixed bowel habit (IBS-M), and 46% of IBS patients with diarrhea (IBS-D) [Camilleri 2008a]. Comparable observations have been made for orocecal transit in IBS [Agrawal 2009; Sadik 2008]. However, despite the low number of patients appearing to have abnormal transit, drugs which normalize GI transit in phase IIb and III IBS clinical trials have.