Volume 135, Issue 6, Pages 1877-1891 (December 2008)

23 of 75

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Challenges to the Therapeutic Pipeline for Irritable Bowel Syndrome: End Points and Regulatory Hurdles

Received 18 June 2008; accepted 4 September 2008. published online 13 October 2008.

Recent advances in our understanding of basic neuroenteric mechanisms and the role of effectors and transmitters in the brain-gut axis have provided opportunities to develop new therapeutic agents for irritable bowel syndrome (IBS). Furthermore, human pharmacodynamic studies utilizing transit, colonic, or rectal sensitivity and brain imaging have been useful in determining therapeutic efficacy (particularly for drugs that act on motor function). This review provides an overview of medications that have not yet been approved for treatment of patients with IBS yet have shown promise in phase IIB trials. These include drugs that act on the serotonin receptor and transporter system: antidepressants, norepinephrine reuptake inhibitors, opioids, cholecystokinin antagonists, neurokinin-antagonists, chloride channel activators, guanylate cyclase C agonists, atypical benzodiazepines, probiotics, and antibiotics. The changing landscape in the regulatory approval process has impacted the development of IBS drugs. Guidance documents from regulatory agencies in Europe and the United States have focused on patients' reported outcomes and associated quality of life. After a decade of experience with different end points that have generated some data on psychometric validation and unprecedented information about responsiveness of the binary or global end points to drug therapy, it is necessary to pursue further validation studies before or during pivotal phase IIB or III trials. The hope of providing relief to patients should galvanize all parties to achieve these goals.

Abbreviations used in this paper: 5-HT, serotonin, IBS, irritable bowel syndrome, IBS-C, irritable bowel syndrome with predominant constipation, IBS-D, irritable bowel syndrome with predominant diarrhea

Article Outline

• Abstract

• What Therapeutic Agents Are in the Pipeline for IBS?

• Appraisal of Drugs That Affect GI Motility, Sensation, Secretion, or Central Actions

• Approaches to Proof of Concept for Novel IBS Drugs

• The Drug Development Path

• Current Considerations in Study Design

• Biomarkers Used in IBS Treatment Studies and Their Validity

• GI and colonic transit

• Visceral hypersensitivity

• Brain imaging

• IBS Trial End Points and Regulatory Insights

• What End Points Were Used in Clinical Trials in the Past Decade?

• Regulatory Guidance on End Points in IBS Clinical Trials: Should the Focus Be on Pain?

• Do Committee for Proprietary Medicinal Products and PRO Guidance Provide a Path to IBS Drug Approval or Impact Current Clinical Practice?

• Conclusion

• Acknowledgment

• References

• Copyright

Irritable bowel syndrome (IBS) involves a broad range of physiologic and psychologic alterations that affect brain-gut dysregulation, gut function, visceral perception, and mucosal integrity and function. In the absence of a reliable biologic marker of IBS, it has been challenging to develop well-targeted, effective IBS drugs and optimal end points for clinical trials. Despite advances in our understanding of basic neuroenteric mechanisms and the role of effectors and transmitters in the brain-gut axis, the pipeline of drugs for IBS and lower functional gastrointestinal (GI) disorders (Table 1), and relevant pharmacodynamics end points to predict proof of efficacy, the changing landscape in the regulatory approval process, particularly the expectations of IBS trial end points, have impacted the development of IBS drugs. This review addresses 3 main topics: the pipeline for IBS and lower functional GI disorders, approaches to the development of medications for IBS, and IBS trial end points and insights into regulatory affairs.

Table 1.

Drugs in Development for IBS in Open or Planned and Classified by Phase I to III Clinical Trials


Drug/agent in development	Mechanism	IBS patients	Phase
SSR241586	NK2/NK3 antagonist	IBS	I
SAR102779	NK2/NK3 antagonist	IBS	I
Octreotide	Somatostatin analog	Women only	I
Guanilib (SP304)	Guanylate cyclase-C agonist	IBS-C	I
RR210	5-HT3 partial agonist	IBS	I
BMS 562086	CRF-1 antagonist	IBS	I
GW876008	CRF-1 antagonist	Women only	I/II
LX1031	Tryptophan hydroxylase inhibitor	IBS	I/II*
Dextofisopam	2,3-Benzodiazepine agonist	IBS	II
Citalopram	Selective serotonin reuptake inhibitor	IBS	II
AST 120 (kremezin)	Adsorbs bile acids and bacterial toxins	Non-IBS-C	II
Traditional Chinese medicine	Herbal medicine	IBS	II
AGN 203818	Alpha 2B agonist	Pain predominant IBS	II
VSL#3	Probiotic combination	IBS-D	II
Flora-Q	Probiotic	IBS-D	II
Lactobacillus farciminis	Probiotic	IBS-D	II
Tianeptine	Enhances serotonin reuptake	IBS	II
DDP733	Partial 5-HT3 agonist	IBS	II
DDP225	Serotonin and noradrenaline reuptake inhibitor	IBS-D	II
Mesalamine	5-Aminosalicylate	PI-IBS	II
Ibaconda (olsalazine/colchicine)	5-aminosalicylate/intestinal secretion	IBS-C	II
Gastrafate IB (sucralfate)	Sucrose sulfate-aluminum salt: cytoprotection	All subtypes	II/III
Arverapamil	Enantiomer of verapamil; calcium channel blocker; 5-HT2b and melatonin (MT1) binding	IBS-D	III
Linaclotide	Guanylate cyclase-C agonist	IBS-C	III
Rifaximin	Antibiotic	IBS-D	III
Saccharomyces boulardii	Probiotic	IBS-D	III

CRF, corticotropin releasing factor; NK, neurokinin.

What Therapeutic Agents Are in the Pipeline for IBS?

There are a number of novel agents with different mechanisms of action that are in various stages of development. Several of the drugs in development that are in ongoing or planned clinical trials for IBS are presented in Table 1. The rationale, putative action, pharmacodynamics, and results in clinical trials1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 are summarized in Table 2.

Table 2.

Summary of Rationale, Mechanisms, and Efficacy of Medications in Pipeline for IBS


Drug class	Examples	Rationale or putative action	Pharmacodynamic (intestine or colon)	Clinical efficacy: phase IIB or III primary end points	Safety issues/comments	Reference No.
5-HT3-agonist	DDP-733	Stimulate intrinsic cholinergic neurons to enhance motility	4-mg dose delayed fasting migrating motor complexes, accelerated small intestinal transit, and induced softer stools or diarrhea in 15% of subjects	IIB, dose-ranging study in 91 IBS-C patients: 1.4-mg dose associated with significantly greater proportion of responders (subject global assessment of relief)	No known vascular effects	1, 2
5-HT4-agonists	Prucalopride	Stimulate intrinsic cholinergic neurons to enhance motility	Increases SB, colon motility and transit in healthy controls and patients with chronic constipation	IIB and III in CC (thousands of patients): BM frequency and satisfaction with bowel function both improved	Greater selectivity for 5-HT4 than 5-HT1B or hERG channel	3, 4, 5, 6, 7, 8, 9, 10
	ATI-7505	Stimulate intrinsic cholinergic neurons to enhance motility	Increases colon transit in healthy controls	None reported	Greater selectivity for 5-HT4; not metabolized by CTP 3A4	11
	TD-5108	Stimulate intrinsic cholinergic neurons to enhance motility	Dose-related increase in SB and colon transit in healthy controls	IIB, dose-ranging study in 401 CC patients increased BM frequency and proportion with adequate relief	Greater selectivity for 5-HT4	12, 13, 14
NARI and 5-HT3-antagonist	DDP-225	May increase synaptic levels of norepinephrine to reduce visceral pain; inhibit intrinsic cholinergic neurons	Uninterpretable	IIB, dose-ranging study in 87 IBS patients increased proportion with adequate relief	No constipation reports suggest low expectation for 5-HT3 antagonist activity	15
Antidepressants		May reduce visceral sensation and relieve depression associated with IBS	SSRIs, fluoxetine and paroxetine, and TCA, amitryptiline, do not reduce visceral sensitivity, in contrast to the SNRI, venlafaxine; SSRI accelerates and TCA slows SB transit	Small studies with SSRI or TCA equivocal; large study had no significant benefit of desipramine over placebo in ITT analysis, but did in per-protocol analysis (completed treatment)	Side effects common with TCA. Post hoc analysis for desipramine showed benefit in those with moderate symptoms, abuse, no depression, and IBS-D	16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28
κ-opioid agonist	Asimadoline	κ-opioid receptors in visceral perception	Reduce sensation in response to colon distentions in the nonnoxious range; relax colon tone in healthy controls; increase sensory thresholds in patients with IBS	On-demand dosing not effective in reducing severity of abdominal pain in 100 IBS patients; IIB, dose-ranging study, 596 IBS patients: at least average moderate pain benefit in IBS-D and IBS-A		33, 34, 35, 36
2,3-Benzodiazepine modulator	Dextofisopam	Potential to reduce stimulation-induced colonic motility and visceral sensitivity	None reported	IIB study in 140 IBS patients: increased number of months of adequate overall relief of IBS symptoms; efficacy lower over time	Possibly more events of worsening abdominal pain; headaches were more frequent with placebo	37, 38
CCK1 antagonist	Dexloxiglumide	Competitive antagonist of the CCK1-receptor	Slower ascending colon emptying with no significant effect on overall colonic transit	Two initial IIB or III trials: not efficacious in IBS-C; a randomized withdrawal design trial showed longer time to loss of therapeutic response, longer for dexloxiglumide		45, 46, 47, 48, 49, 50
NK antagonists	NK1 antagonist, ezlozipant	NK1-receptors' role in nociception	Reduce the emotional response of IBS patients to rectosigmoid distention	None		51, 52, 53
	NK2-antagonist, nepadutant	NK2-receptors' influence on smooth muscle contractility	Reduce contraction frequency and amplitude on MMC in SB in healthy males	None		51, 52, 54, 57
	NK3-antagonist, talnetant	NK3-receptors' role in nociception	No effect on rectal compliance, sensory thresholds, or intensity ratings in healthy controls	Two IIB trials in 1350 IBS patients: no benefit		58, 59
Cl-C2 channel activator	Lubiprostone	Increases intestinal water and electrolyte secretion	Accelerates SB and colonic transit in healthy controls	Two phase III in several hundred CC and IBS-C patients: efficacious	Nausea that is usually mild; FDA approved	62, 63, 64, 65, 66, 67
Guanylate cyclase-C agonist	Linaclotide	Increases intestinal water and electrolyte secretion	Accelerated ascending colonic transit and altered bowel function in 36 women with IBS-C	IIA and IIB studies in CC or IBS: increased BM frequency		73, 74, 75
Probiotics	Several, eg, Bifidobacteria, Lactobacillus, Saccharomyces species, or combinations	Potential mechanisms: immune, barrier, fermentation	Slow colonic transit in IBS-D	Several IIB studies: efficacy in overall IBS and single symptoms, eg, flatulence, pain		76, 77, 78, 79, 80, 81, 82, 83, 84
Antibiotics	Neomycin, metronidazole, rifaximin	Changes in gut microflora may be present in IBS	No consistent reduction in breath hydrogen excretion after lactulose load in those with symptom relief	IIB trials of various sizes: efficacy for global symptoms in some, gas and bloating in others		85, 86, 87, 88, 89, 90

BM, bowel movements; CC, chronic constipation; Cl-C2, chloride channel type 2; IBS, irritable bowel syndrome; ITT, intention to treat; MMC, migrating motor complexes; NARI, norepinephrine reuptake inhibitor; NK, neurokinin; SB, small bowel; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.

Appraisal of Drugs That Affect GI Motility, Sensation, Secretion, or Central Actions

Although there is a greater understanding of the basic neuroenteric mechanisms and the role of effectors and transmitters within the brain-gut axis, which provide opportunities for development of new therapeutic agents in IBS, there are still significant conceptual and practical barriers. IBS is a complex multifactorial disorder with distinct but often interrelated pathophysiologies. These pathophysiologic processes and associated symptom phenotypes can change within an individual over time. Furthermore, several putative mechanisms may control the pathophysiologic processes that might underlie the generation of symptoms. Although a significant number of IBS patients report meal-related symptoms, the interaction of food and intraluminal content with secretory, motor, and sensory mechanisms in IBS is poorly understood. The approach to development of medications for IBS has been based on specificity of targets, analogous to that of, for example, hypertension. The difference is that, whereas hypertension is dominated by the biology of vascular tone, IBS does not have a dominant mechanistic pathway to symptom generation. Moreover, there are single targets that appear to regulate multiple functions, including gut motor function and sensitivity in animal models, such as specific serotonergic (5-HT) receptor subtypes. However, despite the apparent relevance of such targets, efficacy and safety are not always clearly demonstrable in the IBS patient population. As a result of the approach based on targeting specific receptors in a disease that does not have a malfunction of a single receptor or transmitter deficiency, approaches that target one receptor or pathophysiologic mechanism cannot be expected to affect the broad spectrum of patients. Thus, approaches directed at changing motor function could alleviate bowel dysfunction, or induction of intestinal secretion might alleviate constipation, but the component of bloating and pain might be left unattended. Antiinflammatory approaches that have been investigated in small trials, even in those that include many patients with postinfectious IBS, have been disappointing. Therefore, multitargeted approaches are often used in clinical management, particularly in patients with moderate to severe IBS. Centrally acting agents appear to be promising because they might correct disturbances in the brain-gut axis. However, their efficacy has generally been limited in clinical trials, and many patients prefer to avoid taking “mind-altering” medications for symptoms that disturb their quality of life but are not life-threatening. The risk-benefit ratio of any new medication for IBS is clearly a determining factor in the approval and marketing of such compounds. It is understandable, therefore, that approaches with probiotics and antibiotics have reached a level of acceptance in practice that exceeds the available evidence of efficacy in support of their use.

Some of the challenges are, in our current state of knowledge, not easily resolved. Given the high prevalence and disease burden associated with IBS, there needs to be continued and vigorous basic and translational research in the field, rigorous pharmacologic assessment of candidate drugs, or other therapies using validated biomarkers and relevant clinical end points. It is also important to recognize that multiple, complex, and dynamic pathophysiologic processes that underlie IBS might be best addressed with a multicomponent approach. This has to be coupled with awareness of safety signals in drug development programs in IBS. For almost all of the drug classes described here (Table 2), rigorous phase III trials are still awaited.

Approaches to Proof of Concept for Novel IBS Drugs

There are at least 3 different approaches to determining the efficacy of new treatments of IBS. The traditional path is based on identifying the molecular targets in animal models that are thought to mediate the human phenotype, such as visceral hyperalgesia and rapid gut transit.91 If a candidate drug has been shown to be effective in preclinical studies, and it is safe in phase I trials in humans, it is moved into trials in healthy human subjects and subsequently in patients with IBS during different phases of clinical trials.

Other approaches occur at later stages of drug development. For example, a drug in development or one that is already approved for another condition that has an associated effect on GI function or symptoms can be tested in patients with IBS. For example, if a drug has been found to be effective in treating patients with constipation, it could be further investigated as a treatment for patients with IBS with constipation. It is also possible to assess the efficacy of a drug that is used to treat a condition that commonly coexists with IBS and/or is thought to have shared pathophysiology, such as fibromyalgia, anxiety, or depression. Examples of these agents include selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

An alternative approach to drug discovery and development is pharmacologic brain imaging in animal models and humans.91 Brain responses can reflect global IBS symptoms; this approach to drug development is the subject of ongoing study.

The Drug Development Path

Before regulatory approval, candidate drugs move through a long and complex development path that includes toxicology, toxicokinetics, pharmacokinetics, and in vivo efficacy testing in animals as well as 3 phases of clinical trials. Phase I trials are dose-ranging studies designed to measure the safety, tolerability, pharmacokinetics, and pharmacodynamics of a test drug. If the drug is found to be safe and tolerable in phase I trials, phase II studies are then conducted in relatively larger numbers of subjects. Phase IIA trials are designed to assess the dosing in patients and serve as proof-of-concept studies. In phase IIB trials, the efficacy of the drug is determined at specific prescribed doses. Definitive evaluation of efficacy is determined in phase III studies, which are multicenter, randomized, controlled trials in large numbers of patients. To date, few studies have collected biologic samples (or other measurements) for ancillary evaluations of efficacy in IBS. This is a vestige of the belief that IBS is a disorder of function with no valid biologic marker. However, evidence with physiologic (eg, transit), biochemical (eg, serum or other markers of immune activation), and even pharmacogenetic modulation suggests that there is a need to reassess the optimal drug development path.

Current Considerations in Study Design

IBS has no “gold standard” of treatment, so candidate drugs are usually compared with placebo. The study protocol specifies all end points that will be measured, including each domain score that is targeted to support a specific claim.92 Drug approval by regulatory agencies is based on achieving the primary end point in phase III trials.

The Rome III guideline on design of trials for functional GI disorders recommended the use of validated instruments as primary outcome assessment tools in IBS clinical trials.93 Secondary end points in clinical trials support or explain the results of the primary outcome analysis (particularly if a global end point or composite score is used). Improvements in secondary end points can help to characterize the response to a global end point because they represent the multiple manifestations of the global or multidomain measure.94 Primary end points have been described as what is of interest to patients, whereas secondary variables are generally of interest to clinical researchers.95

In the Patient-Reported Outcome (PRO) Guidance Document, released in 2006, the US Food and Drug Administration (FDA) mandated that outcome measures for clinical studies be validated.92 The process for developing a new PRO instrument or modifying an existing instrument is shown in Figure 1. The starting point in developing a valid and meaningful outcome measure is to establish a conceptual framework (ie, a path diagram) for IBS. This framework can be developed using patient-reported information to characterize the full disease experience, factors related to severity, impact on daily activities, and treatment response. In addition, published studies in well-characterized IBS patients that have addressed disease mechanisms or treatment response can help establish a multidimensional conceptual framework. It is recommended that this framework guide the development and measurement of valid, reliable, and reproducible patient reported end points and objective biomarkers. This is followed by creation or modification of the instrument including the generation of items; choice of the data collection method; choice of the recall period; choice of response options (eg, visual analog scale, Likert scale, numeric rating scale, checklist of binary end points); assessment that patients understand the instrument; development of format, instructions, and training of those collecting the instrument data; identification of scoring of items and domains; and assessment of respondent and administrator burden.

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Figure 1. The process recommended by the PRO guidance document for developing of new or for modifying existing instruments for clinical trials (reproduced from 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 Health92).

Biomarkers Used in IBS Treatment Studies and Their Validity

A number of physiologic outcome measures to assess treatment responses have been studied in IBS. These include measures of visceral perception (eg, rectal or colonic pain thresholds and perceptual ratings) and intestinal transit (eg, orocecal and colonic transit times). A recent review of the literature determined that the correlations between biomarkers obtained in preclinical and clinical models and respective symptoms are relatively small, and the ability to predict drug effectiveness for specific as well as for global IBS symptoms is limited.91 On the other hand, colonic transit measurements correctly predict the effects of agents on bowel function and are generally associated with global, binary end points such as adequate or satisfactory relief of IBS pain and discomfort in patients with constipation- or diarrhea-predominant IBS.96, 97

GI and colonic transit

Transit is a clinically relevant and noninvasive measure of GI function, primarily related to motility and secretion. Colonic transit time has been shown to correlate with stool form, as measured by the Bristol Stool Form Scale.98 It can be measured by different techniques including radiopaque markers99, 100 and breath hydrogen tests.101

However, the most robust and consistent results for detailed GI transit measurements have been reported with scintigraphy, which allows for regional transit assessments. Colonic transit is accelerated in IBS-diarrhea (IBS-D) predominant patients, compared with healthy individuals, and those with IBS-constipation (IBS-C) predominant range from normal to slow transit times.102 Approximately 35% of patients with IBS have abnormal overall colonic transit, including 48% of those with IBS-D.

The effect of medications that affect GI transit time has been studied in patients with IBS. These include bulking agents,103, 104 cimetropium bromide,105 imipramine,101 alosetron,106, 107 tegaserod,108 renzapride,109, 110 the guanylate cylase-C agonist linaclotide,73 and the probiotic combination VSL#3.80 Correlations between effects of medications on regional or total colonic transit and stool number or stool form have been shown for a number of drugs, including 5-HT4 agonists such as prucalopride6 and tegaserod,108 the combined 5HT4 agonist-5HT3 antagonist renzapride,109 the guanylate cyclase-C agonist linaclotide,73 and the chloride channel activator lubiprostone.63

Importantly, the results from phase IB or IIA studies using scintigraphic colonic transit have correctly predicted efficacy of treatments in phase IIB or phase III studies in IBS with the following medications: alosetron, tegaserod, prucalopride, renzapride, linaclotide, and lubiprostone. For example, the efficacy of lubiprostone63 in improving colonic transit and stool form in pharmacodynamic studies in healthy volunteers accurately predicted clinical efficacy in patients with IBS-C.66 At present, the only discrepancy between results of scintigraphic transit111 and phase IIB clinical trial data pertains to the drug solabegron (preliminary data, in press); results of larger phase II trials are eagerly awaited. Nonetheless, GI transit assessment can be a useful biomarker for predicting the effects of a test on bowel habits and overall response in patients with IBS.

Visceral hypersensitivity

Twenty percent to 94% of IBS patients are more sensitive than healthy individuals to balloon distention of the colon or rectum via barostat, a computerized distention device used to measure visceral compliance, tone, and perception.91 Variability in the prevalence of visceral hypersensitivity across IBS patients (reviewed in Camilleri et al102) suggests that level of rectal sensitivity is not a biologic marker of IBS, as was previously claimed.112 A number of factors affect visceral perception: gender,113 predominance of bowel dysfunction,114, 115 psychologic factors,116, 117 and specifics of the experimental study protocol, such as inclusion of data on stress118, 119 or food ingestion.120, 121 Whereas levels of pain and bloating have high correlation values with measures of visceral hypersensitivity,122 perceptual thresholds and ratings have only moderate correlation values with IBS symptom severity or response to treatment.91 It is possible that, with more effective visceral analgesics, testing of visceral sensitivity would have utility similar to that of transit measurement in predicting efficacy of drugs affecting intestinal transit.

Barostat testing has been used in patients with IBS to measure the changes in visceral sensitivity to opiates, serotonergic agents, and antidepressants. Small crossover studies support the validity of the barostat test as a valid human experimental model for visceral pain, especially with the μ-opioid agonist fentanyl and, to a lesser extent, the κ-opioid agonist fedotozine.29, 32 However, visceral barostat testing might not predict the effect of a candidate drug on IBS symptoms.17, 91 The barostat studies that correctly identified clinical efficacy of alosetron utilized brain imaging.123

Brain imaging

Neuroimaging techniques such as positron emission tomography or functional magnetic resonance imaging show that brain activation patterns elicited in anticipation of a noxious distention and/or actual intestinal distention are different in IBS patients than controls.112, 124, 125, 126 The mechanisms proposed to explain an altered brain response in patients with IBS are unclear but may include increased signaling from the gut or amplification of a normal signal during transmission from the gut or in the brain.127 Brain activation patterns can be influenced by gender,128, 129 bowel function,130 psychologic symptoms,131 and adaptation to experimental conditions over time.132

There are limited data evaluating brain activation responses to efficacious IBS treatments. In a H215O positron emission tomography study performed in nonconstipated IBS patients, 3 weeks of treatment with the 5-HT3 antagonist alosetron improved IBS symptoms and was associated with reduced regional cerebral blood flow in limbic and paralimbic regions and central autonomic circuits (which contain 5-HT3 receptors), particularly during anticipation of distention.123 In the alosetron-treated patients, lower activity in bilateral orbitofrontal cortex and medial temporal gyrus during pretreatment scans suggested changes in regional cerebral blood flow and psychologic symptoms predicted treatment response.123, 133

In a functional magnetic resonance imaging study134 conducted in 19 women with painful IBS, amitriptyline was associated with decreased activation in the rostral anterior cingulate cortex and the left posterior parietal cortex during the combined rectal distention and psychologic stress but not during the relaxation condition. There was no reported association of brain responses with symptom ratings in this small study. Lackner et al135 measured brain responses using H215O positron emission tomography in 6 women with IBS before and after treatment with cognitive behavioral therapy and found a reduction in regional cerebral blood flow in the parahippocampal gyrus and the ventral portion of the anterior cingulate cortex. These reductions correlated with improvement in GI symptoms and psychologic functioning. Thus, IBS treatments exert beneficial effects via brain regions concerned with pain modulation and autonomic responses; neuroimaging is a promising modality for proof-of-concept studies.

An average of 50% of patients with IBS experience abnormal visceral hypersensitivity or abnormal transit, and approximately 20% have evidence of both pathophysiologies.102 Further research in central processing and its modulation with therapy is necessary to understand its utility in drug development.

IBS Trial End Points and Regulatory Insights

Almost a decade ago, the path to successful development of therapeutics for IBS seemed fairly clear: appropriate trial design, clear pharmacologic efficacy, safety, and use of binary end points that assessed the global effects of medications on a global improvement scale.54 Academics, clinical trial designers, biostatisticians, and the FDA had agreed on this path; there was a significant pipeline of medications with potential for treating patients with IBS and other bowel dysfunction.

With the withdrawal of cisapride, alosetron, and tegaserod and lack of approval of cilansetron for alleged safety concerns, the risk-benefit ratio of new drugs for IBS was reexamined, and the psychometric validation of end points used in previous clinical trials was questioned. The need for psychometric validation of patient response outcomes has been increasingly emphasized by regulatory agencies to be consistent with standards set for other disorders characterized predominantly by patient responses rather than objective biomarkers. It is assumed that application of principles and validation of end points used in chronic pain, fibromyalgia, or cancer pain will prove effective in IBS. The clinical trial experience and responsiveness observed in almost 20,000 IBS patients with at least 5 different medications (alosetron, cilansetron, tegaserod, lubiprostone, dextofisopam) tested with binary or global improvement end points have been devalued on the grounds that some aspects of psychometric validation are not available.

What End Points Were Used in Clinical Trials in the Past Decade?

Table 3 summarizes end points used in clinical trials involving at least 100 patients with IBS. There is compelling evidence in favor of the binary or global end points used in the past 10 years and involving 20,000 people studied with 5 different drugs. First, these trials showed that the end points are responsive: a metaanalysis of 6000 patients in clinical trials of 5-HT3 antagonists with several different outcomes/end points showed that global end points can document responsiveness to this class of medication.97 Second, participants in trials were able to relate the level of relief to the level of their symptoms, determined at baseline, and provided consistent responses. In the trial of alosetron, 80% of patients reported consistent responses in subsequent weeks. Third, the performance measures (validity and reliability) were independently assessed and found to be acceptable; binary or global response end points159 and global improvement scale160 and responses were typically driven by the patients' most bothersome symptoms.159

Table 3.

Spectrum of End Points Used in Trials Involving Drug Treatment in IBS


End point	Description of end point	Response	Medication	Reference No.
Adequate relief	“In the past 7 days, have you had adequate relief of your IBS pain and discomfort?”	Binary end point (Yes/no)	Alosetron	136, 137, 138, 139, 140, 141
	“In the past 7 days, have you had adequate relief of your IBS symptoms?”		Cilansetron	142, 143, 144
	“Would you rate your overall relief of irritable bowel symptoms during the past week as adequate?”		Dextofisopam, Imipamine and Citalopram	38 28
Satisfactory relief	“Over the past week, do you consider that you have had satisfactory relief from your symptoms of IBS?”	Binary end point (Yes/no)	Tegaserod	145, 146, 147, 148
	“Did you have satisfactory relief of your overall IBS symptoms during the last week?”
	“Did you have satisfactory relief of your abdominal discomfort or pain during the last week?”
Subject Global Assessment of Relief (SGA)	“Please consider how you felt during the past treatment period in regard to your IBS, in particular your overall well-being, and symptoms of abdominal pain/discomfort and altered bowel habit”	5-Point Likert scale (worse, not at all relieved, somewhat relieved, considerably relieved, completely relieved).	Tegaserod	149, 150, 151, 152
	As above, + “Compared to the way you usually felt before entering the study, how would you rate your relief of symptoms during the past week?”	5-point Likert scale (completely relieved, considerably relieved, somewhat relieved, unchanged, worse)
Modified version of the SGA (secondary end point)	Responder defined by 4/4 weeks of at least a little bit effective, or ≥2/4 weeks of at least quite a bit effective	5-Point Likert scale (0, not at all effective; 1, a little bit effective; 2, somewhat effective; 3, quite a bit effective; 4, extremely effective)	Lubiprostone	66
Modified version of the SGA	“How would you rate your relief of IBS symptoms (abdominal discomfort/pain, bowel habits, and other IBS symptoms) over the past week compared with how you felt before you entered the study?”	7-Point Likert scale: substantially worse, moderately worse, slightly worse, no change, slightly improved, moderately improved, or substantially improved	Lubiprostone	67
Global Improvement Scale	“Compared to the way you felt during the 3 months before you entered the study, are your IBS symptoms over the past 4 weeks … ?”	7-Point Likert scale: substantially worse, moderately worse, slightly worse, no change, slightly improved, moderately improved, or substantially improved	Alosetron (phase IV)	153, 154, 155, 160
IBS Severity Scoring System (IBS-SSS)	5-Item instrument that includes abdominal pain (severity), abdominal pain (number of days with pain), abdominal distention (severity only), satisfaction with bowel habit, and interference with life in general	Responses to 5 items measured on a 0–100 visual analog scale summed to derive total score between 0 and 500: <75 normal, 75–175 mild, 175–300 moderate, >300 severe	Nonpharmacologic treatment	156, 157, 158
Abdominal discomfort/pain score	Abdominal pain/discomfort responses: •coded on a scale of 0 (absent) to 4 (very severe) •recorded as responses to specific queries in patients' daily electronic diaries	Change from baseline in mean abdominal discomfort/pain score during the first 28 days of treatment calculated by subtracting the average of all scores during the baseline period from the average of all scores during the first month of treatment	Lubiprostone	66
Abdominal pain severity score	Abdominal pain severity on 100-mm visual analog scale in the diary	Whenever pain of at least moderate intensity felt the first time during a day and 2 hours after the intake of the medication	Asimadoline on demand	35
	Change from baseline in mean abdominal discomfort/pain score during the first 28 days of treatment; abdominal discomfort/pain recorded as responses to specific queries in daily electronic diaries	5-Point Likert scale: 0, absent; 1, mild; 2, moderate; 3, severe; 4, very severe	Lubiprostone	66

A review of the validation of the diverse end points (Table 4) on the basis of 12 prespecified criteria concluded that the weight of evidence is in favor of adequate relief,161 confirmed by an independent group.162 The 7-point Likert global improvement scale has also been validated for clinical, satisfaction, and productivity significance,160 and responsiveness of the global improvement scale in several trials with alosetron and cilansetron has been reviewed.97 Fourth, drugs that are effective, based on the binary or global response end points, were also found to improve general or disease-specific quality of life.163

Table 4.

Comparison of Psychometric and Methodologic Properties of Standardized IBS Outcome Measures: Symptoms Questionnaires


Instrument	Assessment criteria
Instrument	Reliability	Sensitive to change	Face validity	Content validity	Construct validity	Interpretable	Practical utility	Appropriate for use	Variables clearly defined	Eligibility criteria reported	Patients defined	Use in Primary care
AR	−	+	+	±	+	+	+	+	+	+	+	−
IBS-SSS	−	+	+	+	+	+	±	+	+	±	+	−
GSRS	+	±	+	+	+	±	±	+	±	−	−	−
FBDSI	−	−	±	+	+	±	+	+	+	±	+	−
IBS-Q	+	+	±	±	±	−	−	±	±	+	±	−

NOTE. Reproduced from Bijkerk et al.161

Twelve Criteria Used for Assessment of Symptom Questionnaires and Health-Related Quality of Life Instruments: (1) Does the measure have satisfactory reliability (internal consistency)? (2) Is the measure sensitive to change (responsiveness)? (3) Does the measure measure what it is supposed to measure (face validity)? (4) Does the measure sample the domain of interest comprehensively (content validity)? (5) Is the measure compared with other measures, and is the relation between measure and patient characteristics defined (construct validity)? (6) Is the outcome interpretable; are changes in score related to clinical indicators that are familiar and meaningful to clinicians? (7) Is the measure easy to administer, showing practical utility? (8) Is the measure appropriate for use? (9) Are the variables clearly and unambiguously defined? (10) Are criteria for inclusion and exclusion reported? (11) Is the population in the validation report described? (12) Has the measure been used in a primary care population?

AR, adequate relief question; FBDSI, functional bowel disorder severity index; GSRS, GI symptom rating scale; IBS-Q, IBS symptom questionnaire; IBS-SSS, IBS severity scoring system. +, 5 or more reviewers agree that the measure satisfies the assessment criterion; ±, 5 or more reviewers agree that the measure partly satisfies the criterion, or less than 5 agree that it fully meets the criterion or less than 5 agree that it does not meet the criterion; −, 5 or more reviewers agree that the measure does not satisfy the assessment criterion or that the measure provides no information on the assessment criterion.

The Rome III guidance on clinical trials93 has endorsed use of a global measure that integrates the symptom data into a single numerical index: “alternative outcome measures such as integrative symptom questionnaires” and an IBS Symptom Severity Scale (IBS-SSS164). This scale was described as the only IBS symptom severity scale “shown to be responsive to treatment effects,” even though the last claim pertained to nonpharmacologic trials (eg, hypnotherapy). The IBS-SSS measures pain, distention, an overall gestalt of interference with life, and bowel “dissatisfaction”; the latter has been shown by focus groups to be an unclear term.

Another severity scale, the Functional Bowel Disorder Severity Index,165 includes only current and chronic pain and the number of doctor visits during the past 6 months; however, data on the number of doctor visits are not relevant in a structured clinical trial, and the 6-month period of appraisal does not allow for changes or measurement of treatment response during short periods of time.166

In contrast, one observational study of usual care in a health maintenance organization setting that compared satisfactory relief with the IBS-SSS found that the performance of a satisfactory relief end point was significantly influenced by baseline symptom severity.167 The generalizability of these observations has therefore been questioned because clinical trials assess specific interventions rather than usual care, the clinical-trial population can differ from a managed-care population, and patients with mild symptoms are less likely to meet screening criteria and be included in a clinical trial. The concern167 that baseline severity compromises the performance of a dichotomous end point, such as satisfactory relief, does not appear to affect the current design of clinical trials. For example, trials with alosetron and dextofisopam38, 168 and one involving behavioral treatment169 have not confirmed the impact of baseline severity on the performance of adequate relief as a trial end point.

Regulatory Guidance on End Points in IBS Clinical Trials: Should the Focus Be on Pain?

A regulatory agency in Europe has specifically addressed the issue of end points for IBS trials170; a more general guidance document from the FDA (the PRO) describes development of end points that involve patient response outcomes.92 However, academic clinicians from Europe responded to the publication of the European guidance document with a scholarly critique171 and endorsed global assessments as end points, rather than focusing on pain.

Appropriate psychometric validation of all PROs is essential but not necessarily sufficient for utility as an end point in IBS. All end points must also be conceptually sound, reliable, and valid measures, incorporated into well-designed clinical trials with interpretable findings, and include the “right concepts.”172 It is unclear whether psychometrically validated PROs borrowed from other fields, such as pain syndromes or cancer, are pertinent to IBS or what the minimally important difference is for any end point in IBS, based on PRO guidance.

After extensive research on the visceral pain component in IBS, some researchers consider IBS to be a pain syndrome, and regulatory agencies have advised development of clinical trials that use pain level as an end point, measured with instruments that have validated psychometric properties. For example, the Brief Pain Inventory could be used to measure pain level; this instrument was originally developed to measure cancer-related chronic pain173 and was subsequently validated for nonmalignant chronic pain.174 However, no information has been published regarding the performance, validation, or minimally important difference data obtained using the Brief Pain Inventory in patients with IBS. Clinicians recognize that the pain of IBS is linked to bowel dysfunction or motor pathophysiology.39, 102, 175 Typical pain in IBS-D is described as colicky, propagates around the periphery of the abdomen over the colon, precedes the bowel movement, and is relieved after the passage of the bowel movement. Alternatively, patients with IBS-C report a sense of chronic distention, discomfort and bloating, and absence of the colicky propagated pain described above. IBS pain is linked with bowel function or dysfunction, whereas chronic pain syndromes are typically unrelated to bodily functions. IBS is not chronic functional abdominal pain, which is unrelated to bowel function, and might be conceptually closer to chronic pain syndromes such as fibromyalgia or chronic back or temporomandibular joint pain. For chronic functional abdominal pain, it is reasonable to consider a recent consensus statement on interpreting the clinical importance of treatment outcomes in chronic pain clinical trials (IMMPACT176) with specific outcome measures for 4 core chronic pain outcome domains: pain intensity, physical functioning, emotional functioning, and participant ratings of overall improvement.

Given the regulatory agencies' focus on pain, it is also worth noting the Rome definition of discomfort in IBS: “Discomfort means an uncomfortable sensation not described as pain,”177 suggesting a continuum between discomfort and pain.178 Symptoms of “pain” and “discomfort” were interpreted to be 2 distinct symptoms by 14 of 16 participants with IBS-C in a focus group159; this finding raises questions about the combined assessment of these symptoms in patients with IBS.177

A preliminary report179 of an ongoing study conducted in a longitudinal IBS registry from 8 geographically diverse US centers developed a single item numeric rating scale for overall severity during the past week: from 0 (no symptoms) to 20 (the most intense symptoms imaginable). Data from 170 patients (79% female) collected at baseline and from 64 patients 3 months later showed correlations between this single numeric rating scale and bowel symptoms; severity indices; quality of life; and worker productivity, absenteeism, and presenteeism, with R values ranging from 0.18 to 0.47. The correlation coefficient of the single numeric rating scale and IBS-SSS was 0.65. The minimally important difference was identified to be 4 ± 5 points. In a study of 755 patients with IBS, performed at a single center, predictors of severity included pain, the belief that something was seriously wrong with the body, straining with defecation, urgency with defecation, myalgias, and bloating.180 Therefore, the domain of bowel dysfunction is integral and relevant to symptoms of IBS patients. Further clinical studies are required to determine responsiveness and the level of correlation between specific symptoms and secondary end points to ensure that this single numeric rating scale179 accurately predicts the severity of IBS and the efficacy of potential therapeutics.

The development of new drugs that affect visceral sensations might improve prospects for reducing abdominal pain. On the other hand, the benefits of a drug designed to improve motility, transit, intraluminal fermentation, secretion, absorption, or inflammation (all relevant concepts in IBS) might not affect a chronic pain end point. Such a drug might still affect the important components of IBS, relieve bothersome symptoms, and could be regarded as effective by many patients with IBS. By the same token, a drug that relieves chronic pain with little clinical impact on other IBS symptoms, such as the bowel dysfunction or pain during bowel function, could be regarded as ineffective by many patients with IBS. Thus, it is important to select trial end points that can identify medications that relieve important symptoms based on their effect on pathophysiologic mechanisms in patients with IBS.

Do Committee for Proprietary Medicinal Products and PRO Guidance Provide a Path to IBS Drug Approval or Impact Current Clinical Practice?

Experts in psychometric validation and PRO have cautioned that, “Using the PRO in a clinical trial may be risky, because clinically meaningful effects may go undetected.”181 Identifying a clinically meaningful difference has value; however, demonstrating the minimal clinically important difference for a PRO measure presents challenges beyond responsiveness.181 These challenges suggest that it is essential that the right concepts of IBS are selected into a PRO rather than simply borrowing validated end points from other fields of clinical research.

Given the lack of approval of alosetron, cilansetron, and tegaserod for treatment of IBS in the European Union and the restricted access to alosetron in the United States, this is a challenging time for clinicians. Despite the best quality evidence on the pharmacodynamic actions and clinical benefit in well-constructed clinical trials for IBS, medications such as tegaserod have been withdrawn because of equivocal safety reasons. In an effort to help their patients, clinicians revert to prescription of medications approved for other indications, despite limited, anecdotal, or unproven efficacy in IBS. For example, gastroenterologists frequently prescribe off-label use of antidepressant medications, which have been shown to be of limited benefit in large clinical trials for IBS22 and in metaanalyses182 and have significant side effects.

The lack of clear, realistic, and consistent guidelines for the approval of IBS therapeutics has caused drug companies to leave this field of research. Ultimately, we all bear responsibility because treatment delayed is treatment denied.

Conclusion

The pipeline of drugs for IBS is fairly healthy; pharmacodynamic studies provide reasonable prediction on proof of efficacy; clinical trial methodology and mechanics have improved considerably in the last decade. The main challenges that should galvanize the efforts of all parties lie in regulatory affairs.

It is essential that academic-clinical leaders be invited to work with regulatory agency clinicians and psychometricians to facilitate a greater understanding of the pathophysiology, mechanisms, and symptom complex of IBS. This approach will identify the right concepts for the PROs and improve measurement of severity in IBS. There is a need for a high-level National Institutes of Health consensus conference on clinical trial end points for functional GI disorders, followed by a deliverable consensus paper.

PRO end points should be enhanced with clinically applicable biomarkers. Thus, whereas endoscopic, blood, and rectal sensitivity tests do not currently provide sufficiently sensitive biomarkers in IBS, data regarding colonic transit from 2 centers100, 102 independently suggest that transit responses are significant factors in defining the IBS phenotype, determining the severity of the pathophysiology, and predicting response to therapy with a wide range of pharmacologic agents that target different mechanisms (transit, motility, and mucosal secretion63, 73, 80, 107, 108, 109, 183). A paradigm shift has been proposed for the approval and surveillance standards for new drugs (see Table 5 184). Given the current position of the FDA,185 future attempts to develop or modify an existing PRO instrument are inevitable.

Table 5.

A Paradigm Shift in the Approval and Surveillance Standards for New Drugs

	1.Careful mechanistic studies in small numbers of patients and volunteers 2.Expanded and more integrated approach to the use of preclinical information to inform human pharmacology 3.Detailed human investigations, including phenotypic manipulations in a controlled environment, to elucidate the mechanism of drug action and refine dose selection in humans 4.More complex analysis of the factors that contribute to inter- and intraindividual differences in drug response. 5.Greatly expanded phase II to yield a range of indices—pharmacokinetic and dynamic, biochemical, and genetic—of drug efficacy and safety 6.Need of investigators capable of developing and projecting hypotheses on the basis of quantitative biomarkers of mechanism, drug efficacy, and safety from model systems into studies of drug response in humans 7.Harness unbiased technologies to select candidates from among multiple compounds directed at a single molecular target 8.Focus on individualized medicine and thereby transform and expand phase II trials, while potentially shrinking, shortening, and reducing the costs of phase III studies

NOTE. Adapted from Fitzgerald.184

At this stage, all aspects of validation, including prior performance in clinical trials and responsiveness, should be used to select IBS end points for drug development programs. Until new end points are validated, it is imperative that, for the sake of the patients, regulators approve binary or global improvement end points that have been previously shown to have responsiveness, longitudinal construct validity, and interpretability and also insist on validation of additional end points and definition of minimally important difference for future studies.

The authors thank Cindy Stanislav for excellent secretarial assistance.

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⁎ Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota

‡ Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, VAGLAHS, Los Angeles, California

Address requests for reprints to: Michael Camilleri, MD, Mayo Clinic, Charlton 8-110, 200 First Street, SW, Rochester, Minnesota 55905

The authors disclose the following: Dr Camilleri reports consulting for Albireo, Tioga, Dynogen, Axcan, Procter & Gamble, SK Bio-Pharmaceuticals, and Salix. As a consultant with GlaxoSmithKline, he attended a meeting at the FDA in January 2008 regarding end points for irritable bowel syndrome. He has received research grants from Novartis, Theravance, Takeda/Sucampo, Johnson & Johnson, Bristol-Myers Squibb, as well as support for studies in irritable bowel syndrome from National Institutes of Health (RO1-DK-54681). Dr. Chang reports consulting for Albireo, GlaxoSmithKline, Forest, Ironwood, McNeil, Prometheus, Salix, Synergy, Takeda, and Tioga and research grant support from GlaxoSmithKline, Prometheus, Rose Pharma. She also receives funding from the National Institutes of Health for studies in irritable bowel syndrome (RO1 AR46122 and P50 DK64539).

PII: S0016-5085(08)01668-5

doi:10.1053/j.gastro.2008.09.005

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