Review
Primary Endpoints for Irritable Bowel Syndrome Trials: A Review of Performance of Endpoints

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The choice of primary endpoint for a clinical trial is one of the most important determinants of the ability of a clinical trial to demonstrate efficacy of therapeutic agents. Although there are still no clear, universally accepted guidelines on the definition of clinical benefit for irritable bowel syndrome (IBS), consensus guidelines stress the importance of using validated endpoints. This article reviews the evidence available in the literature on the psychometric validation and performance of the 3 endpoints recommended by the Rome III Committee for use as primary endpoints in treatment trials of IBS. The Rome III Committee recommends 2 types of measures: binary endpoints addressing the construct of relief (that is, adequate relief and satisfactory relief) and an integrative symptom questionnaire that addresses the change in severity of a representative group of symptoms of IBS (that is, the IBS Severity Scale). The current evidence suggests that at present, adequate relief should be recognized by regulatory authorities as an acceptable primary endpoint in clinical trials. This analysis also suggests that data from individual clinical trials should be pooled and undergo meta-analysis, and that prospective studies should be considered to further characterize the performance of available endpoints as outcome measures in pharmacotherapeutic trials in IBS.

Section snippets

Psychometric Validation Standards

Although psychometric validation is considered “an on-going process of conducting various studies to confirm various hypotheses regarding the internal structure of the construct and its relationships with other variables,”5 validation of a symptom-based measure generally requires evidence for a basic set of properties. In particular, it must be demonstrated that the instrument addresses all symptoms that are indicative of the disorder and importance to patients (content validity); is adequately

Recommendations of Rome III Committee on Selection of Endpoints

After appraising the wide range of endpoints proposed or used in the published literature, the general recommendations included in the Rome III guideline3 were summarized as follows: “Adequate relief and satisfactory relief are the current standards for primary outcome assessment in treatment trials in FGIDs. Alternative outcome measures such as integrative symptom questionnaires are also acceptable. All of these measures require additional validation.”

The Rome III Committee further commented

Objective of the Review

This review appraises the relative merits and level of validation of the 3 endpoints recommended by the Rome III Committee as primary endpoints in treatment trials of IBS, adequate and satisfactory relief and the IBS-SS.

Description

The adequate relief endpoint incorporates 2 unique features; it lets the patient integrate all relevant symptoms and normalizes the assessment to the patient’s own reference system of improvement (ie, adequate is relative to the patient’s own reference system). Both of these features are considered crucial in the case of evaluating treatment responses in IBS, because patients with IBS have multiple symptoms, and the relative contribution of each symptom, including the most bothersome symptom to

Irritable Bowel Syndrome Severity Scale

The Rome III guidance document considers the IBS-SS25 to be the only IBS symptom severity scale available to assess responsiveness for clinical trials. Its validation and responsiveness to treatment were based on studies of usual medical care or hypnotherapy rather than drug therapeutic studies. Given this endorsement by Rome III, it is important to understand the content, validation, and characteristics of the IBS-SS total score as a trial endpoint.

Comparison of Performance of Satisfactory Relief and an Integrated Symptom Questionnaire

Whitehead et al2 have reported that the endpoint of satisfactory relief, when used by IBS patients receiving usual medical care without a placebo control group, is confounded by baseline symptom severity and does not accurately reflect symptom improvement. They compared a binary satisfactory relief measure to the IBS-SS, which assessed symptom severity as mild, moderate, or severe, in 350 patients (81% female; average age, 50 years). This study was performed in a health maintenance organization

Conclusion

There is a need for greater validation of all IBS endpoints. Trials are required to characterize the responsiveness of the IBS-SS to drug therapy. This analysis suggests that although further validations of binary endpoints are desirable, the adequate relief endpoint is currently supported by psychometric data based on published studies and is easily understood by IBS patients.35 Those trials have demonstrated the responsiveness of the measure to a variety of orally administered medications in

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    Drs Camilleri (RO1 DK54681, K24 DK02638), Drossman (R24 DK067674), Mayer (P50 DK64539, R24 AT002681, R01 DK58173, R01 DK48351), and Talley (UO1 DK 65713) receive grants for studies in the field of functional gastrointestinal disorders from the National Institutes of Health. The authors received support from RTI, a not-for-profit research institute, for travel to a face-to-face meeting. Dr Camilleri receives current research support for single center pharmacodynamic studies from GlaxoSmithKline, Johnson and Johnson, and Bristol-Myers Squibb and serves as a consultant for Astellas, Dynogen, GlaxoSmithKline, Novartis, Theravance, and Zeria. Dr Drossman receives research support from Novartis Pharmaceuticals, Microbia, and Procter & Gamble pharmaceuticals and is a consultant for Novartis, Procter & Gamble, Microbia, Astellas, and Tioga. Dr Fehnel is a consultant for Microbia, Novartis, and Tioga. Dr Mangel is a consultant for Tioga, Vela, Bristol-Myers Squibb, Astellas, GlaxoSmithKline, Trine, Napo, Microbia, Novartis, Boehringer Ingelheim, Pharmos, and Theravance. Dr Mayer receives research support for single center pharmacodynamic studies from Avera, GlaxoSmithKline, Johnson & Johnson, Lilly, and Novartis and serves as a consultant for GlaxoSmithKline, Novartis, Avera, Allergan, AstraZeneca, and Sanofi. Dr Talley is a consultant for AstraZeneca, Axcan, Chugai, EBMed, Giaconda, GlaxoSmithKline, Kosan, KV Pharmaceuticals, Medscape, ProEd Communication, Renovis, Inc, Solvay, Strategic Consultants International, Takeda Pharmaceuticals, Inc, TAP Pharmaceutical Products, Inc, Therapeutic Gastrointestinal Group, Theravance, Yamanouchi and receives research support from Merck KGaA, Novartis, TAP Pharmaceuticals, Axcan, Boehringer-Ingelheim, and Forest.

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