• Journal Article

An evaluation of the FDA Responder Endpoint for IBS-C clinical trials: Analysis of data from linaclotide Phase 3 clinical trials

Citation

Macdougall, J. E., Johnston, J. M., Lavins, B. J., Nelson, L., Williams, V., Carson, R. T., ... Lembo, A. J. (2013). An evaluation of the FDA Responder Endpoint for IBS-C clinical trials: Analysis of data from linaclotide Phase 3 clinical trials. Neurogastroenterology and Motility, 25(6), 481-486. DOI: 10.1111/nmo.12089

Abstract

Background Our objective was to evaluate the performance of the Food and Drug Administration (FDA) Responder Endpoint for clinical trials in IBS-C, using data from two large Phase 3 clinical trials of linaclotide. The FDA interim endpoint requires that, for 50% of trial weeks, patients report 30% decrease in Abdominal Pain at its worst and (in the same week) an increase in Complete Spontaneous Bowel Movements (CSBMs) of 1 from baseline. Methods Anchor-based methodology was used to estimate thresholds of clinically meaningful change using symptom-specific patient rating of change questions (PRCQs) and symptom severity questions. The diagnostic accuracy of the FDA Responder Endpoint was assessed using sensitivity/specificity-based methods. Key Results Using anchor-based methods, the estimates of the clinically meaningful improvement thresholds for Abdominal Pain ranged from 25.9% to 32.4% and thresholds for increase in weekly CSBM rate ranged from 1.4 to 1.6 CSBMs per week. Compared with the symptom-specific PRCQs for patient rating of relief, the FDA Responder Endpoint has a sensitivity of 60.7%, a specificity of 93.5%, and an accuracy of 82.0%. Changing the number of weeks required to be a responder or the percentage improvement in the Abdominal Pain criteria did not result in notable improvement in the accuracy of the FDA Responder Endpoint. Conclusions & Inferences The FDA Responder Endpoint for IBS-C clinical trials represents clinically meaningful improvements in IBS-C symptoms for patients with excellent specificity and reasonable sensitivity