title: Challenges to the design, execution, and analysis of randomized controlled trials for inflammatory bowel disease.
abstract: Treatment of inflammatory bowel disease has greatly improved with the development of targeted, monoclonal antibody-based therapies. Tumor necrosis factor antagonists are frequently used to treat patients with Crohn's disease or ulcerative colitis, but they have side effects and their efficacy often decreases with use. New, more effective drugs are therefore needed and in development. However, many agents that appeared to be promising in preclinical studies have failed to show efficacy in clinical trials. We discuss possible reasons for the failures of these reagents in trials, which include the high rate of response to placebo, an inadequate range of doses, inappropriate timing of end point measurements, the changing therapeutic environment, and the competitive trial system. We also review regulatory guidelines for end points and trial design and recommend ways to improve trials.
authors.affiliation: Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands. g.dhaens@amc.uva.nl
authors.forename: Geert
authors.initials: G
authors.lastname: D'Haens
authors.forename: Brian
authors.initials: B
authors.lastname: Feagan
authors.forename: Jean-Frédéric
authors.initials: JF
authors.lastname: Colombel
authors.forename: William J
authors.initials: WJ
authors.lastname: Sandborn
authors.forename: Walter
authors.initials: W
authors.lastname: Reinisch
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Frank
authors.initials: F
authors.lastname: Carbonnel
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Mary
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.forename: Richard N
authors.initials: RN
authors.lastname: Fedorak
authors.forename: Steven
authors.initials: S
authors.lastname: Hanauer
authors.forename: Marc
authors.initials: M
authors.lastname: Lémann
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D023381:Endpoint Determination; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic / Q000592:standards* / Q000639:trends; D012107:Research Design / Q000592:standards* / Q000639:trends; D013223:Statistics as Topic / Q000592:standards* / Q000639:trends; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha