The Future of Clinical Trials in Inflammatory Bowel Disease

Abstract

The medical management of inflammatory bowel disease (IBD) has been transformed over the past few decades by the approval of multiple classes of advanced therapies and the integration of more targeted treatment strategies for Crohn’s disease and ulcerative colitis. These changes have been driven by an increasing number of pivotal randomized controlled trials, which have grown in size and complexity over time. Several landmark studies that are anticipated to change current IBD management paradigms have recently been completed or are on-going, including the first head-to-head biologic trials, advanced combination treatment trials, therapeutic strategy and treatment target trials, and multiple phase 3 registrational programs of novel compounds. Despite these advances, the future of IBD trials also faces major challenges with respect to cost, feasibility, and recruitment. Accordingly, innovative methods for early and late phase randomized controlled trials must be adopted. In this review, we provide a comprehensive overview of the evolution of modern IBD trials, discuss methods for improving trial efficiency in early and late phase development, and provide insights into the interpretation and implications of these data for clinical care. The medical management of inflammatory bowel disease (IBD) has been transformed over the past few decades by the approval of multiple classes of advanced therapies and the integration of more targeted treatment strategies for Crohn’s disease and ulcerative colitis. These changes have been driven by an increasing number of pivotal randomized controlled trials, which have grown in size and complexity over time. Several landmark studies that are anticipated to change current IBD management paradigms have recently been completed or are on-going, including the first head-to-head biologic trials, advanced combination treatment trials, therapeutic strategy and treatment target trials, and multiple phase 3 registrational programs of novel compounds. Despite these advances, the future of IBD trials also faces major challenges with respect to cost, feasibility, and recruitment. Accordingly, innovative methods for early and late phase randomized controlled trials must be adopted. In this review, we provide a comprehensive overview of the evolution of modern IBD trials, discuss methods for improving trial efficiency in early and late phase development, and provide insights into the interpretation and implications of these data for clinical care. The past 2 decades have witnessed major advancements in the management of inflammatory bowel disease (IBD). This has been highlighted by the approval of several classes of advanced biologic and oral small molecule therapies for moderately-to-severely active Crohn’s disease (CD) and ulcerative colitis (UC) in addition to an increasing emphasis on (1) early disease recognition and treatment initiation1Danese S. Fiorino G. Fernandes C. et al.Catching the therapeutic window of opportunity in early Crohn's disease.Curr Drug Targets. 2014; 15: 1056-1063Crossref PubMed Scopus (52) Google Scholar; (2) comprehensive disease assessment and monitoring capturing patient-reported outcomes (PROs) and objective biomarker, endoscopic, radiographic, and histologic disease measures2Plevris N. Lees C.W. Disease monitoring in inflammatory bowel disease: evolving principles and possibilities.Gastroenterology. 2022; 162: 1456-1475.e1Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar; and (3) adoption of treat-to-target therapeutic paradigms that focus on long-term mucosal healing, normalization of quality of life, and prevention of bowel damage and disability.3Turner D. Ricciuto A. Lewis A. et al.STRIDE-II: an update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD.Gastroenterology. 2021; 160: 1570-1583Abstract Full Text Full Text PDF PubMed Scopus (1184) Google Scholar Much of this progress has been driven by rigorously executed randomized controlled trials (RCTs), including both premarketing registrational studies to demonstrate the efficacy and safety of novel therapies and postmarketing, large-scale therapeutic strategy trials that have advanced the thinking and ambitions for the potential of disease modification and positively changing the otherwise progressive and debilitating natural history of IBD.4Le Berre C. Peyrin-Biroulet L. Selecting end points for disease-modification trials in inflammatory bowel disease: the SPIRIT consensus from the IOIBD.Gastroenterology. 2021; 160: 1452-1460.e21Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar The complexity, scope, and investment of monetary, operational, and patient resources in clinical trials in IBD have increased over time. Trials of advanced therapies in IBD have evolved from isolated short-term induction trials to open-label induction with randomized maintenance studies, and subsequently to integrated “treat-through” combined induction and maintenance studies and induction and responder rerandomization trials with withdrawal of some patients to maintenance placebo.5Ghosh S. Sandborn W.J. Colombel J.F. et al.Interpreting registrational clinical trials of biological therapies in adults with inflammatory bowel diseases.Inflamm Bowel Dis. 2016; 22: 2711-2723Crossref PubMed Scopus (14) Google Scholar Although these different designs has allowed greater possibilities for the types of clinical questions that can be answered in RCTs, tremendous challenges also exist.6Uzzan M. Bouhnik Y. Abreu M. et al.Declining enrolment and other challenges in IBD clinical trials: causes and potential solutions.J Crohns Colitis. 2023; 17: 1066-1078Crossref PubMed Scopus (11) Google Scholar For example, despite rising prevalence rates of IBD, enrolment in clinical trials has decreased and now averages <0.2 patients per site per month and even less in North America.7Harris M.S. Wichary J. Zadnik M. et al.Competition for clinical trials in inflammatory bowel diseases.Gastroenterology. 2019; 157: 1457-1461.e2Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Up to half of trials fail to meet recruitment timelines, 20% of development programs are prematurely terminated, and the duration and cost of running large-scale studies has increased exponentially.6Uzzan M. Bouhnik Y. Abreu M. et al.Declining enrolment and other challenges in IBD clinical trials: causes and potential solutions.J Crohns Colitis. 2023; 17: 1066-1078Crossref PubMed Scopus (11) Google Scholar Second, although there are now more medical options than ever to treat patients with IBD, the “therapeutic ceiling” constraining long-term remission rates has yet to be broken.8Raine T. Danese S. Breaking through the therapeutic ceiling: what will it take?.Gastroenterology. 2022; 162: 1507-1511Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Third, there has been an explosion in the generation of “real-world” data that often includes a broader range of participants compared with RCTs, and can evaluate different components of treatment effectiveness, assess long-term treatment safety, and inform treatment decisions that are not directly answered in controlled studies.9Dulai P.S. Singh S. Jairath V. et al.Integrating evidence to guide use of biologics and small molecules for inflammatory bowel diseases.Gastroenterology. 2024; Full Text Full Text PDF PubMed Scopus Google Scholar data from studies are by the to for with respect to patient and potential in and trials that target strategies for improving and rates of remission a for the generation of IBD In this review, we advancements in the and of early and trials, on IBD have over and to the of and clinical care. In early development, the goals are to evaluate safety and for potential assess and and to phase and a registrational phase this has of and multiple and safety studies in by and or multiple trials that have clinical outcomes the in or the Crohn’s Disease in et of a Crohn's disease Crohn's Disease Full Text PDF PubMed Google W.J. oral for to active ulcerative colitis. randomized PubMed Google Scholar programs have of patients with IBD this and multiple phase to some of safety and target this of development and often participants randomized to multiple which to site and on a C. L. Jairath V. clinical trial efficiency in 2019; 157: Full Text Full Text PDF PubMed Scopus Google Scholar Accordingly, several for more early phase development have been has been to multiple that are in phase 2 to assess for potential there and in of biologic on disease and M. et of in patients with ulcerative colitis and Crohn's PubMed Scopus Google C. et and of in patients with to active Crohn's 2022; Full Text Full Text PDF PubMed Scopus Google M. et of in and adults with Crohn's disease: a of data from 2 phase clinical Full Text Full Text PDF PubMed Scopus Google Scholar that be with clinical in early phase trials on treatment be more than to the of of This in the phase 2 trial in patients with moderately-to-severely active W.J. M. et and safety of in a randomized phase 2 of patients with ulcerative Full Text Full Text PDF PubMed Scopus Google Scholar patients randomized to or and and for to and Although clinical and remission rates not by to patients with the therapeutic the first 2 an and that the in the treatment not by to be than for clinical remission in the phase 3 G. M. T. et induction and maintenance for ulcerative 2023; PubMed Scopus Google Scholar and remission the or have been to assess efficacy in phase 2 these outcomes are clinical are of not be to early treatment and to inform phase 3 trials are often on J. C. et trials in inflammatory bowel disease of efficacy from a of induction Crohns Colitis. 2023; 17: Scopus Google Scholar of these outcomes advancements in and now of target to in or T. to the efficiency of phase IBD clinical 2023; Scopus Google Scholar This greater in early decisions trial of changes and of biologic the phase a open-label including patients with active and with that S. et by in patients with active inflammatory bowel 2021; 160: Full Text Full Text PDF PubMed Scopus Google Scholar This trial efficacy target of and of and changes from from this the of with a of with of multiple This the in of target Although treatment end points into this not be for change In the a in early phase development that for can to the of the to this to use a more or end to for treatment For example, the and for this V. J. G. et disease for early development in ulcerative development and of the 2019; Full Text Full Text PDF PubMed Google Scholar This a that includes assessment of histologic the and the In a of the the of the a trial with a in V. et of disease in moderately-to-severely active ulcerative a of the Crohns Colitis. 2024; Google Scholar In phase trials, the of randomized to often an for and it it to patients to the of other and therapeutic A. et use in the of inflammatory bowel disease clinical Google Scholar for the number of participants randomized to have been to an open-label trial an and end this participants to active treatment yet the of efficacy of this the phase Danese et S. M. et safety and efficacy for ulcerative a phase 2021; Full Text Full Text PDF Scopus Google Scholar the efficacy and safety of a The end of this trial The trial a for in the first and the of participants a of in participants in the phase 3 Although Danese et S. 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L. et with and histologic rates in induction and maintenance trials of ulcerative PubMed Scopus Google M. et and endoscopic, and safety rates in induction and maintenance trials of ulcerative Crohns Colitis. 2022; PubMed Scopus Google Scholar Second, both and with have been P.S. et of clinical remission to in clinical trials of Crohn's Bowel Dis. 2023; PubMed Scopus Google P.S. et of induction and remission in ulcerative 2023; Full Text Full Text PDF PubMed Scopus Google Scholar The of a in IBD a which S. et a for to Crohn's disease: of a PubMed Scopus Google Scholar the trial a open-label which patients with with combination and J.F. et and combination in Crohn's disease 2024; 22: Full Text Full Text PDF PubMed Scopus Google Scholar from past and it that remission on combination more compared with or are to be combined with trial that multiple or have that active et designs in clinical trials: use and to and PubMed Scopus Google Scholar Although this trial it be that trials be to and methods to the of although this to be in designs are to that can with of For example, the of the of end must the although it to of and patient over and and treatment must be anticipated to be in the compared with M. 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Jairath V. et and trials: the potential for trials in inflammatory bowel 2024; Full Text Full Text PDF Scopus (1) Google Scholar the past 3 there has been evolution in the of late phase registrational studies in IBD, from isolated short-term induction trials to open-label induction with randomized maintenance studies, to “treat-through” induction and to integrated induction and responder rerandomization These different different clinical with and with respect to of of to and interpretation of treatment efficacy and S. Sandborn W.J. Colombel J.F. et al.Interpreting registrational clinical trials of biological therapies in adults with inflammatory bowel diseases.Inflamm Bowel Dis. 2016; 22: 2711-2723Crossref PubMed Scopus (14) Google Scholar Although the induction and rerandomization of by randomized withdrawal induction to active treatment are has been a it can be that this are on long-term there have been multiple in phase 3 designs and advancements in late phase trials are there has been a induction and maintenance for IBD In induction studies, outcomes often yet this with the that in clinical patients to Accordingly, phase 3 trials have induction outcomes and often an to and For example, in the phase 3 and trials that the efficacy and safety of induction to an of open-label G. et induction for Crohn's disease: from the phase 3 and induction 2022; Full Text Full Text PDF PubMed Google Scholar than of induction clinical and an to treatment with the clinical that be for induction to early The of induction the induction and maintenance which has not been in trials for other inflammatory of this in induction responder rerandomization designs be (1) maintenance efficacy of induction and the of this be different than randomized (2) induction can the interpretation of data from the withdrawal of in for with or M. et maintenance for to active Crohn's disease: from the withdrawal phase 3 maintenance 2022; Full Text Full Text PDF PubMed Google Scholar; and (3) rerandomization induction trials are must be to have the maintenance these there has been increasing in to “treat-through” For the trial a induction and maintenance participants randomized treatment from W.J. S. Peyrin-Biroulet L. et induction and maintenance for ulcerative colitis phase 3 2023; Full Text Full Text PDF PubMed Scopus Google Scholar This registrational trial with a size that clinical remission in randomized than in rerandomization studies, yet in clinical remission S. et of clinical of the phase 3 Crohns Colitis. 2023; 17: Google Scholar studies are also greater for the trial in of participants compared with of participants Although this to disease it that participants early have objective evidence of active disease and that the interpretation of rates for in S. Peyrin-Biroulet L. 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M.S. Danese S. et for the treatment of 2023; PubMed Scopus Google Scholar This trial the approval of for a disease with medical and few therapeutic trials are in patients with other and isolated ulcerative For example, the trials of a of of patients with isolated and efficacy in this that has been to L. et and safety of in with to active isolated a of the phase 3 and Crohns Colitis. 2023; 17: Google Scholar The current for end points in registrational phase 3 trials includes a end of clinical remission and remission for or for with in and a of clinical remission of or of and of or and Drug for and Drug for Scholar Although these have some that are C. Jairath V. et assessment of inflammatory bowel disease in clinical 2022; Full Text Full Text PDF PubMed Scopus Google Scholar the of end points in phase 3 trials are with current clinical treatment with the of remission in both and a for improving long-term and future disease Colombel J.F. et of outcomes with with and rates in patients with Crohn’s Crohns Colitis. 2022; Google C. et remission of early Crohn's Full Text Full Text PDF PubMed Scopus Google Scholar consensus has outcomes that be and in IBD C. J. et a consensus initiative to a for randomized controlled trials in inflammatory bowel 2022; Full Text Full Text PDF PubMed Scopus Google Scholar this to programs have more novel end In multiple large-scale studies have now been that the use of a of in and there increasing emphasis on histologic combined mucosal in S. S. G. et to target of for patients with Crohn's disease with an phase 2022; Full Text Full Text PDF PubMed Scopus Google C. A. et International consensus to integration of in ulcerative colitis clinical 2021; 160: Full Text Full Text PDF PubMed Scopus Google Scholar In the even more assessment of healing, greater into the therapeutic efficacy of novel although these are more to or T. J. et to and histologic remission for major outcomes in inflammatory bowel disease: the 2023; Full Text Full Text PDF PubMed Scopus Google Scholar have also the to to treatment and although an has yet to be In the and in and in have been both to medical treatment despite capturing a of the disease V. et of patient-reported for the assessment of ulcerative colitis disease in clinical PubMed Scopus Google G. G. et the development of patient for the assessment of Crohn's disease PubMed Scopus Google Scholar et G. M. T. et induction and maintenance for ulcerative 2023; PubMed Scopus Google Scholar have recently an which in The and for and and for use in future registrational P.S. 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G. S. et Disease of treatment with in patients with to ulcerative an from the Crohns Colitis. 2024; Google Scholar Although these studies advanced and the to the therapeutic strategy that or than the efficacy of the the other in the These types of trials are for clinical and often a broader of patients than in registrational phase 3 Accordingly, strategy trials often a more than for treatment and to for Fiorino G. A. et trial to of different for inflammatory bowel the Crohns Colitis. 2024; Google Scholar Despite in IBD trial a in long-term remission has yet to be and be of Several potential have been there has been in a or that an are the to to a be the addition of a for in the phase 2 in patients with moderately-to-severely active rates of remission with Peyrin-Biroulet L. 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