The Future of Clinical Trials in Inflammatory Bowel Disease
Authors: Christopher Ma, Virginia Solitano, Silvio Danese, Vipul Jairath
Journal: Clinical Gastroenterology and Hepatology (2024)

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; 166: 396-408.e2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar However, data collected from observational studies are limited by the inability to control for unmeasured confounders, bias with respect to patient selection, and potential inaccuracies in outcome ascertainment. Therefore, designing practical, recruitable, and generalizable trials that target creative strategies for improving patient- and population-level rates of remission remains a priority for the next generation of IBD RCTs. In this review, we summarize important advancements in the conceptualization, design, and conduct of early and late-phase trials, focusing on how IBD RCTs have changed over time and where opportunities exist to advance the standard of research and clinical care. In early drug development, the primary goals are to evaluate safety and tolerability, establish proof-of-concept (POC) for potential mechanistic efficacy, assess pharmacokinetic (PK) and pharmacodynamic dose-response relationships, and determine progression to phase II and ultimately a registrational phase III program. Conventionally, this has consisted of single and multiple ascending dose PK and safety studies in healthy volunteers, followed by POC and parallel or multiple group dose-finding trials that have assessed clinical outcomes using the Mayo Clinic Score in UC or the Crohn's Disease Activity Index (CDAI) in CD.10Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Google Scholar,11Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.N Engl J Med. 1987; 317: 1625-1659Crossref PubMed Google Scholar Some programs have incorporated cohorts of patients with IBD at this single and multiple ascending dose phase to obtain some very preliminary signals of safety and drug target engagement. However, this "traditional" model of drug development is inefficient and often requires >150 participants randomized to multiple groups, which is infeasible to rapidly recruit without coordinated efforts at site activation and aggressive screening on a global scale.12Ma C. Guizzetti L. Jairath V. Improving clinical trial efficiency in gastroenterology.Gastroenterology. 2019; 157: 892-893Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Accordingly, several considerations for more efficient early phase drug development have been proposed. Historically, population-based PK modelling has been used to refine multiple fixed dosing regimens that are tested in phase 2 to assess for potential dose-response relationships. However, there is considerable intraindividual and interindividual variability in PK, particularly of biologic therapies, based on such factors as body weight, disease activity, albumin, and drug-related immunogenicity.13Rosario M. Dirks N.L. Gastonguay M.R. et al.Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease.Aliment Pharmacol Ther. 2015; 42: 188-202Crossref PubMed Scopus (207) Google Scholar, 14Adedokun O.J. Xu Z. Gasink C. et al.Population pharmacokinetics and exposure-response analyses of ustekinumab in patients with moderately to severely active Crohn's disease.Clin Ther. 2022; 44: 1336-1355Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 15Fasanmade A.A. Adedokun O.J. Blank M. et al.Pharmacokinetic properties of infliximab in children and adults with Crohn's disease: a retrospective analysis of data from 2 phase III clinical trials.Clin Ther. 2011; 33: 946-964Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar Recognizing that systemic drug levels may be correlated with clinical response, dosing in early phase trials based on measured treatment exposure may be more efficient than fixed dosing, to minimize the risk of primary nonresponse because of suboptimal PK. This approach was used in the phase 2 AMAC mirikizumab trial in patients with moderately-to-severely active UC.16Sandborn W.J. Ferrante M. Bhandari B.R. et al.Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with ulcerative colitis.Gastroenterology. 2020; 158: 537-549.e10Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar Eligible patients were randomized to placebo, 600-mg mirikizumab fixed-dose, or 50-mg and 200-mg mirikizumab exposure-based dosing administered at Weeks 0, 4, and 8 (allowing for up to 12-fold dose escalation at Weeks 4 and 8). Although clinical response and remission rates did not vary by dose adjustment, investigators were able to increase serum mirikizumab concentrations among patients with the lowest therapeutic exposure after the first 2 doses, exclude an obvious exposure-dependent response, and identify that the lower responses observed in the 600-mg treatment arm were not caused by inadequate exposure. Subsequently, mirikizumab 300 mg was demonstrated to be significantly superior than placebo for inducing clinical remission at Week 12 in the LUCENT-1 phase 3 trial.17D'Haens G. Dubinsky M. Kobayashi T. et al.Mirikizumab as induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2023; 388: 2444-2455Crossref PubMed Scopus (0) Google Scholar Clinical response and remission using the CDAI or Mayo Clinic Score have historically been used to assess efficacy in phase 2 trials. However, these outcomes are inefficient: clinical assessments are only indirect measures of pharmacodynamic effects, they may not be sufficiently sensitive to capture early treatment response, and subsequent power calculations to inform phase 3 trials are often based on imprecise estimates.18Bahnam P. Hanzel J. Ma C. et al.Most placebo-controlled trials in inflammatory bowel disease were underpowered because of overestimated drug efficacy rates: results from a systematic review of induction studies.J Crohns Colitis. 2023; 17: 404-417Crossref Scopus (5) Google Scholar Furthermore, dichotomization of these outcomes loses important information. Novel advancements in translational techniques, such as single-cell RNA sequencing and spatial transcriptomics, now allow better direct measurement of target engagement to confirm POC, either in peripheral blood or intestinal tissue.19Noor N.M. Raine T. Innovations to improve the efficiency of phase II IBD clinical trials.Nat Rev Gastroenterol Hepatol. 2023; 20: 555-556Crossref Scopus (4) Google Scholar This allows potentially greater confidence in making early go/no-go decisions regarding trial progression using detection of molecular changes and confirmation of biologic efficacy. One such example is the phase 2a FUTURE trial, a 12-week open-label prospective study including only 16 patients with active UC and CD, treated with olamkicept (a sgp130Fc decoy protein that blocks interleukin [IL]-6 signaling).20Schreiber S. Aden K. Bernardes J.P. et al.Therapeutic interleukin-6 Trans-signaling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease.Gastroenterology. 2021; 160: 2354-2366.e11Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar This POC trial demonstrated efficacy using target inhibition of phosphorylated signal transduction and activation of transcription (STAT)-3 and transcriptional changes from intestinal biopsies. An important consideration from this study is whether the demonstrated inhibition of STAT3 phosphorylation with olamkicept is simply a surrogate measure of biologically reduced inflammation, with downregulation of multiple STAT3-dependent gene transcripts. This illustrative example highlights the difficulty in finding true markers of target engagement. Although dichotomizing treatment end points into binary response versus nonresponse is clinically intuitive, this approach may not be sensitive for detecting change after treatment. In the worst-case scenario, using a binary outcome in early phase development that is insensitive for responsiveness can lead to the erroneous abandonment of potentially effective medications at the POC stage. One alternative to mitigate this risk is to use a more sensitive composite or continuous end point to enhance signal detection for treatment efficacy. For example, the UC-100 score was developed and validated for this purpose.21Jairath V. Jeyarajah J. Zou G. et al.A composite disease activity index for early drug development in ulcerative colitis: development and validation of the UC-100 score.Lancet Gastroenterol Hepatol. 2019; 4: 63-70Abstract Full Text Full Text PDF PubMed Google Scholar This is a 100-point continuous measure that includes weighted assessment of stool frequency, histologic activity measured using the Robarts Histopathology Index, and the Mayo Clinic endoscopy subscore. In a post hoc analysis of the ustekinumab UNIFI trial, using the UC-100 instead of the Mayo Clinic Score would allow a similarly powered trial with a 30% reduction in total sample size.22Solitano V. Panaccione R. Sands B.E. et al.P280 Comparative responsiveness of disease activity indices in moderately-to-severely active ulcerative colitis: a post-hoc analysis of the UNIFI trial.J Crohns Colitis. 2024; 18: i647-i648Crossref Google Scholar In earlier phase trials, the possibility of being randomized to placebo is often an important deterrent for participants, and indeed, it is debatable whether it remains ethical to randomize patients to placebo given the availability of other effective and safe therapeutic options.23Lasa J.S. Zubiaurre I. Rausch A. et al.Placebo use in the context of inflammatory bowel disease clinical trials.Arq Gastroenterol. 2020; 57: 87-90Crossref Google Scholar Different proposals for minimizing the number of participants randomized to placebo have been considered. One solution is to conduct an open-label single-arm trial using an objective, centrally evaluated and blinded end point: this allows all participants to receive active treatment yet preserves the validity of efficacy assessments. An example of this design is the phase 2a single-arm TUSCANY trial, where Danese et al24Danese S. Klopocka M. Scherl E.J. et al.Anti-TL1A antibody PF-06480605 safety and efficacy for ulcerative colitis: a phase 2a single-arm study.Clin Gastroenterol Hepatol. 2021; 19: 2324-2332.e6Abstract Full Text Full Text PDF Scopus (0) Google Scholar evaluated the efficacy and safety of PF-06480605, a monoclonal antibody targeting tumor necrosis factor-like ligand 1 (TL1A). The primary end point of this trial was centrally read endoscopic improvement at Week 14. The trial was conducted using a Simon's 2-stage design, initially assessing for futility in the first 12 participants, and then testing the proportion of participants achieving endoscopic improvement against a historical placebo response rate of ≤6% (observed in tumor necrosis factor antagonist experienced participants in the phase 3 OCTAVE tofacitinib trials). Although Danese et al24Danese S. Klopocka M. Scherl E.J. et al.Anti-TL1A antibody PF-06480605 safety and efficacy for ulcerative colitis: a phase 2a single-arm study.Clin Gastroenterol Hepatol. 2021; 19: 2324-2332.e6Abstract Full Text Full Text PDF Scopus (0) Google Scholar used a frequentist framework for testing a null hypothesis using observed data from the TUSCANY study, an alternative solution for minimizing patients randomized to placebo is to conduct a Bayesian trial. Bayesian designs summarize previous observations in the literature about an outcome to estimate a prior distribution, which is then updated using data collected from the trial to a posterior distribution from which probabilities with credible intervals can be derived for making comparative inference.25Ruberg S.J. Beckers F. Hemmings R. et al.Application of Bayesian approaches in drug development: starting a virtuous cycle.Nat Rev Drug Discov. 2023; 22: 235-250Crossref PubMed Scopus (17) Google Scholar Bayesian trials are potentially viable in IBD because a large body of evidence synthesizing clinical, endoscopic, and histologic placebo responses in CD and UC using both trial- and individual patient-level data has been conducted to inform prior estimates.26Almradi A. Sedano R. Hogan M. et al.Clinical, endoscopic, and safety placebo rates in induction and maintenance trials of Crohn's disease: meta-analysis of randomised controlled trials.J Crohns Colitis. 2022; 16: 717-736Crossref PubMed Scopus (10) Google Scholar, 27Duijvestein M. Jeyarajah J. Guizzetti L. et al.Response to placebo, measured by endoscopic evaluation of Crohn's Disease Activity, in a pooled analysis of data from 5 randomized controlled induction trials.Clin Gastroenterol Hepatol. 2020; 18: 1121-1132.e2Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 28Ma C. Guizzetti L. Panaccione R. et al.Systematic review with meta-analysis: endoscopic and histologic placebo rates in induction and maintenance trials of ulcerative colitis.Aliment Pharmacol Ther. 2018; 47: 1578-1596Crossref PubMed Scopus (29) Google Scholar, 29Sedano R. Hogan M. Nguyen T.M. et al.Systematic review and meta-analysis: clinical, endoscopic, histological and safety placebo rates in induction and maintenance trials of ulcerative colitis.J Crohns Colitis. 2022; 16: 224-243Crossref PubMed Scopus (9) Google Scholar Second, both trial- and patient-level factors associated with placebo responses have been evaluated.30Wong E.C.L. Dulai P.S. Marshall J.K. et al.Predictors of clinical remission to placebo in clinical trials of Crohn's disease.Inflamm Bowel Dis. 2023; 29: 1390-1398Crossref PubMed Scopus (0) Google Scholar,31Wong E.C.L. Dulai P.S. Marshall J.K. et al.Predictors of placebo induction response and remission in ulcerative colitis.Clin Gastroenterol Hepatol. 2023; 21: 1050-1060.e9Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The earliest example of a Bayesian RCT in IBD evaluated secukinumab, a monoclonal antibody targeting IL17A, which demonstrated harm after enrolling only 59 participants.32Hueber W. Sands B.E. Lewitzky S. et al.Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial.Gut. 2012; 61: 1693-1700Crossref PubMed Scopus (1244) Google Scholar More recently, the EXPLORER trial was a single arm, open-label study, which treated 55 biologic-naive patients with CD with triple combination vedolizumab, adalimumab, and methotrexate.33Colombel J.F. Ungaro R.C. Sands B.E. et al.Vedolizumab, adalimumab, and methotrexate combination therapy in Crohn's disease (EXPLORER).Clin Gastroenterol Hepatol. 2024; 22: 1487-1496.e12Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar A Bayesian prior was developed from past vedolizumab and adalimumab studies; it was estimated that Week 26 centrally read endoscopic remission on triple combination therapy was more likely compared with placebo (≥99.99%), vedolizumab (≥86.26%), or adalimumab monotherapy (≥71.35%). Finally, Bayesian approaches are typically better suited to be combined with adaptive trial designs, particularly those that combine multiple phases or have adaptive randomization allocation ratios that favor active treatment.34Pallmann P. Bedding A.W. Choodari-Oskooei B. et al.Adaptive designs in clinical trials: why use them, and how to run and report them.BMC Med. 2018; 16: 29Crossref PubMed Scopus (423) Google Scholar Although this improves trial efficiency, it should be cautioned that adaptive Bayesian trials may be logistically challenging to design and require complex analytic methods to control the risk of type 1 error. Furthermore, although this methodology is well established, regulatory authorities tend to be very conservative in their recommendations when such designs are proposed to mitigate pitfalls that can occur with using historical estimations of placebo response. For example, the lack of blinding may influence the estimation of nonobjective end points, historical controls must adequately mimic the study population although it is difficult to ascertain unmeasured sources of confounding and patient characteristics may shift over time, and finally, very large and convincing treatment effects must be anticipated to be confident in the findings compared with historical placebo groups.35Jahanshahi M. Gregg K. Davis G. et al.The use of external controls in FDA regulatory decision making.Ther Innov Regul Sci. 2021; 55: 1019-1035Crossref PubMed Scopus (66) Google Scholar A third potential solution for minimizing the number of participants randomized to placebo is to adopt a master trial protocol, which involves a single, over-arching protocol to answer multiple questions. An umbrella trial that evaluates multiple treatments in a single disease state can share a common comparator group and skew the randomization toward heavily favoring active treatment. For example, the phase 2b VIBRATO trial simultaneously evaluated the efficacy and safety of ritlecitinib and brepocitinib in moderately-to-severely active UC.36Woodcock J. LaVange L.M. Master protocols to study multiple therapies, multiple diseases, or both.N Engl J Med. 2017; 377: 62-70Crossref PubMed Scopus (653) Google Scholar Both agents were compared with a shared placebo arm and fewer than 10% of participants (25/319) were randomized to placebo. In contrast, a basket trial evaluates the same drug for multiple diseases under the same protocol. RELIEVE UCCD is an example of a phase 2b basket trial evaluating the efficacy, safety, and tolerability of anti-TL1A in both patients with UC and CD, incorporating a common protocol with the goal of improved efficiency for recruitment for both indications without the need for separate trials.37Reinisch W. Stoyanov S. Raphael G. et al.P998 Phase 2 basket design study evaluating the efficacy and safety of an anti-TL1A antibody (TEV-48574) in moderate to severe ulcerative colitis or Crohn's Disease (RELIEVE UCCD).J Crohns Colitis. 2024; 18: i1811Crossref Google Scholar Finally, a platform trial design can be considered: platform trials are "open-ended" designs, that allow new interventions to be added so that multiple therapies can be simultaneously or sequentially evaluated, with no prespecified trial end date. The ongoing MACARONI-23 platform trial is evaluating pediatric patients with moderate-to-severe CD, treated with guselkumab or mirikizumab, and with the anticipation of additional treatment arms being added in the future.38Honap S. Sands B.E. Jairath V. et al.Basket, umbrella, and platform trials: the potential for master protocol-based trials in inflammatory bowel disease.Gastroenterology. Published online April 25, 2024; https://doi.org/10.1053/j.gastro.2024.04.020Abstract Full Text Full Text PDF Scopus (1) Google Scholar Over the past 3 decades, there has been substantial evolution in the design 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 maintenance, to integrated induction and responder rerandomization designs. These different configurations answer fundamentally different clinical questions, with each having unique advantages and disadvantages with respect to feasibility of recruitment, risk of drop-out, generalizability to routine care, and interpretation of treatment efficacy and safety.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 recently, the induction and rerandomization of responders (also termed "induction followed by randomized withdrawal maintenance" when only induction responders to active treatment are rerandomized) has been a preferred design: it can be argued that this most closely mimics real world practice where primary nonresponders are continued on long-term treatment. However, there have been multiple recent variations in phase 3 designs and advancements in how late phase trials are conducted. Historically, there has been a dichotomy between induction and maintenance periods for IBD trials. In earlier induction studies, outcomes were often measured 4–8 weeks after randomization, yet this is inconsistent with the observation that in clinical practice, many patients take longer to respond. Accordingly, recent phase 3 trials have measured induction outcomes later at 12–16 weeks, and often included an "extended induction" period to try and capture delayed responses. For example, in the phase 3 ADVANCE and MOTIVATE trials that evaluated the efficacy and safety of risankizumab, induction nonresponders at Week 12 were eligible to receive an additional 12 weeks of open-label therapy.39D'Haens G. Panaccione R. Baert F. et al.Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials.Lancet. 2022; 399: 2015-2030Abstract Full Text Full Text PDF PubMed Google Scholar More than 50% of induction nonresponders experienced clinical improvement and one-third had an endoscopic response to extended treatment with risankizumab, supporting the clinical message that risankizumab could be continued for 6 months after induction to capture early delayed responders. The concept of extending induction highlights the rather artificial separation between induction and maintenance periods, which has not been commonly adopted in trials for other chronic inflammatory diseases, such as rheumatoid arthritis. Some limitations of using this dichotomy in induction responder rerandomization designs should be noted: (1) maintenance efficacy is only reflective of induction responders and the characteristics of this subgroup may be different than those randomized at baseline; (2) "carry-over" effects after induction can influence the interpretation of data from the withdrawal of therapy arm in maintenance, particularly for treatments with long half-lives or prolonged pharmacodynamic effects40Ferrante M. Panaccione R. Baert F. et al.Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled,