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  • Review Article
  • Published:

Interpreting modern randomized controlled trials of medical therapy in inflammatory bowel disease

Nature Reviews Gastroenterology & Hepatology volume 21, pages 792–808 (2024)Cite this article

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Abstract

Treatment options for the medical management of inflammatory bowel disease (IBD) have expanded substantially over the past decade. Multiple classes of advanced therapies, including both monoclonal antibodies and novel oral small molecules, are now available for the treatment of moderately-to-severely active Crohn’s disease and ulcerative colitis, highlighted by the approvals of the first IL23p19 antagonists, selective Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators. These advances have been accompanied by the identification of novel targets and the rapid growth in both the number and size of IBD clinical trials. Over a dozen landmark randomized controlled trials (RCTs) have been completed in the past 5 years, including the first head-to-head biologic trials, the first combination biologic studies, and multiple phase III registrational trials of novel compounds with new co-primary and composite end points that will change the treatment landscape for years to come. Importantly, the methodology of RCTs in IBD has evolved substantially, with new trial designs, evaluation of unique patient populations, and different types of efficacy and safety end points being key innovations. In this Review, we provide a comprehensive evaluation of how modern RCTs of IBD medical therapies have evolved and the implications for their appraisal that will help guide the application of these data to clinical practice.

Key points

  • Evidence generated from high-quality, randomized controlled trials is essential for the approval of new drugs for the treatment of inflammatory bowel disease (IBD); over time, these trials have increased in size, scope and complexity.

  • There have been substantial advancements in the design of IBD trials, including re-evaluations of which participants are enrolled, how participants are qualified, and how disease activity is measured.

  • For trials in Crohn’s disease, the co-primary end points include both clinical and endoscopic assessment; for trials in ulcerative colitis, the composite primary outcome of clinical remission includes patient-reported and endoscopic measures.

  • Direct comparisons of advanced agents will inform treatment positioning and relative efficacy and safety; some head-to-head trials have now been conducted, and others with active comparator arms are soon to be completed.

  • The long-term sustainability of trials in IBD is threatened by poor recruitment, prolonged study durations and increased costs; future innovations using Bayesian approaches, adaptive trial designs and master protocols might improve trial efficiency.

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Fig. 1: Historical trial designs in IBD.
Fig. 2: Innovations for modern and future trials in IBD.

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Authors and Affiliations

  1. Division of Gastroenterology & Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada

    Christopher Ma & Remo Panaccione

  2. Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada

    Christopher Ma

  3. Alimentiv Inc., London, Ontario, Canada

    Christopher Ma, Vipul Jairath & Brian G. Feagan

  4. Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada

    Vipul Jairath & Brian G. Feagan

  5. Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada

    Vipul Jairath & Brian G. Feagan

  6. Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Nancy, France

    Laurent Peyrin-Biroulet

  7. Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy

    Silvio Danese

  8. The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Bruce E. Sands

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Contributions

C.M. researched data for the article, made a substantial contribution to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission. V.J., B.G.F., B.E.S. and R.P. made a substantial contribution to discussion of the content, and reviewed and/or edited the manuscript before submission. L.P.-B. and S.D. reviewed and/or edited the manuscript before submission.

Corresponding author

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Competing interests

C.M. has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol-Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda and Tillotts Pharma; speaker’s fees from AbbVie, Amgen, AVIR Pharma Inc., Alimentiv, Bristol-Myers Squibb, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Sanofi and Takeda; royalties from Springer Publishing; and research support from AbbVie, Ferring and Pfizer. V.J. has received consulting/advisory board fees from AbbVie, Alimentiv Inc., Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol-Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, SCOPE, Second Genome, Sorriso, Takeda, TD Securities, Teva, Topivert, Ventyx and Vividion; and speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda and Fresenius Kabi. B.G.F. is a scientific advisory board member for AbbVie, Allergan, Amgen, AstraZeneca, Avaxia Biologics Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Elan, Biogen, Ferring, Genentech-Roche, Janssen–Johnson & Johnson, Merck, Millennium, Nestlé, Novo Nordisk, Novartis, Pfizer, Prometheus, Protagonist, Receptos, Salix, Sigmoid Pharma, Takeda, Teva, TiGenix, Tillotts Pharma and UCB Pharma; has received consulting fees from AbbVie, Actogenix, Akros, Albireo Pharma, Allergan, Amgen, AstraZeneca, Avaxia Biologics, Avir Pharma, Axcan, Baxter Healthcare, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan-Biogen, EnGene, Ferring, Genentech-Roche, GiCare Pharma, Gilead Sciences, Given Imaging, GlaxoSmithKline, Ironwood, Janssen Biotech-Centocor, Janssen–Johnson & Johnson, Kyowa Hakko Kirin, Eli Lilly, Merck, Mesoblast Pharma, Millennium, Nestlé, Novo Nordisk, Novartis, Pfizer, Prometheus, Protagonist, Receptos Salix, Sanofi, Shire, Sigmoid Pharma, Synergy Pharma, Takeda, Teva, TiGenix, Tillotts Pharma, UCB Pharma, Vertex, VHsquared, Wyeth, Zealand and Zygenia; has received lecture fees from AbbVie, Janssen–Johnson & Johnson, Takeda and UCB Pharma; has received grant support from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen Biotech-Centocor, Janssen-Johnson & Johnson, Pfizer, Receptos, Sanofi and Takeda; and is the Senior Scientific Officer of Alimentiv Inc. L.P.-B. has received personal fees from AbbVie, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic Pharma, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax, Samsung, Ventyx, Roivant and Vectivbio. S.D. reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen-Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial and Vifor; and reports lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer and Takeda. B.E.S. has served as a consultant or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calibr, Celltrion, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead Sciences, Genentech, Glaxo SmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen–Johnson & Johnson, Kaleido, Kalyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences and Viela Bio; and had stock options from Ventyx Biosciences. R.P. has served as a consultant for Abbott, AbbVie, Abbivax, Alimentiv Inc. (formerly Robarts Clinical Trials), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx and UCB; received speaker’s fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda Pharmaceuticals; and served on advisory boards for AbbVie, Alimentiv Inc. (formerly Robarts Clinical Trials), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, SandozShire, Sublimity Therapeutics, Takeda Pharmaceuticals and Ventyx.

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Supplementary information

Glossary

Active comparators

Treatment or intervention used as a comparison group in a clinical trial, which is known to be effective for the condition being studied or is already used as a standard treatment.

Adaptive trial

Type of clinical trial that allows for modifications to certain aspects of the trial protocol during its conduct, typically based on accumulating data from the study, making trials more flexible and responsive to emerging evidence while maintaining scientific validity.

Adverse events

Any untoward medical occurrence or undesirable experience that happens in the course of a clinical trial, regardless of whether it is related to the treatment being studied. Adverse events are categorized by their frequency, severity and nature.

Basket trials

Type of clinical trial that evaluates efficacy of a targeted therapy across multiple different diseases or conditions (for example, testing a novel therapy in both Crohn’s disease and ulcerative colitis within the same protocol).

Bayesian approaches

Bayesian statistics use a framework for probabilistic reasoning and inference that treats unknown parameters as random variables with probability distributions and uses observed data to update the prior probability of a hypothesis. Bayesian approaches incorporate prior information, and not just data observed within a trial.

Blinded

Method used in clinical trials to reduce bias by ensuring that certain individuals are unaware of key information (typically treatment assignment); investigators, site personnel, trial sponsors or patients may be blinded during the course of a trial.

Cluster randomization

A method of randomization where groups (or clusters) are randomly assigned to different intervention arms, rather than randomization of individual patients.

Equivalence trials

Type of clinical trial designed to demonstrate that two or more treatments/interventions are equivalent in terms of efficacy within a prespecified equivalence margin.

Explanatory

Type of clinical trial designed to assess efficacy of interventions under ideal or controlled conditions.

Feeder cohorts

A secondary group of patients in a trial, separate from those involved in the primary treatment comparison, that is used to increase participants that can enrol into later phases of a clinical trial.

Frequentist inference

Frequentist (classical) statistics is a traditional approach to statistical inference that estimates unknown parameters solely based on observed data within a clinical trial. Unknown parameters are treated as fixed values, inference is based on hypothesis testing against a null hypothesis to calculate the probability of observing the data (or more extreme data) under the assumption that the null hypothesis is true.

Master trial protocols

A comprehensive clinical trial framework designed to evaluate multiple research questions, interventions or treatment strategies within the same overarching protocol.

Non-inferiority trials

Type of clinical trial designed to demonstrate that a new treatment or intervention is not significantly worse than the comparator treatment, by a prespecified non-inferiority margin (conclusions from non-inferiority trials are that the new treatment is not clinically worse than the comparator, by an acceptable margin).

Null hypothesis

The null hypothesis is the statement/assumption that there is no treatment effect with the intervention being studied and serves as the reference point for statistical testing for significance (that is, if the observed trial data are not consistent with the null hypothesis, then statistical testing is performed to reject the null hypothesis and accept the alternative hypothesis that there is a true treatment effect).

Open-label

Type of trial in which the participant and investigators are aware of the treatments being administered.

Patient-reported outcome

A patient-reported outcome is a measure of patient health status that is directly reported by the patient, without interpretation by a health-care professional or anyone else.

Placebo

A substance or treatment that has no therapeutic effect used as a control treatment in randomized controlled trials.

Post hoc

A post hoc analysis refers to analyses conducted after the data have been collected and is not part of the original planned analyses, typically to explore unexpected findings to identify other potential relationships or patterns in the data.

Power

Power in a clinical trial refers to the probability that the study will detect a true effect of the intervention being tested, if such an effect exists. Studies that are under-powered do not have enough participants to show a true treatment effect, whereas over-powered studies enrol more patients than necessary to show the same treatment effect.

Pragmatic trials

Type of clinical trial designed to assess effectiveness of interventions in more routine or real-world clinical practice settings.

Primary outcomes

The main measure of interest in a clinical trial designed to assess efficacy of an intervention, corresponding to the primary research question/objective.

Proof-of-concept

Demonstration that a specific therapeutic approach is feasible and has potential for efficacy; typically relates to preliminary studies that show a novel treatment has the desired effect or works via the purported mechanism.

Randomization

Process for assigning participants to different treatment groups within a clinical trial.

Registrational trial

(Also known as pivotal trial). Clinical trial designed to provide primary evidence to support efficacy and safety claims for regulatory approval.

Regulatory approval

Process by which governmental regulatory agencies (for example, the FDA and EMA) review and evaluate the efficacy, safety and quality of new medical products before they can be marketed and distributed for use in patients.

Reliability

Extent to which a measurement tool consistently produces the same results when used repeatedly under consistent conditions (degree of stability in the measurements); inter-rater reliability evaluates consistency of measurements obtained by different raters, intra-rater reliability evaluates consistency within the same observer.

Rescue arms

Predefined component of a trial designed to allow participants who have not responded or cannot tolerate the assigned treatment to be offered an alternative treatment or intervention (typically, allows participants randomized to placebo to end participation in a blinded component of the trial and receive the investigational product open-label).

Responder re-randomization

Trial design wherein participants who improved during induction therapy are re-randomized to different study groups in a maintenance trial.

Responsiveness

Ability of a measurement instrument to detect meaningful change in a particular outcome over time or in response to an effective intervention (sensitivity to change in the condition being measured).

Secondary outcomes

Secondary outcomes are additional variables or measures that provide supplementary information about other aspects of an intervention’s efficacy or impact on patient health outcomes.

Significance

Statistical significance is a measure of the likelihood that an observed treatment effect is not due to random chance, but reflects a true effect of the treatment. Significance level (denoted by α) represents the threshold for deciding if results are significant and represents the maximum probability of making a type I error. The commonly used significance level in trials is α = 0.05.

Superiority trials

Type of clinical trial designed to test whether one treatment/intervention is better than another with statistical significance. This is the most common type of trial for obtaining regulatory approval for a novel therapy.

Synthetic control arms

A statistical method used to estimate the outcomes of a treatment group in the absence of a traditional control group, wherein participants are not randomized to an active comparator or placebo, but data from such a group is constructed using either historical or external sources to closely resemble those undergoing treatment.

Treat-through designs

A trial design wherein participants are randomized at the beginning of treatment and continue in the same treatment assignment through to the end of the study.

Umbrella trials

Type of clinical trial that evaluates multiple treatments or interventions simultaneously within the same overarching trial framework (for example, testing multiple novel therapies in a single trial in patients with Crohn’s disease).

Withdrawal

Decision to discontinue trial participation before study completion, which may be voluntary or related to factors such as developing adverse events or lack of efficacy.

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Ma, C., Jairath, V., Feagan, B.G. et al. Interpreting modern randomized controlled trials of medical therapy in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 21, 792–808 (2024). https://doi.org/10.1038/s41575-024-00989-y

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