Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2023 Nov 1;14(11):e00629.
doi: 10.14309/ctg.0000000000000629.

A Comparison of Treatment Effect Sizes in Matched Phase 2 and Phase 3 Trials of Advanced Therapeutics in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis

Jurij Hanzel  1   2 , Virginia Solitano  3   4 , Lily Zou  5 , G Y Zou  2   6   7 , Laurent Peyrin-Biroulet  8 , Silvio Danese  9 , Siddharth Singh  10 , Christopher Ma  2   11   12 , Pauline Wils  13   14 , Vipul Jairath  2   3   6
Affiliations
Meta-Analysis

A Comparison of Treatment Effect Sizes in Matched Phase 2 and Phase 3 Trials of Advanced Therapeutics in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis

Jurij Hanzel et al. Clin Transl Gastroenterol. .

Abstract

Introduction: Phase 2 trials are fundamental to the rational and efficient design of phase 3 trials. We aimed to determine the relationship of treatment effect size estimates from phase 2 and phase 3 clinical trials on advanced therapeutics in inflammatory bowel disease.

Methods: MEDLINE, EMBASE, CENTRAL, and the Cochrane library were searched from inception to December 19, 2022, to identify paired phase 2 and 3 placebo-controlled induction studies of advanced therapeutics for Crohn's disease (CD) and ulcerative colitis (UC). Treatment effect sizes were expressed as a risk ratio (RR) between the active arm and placebo arm. For the same therapeutics, RRs from phase 2 trials were divided by the RR from phase 3 trial to quantify the relationship of effect sizes between phases.

Results: Twenty-two studies (9 phase 2 trials, 13 phase 3 trials) were included for CD and 30 studies (12 phase 2 trials, 18 phase 3 trials) for UC. In UC (pooled RR 0.72; 95% confidence interval: 0.58-0.86; RR <1 indicates smaller treatment effect sizes in phase 2 trials), but not CD (pooled RR 1.01; 95% confidence interval: 0.84-1.18), phase 2 trials systematically underestimated treatment effect sizes for the primary endpoint compared with phase 3 trials. The underestimation was observed for clinical, but not endoscopic, endpoints in UC.

Discussion: Treatment effect sizes for the primary and clinical endpoints were similar across clinical trial phases in CD, but not UC, where only endoscopic endpoints were comparable. This will help inform clinical development plans and future trial design.

PubMed Disclaimer

Conflict of interest statement

Guarantor of the article: Vipul Jairath, MBChB, DPhil.

Specific author contributions: J.H., V.J.: design. J.H., V.S., L.Z., G.Z., V.J.: data acquisition, analysis, and interpretation. J.H., V.S.: manuscript drafting. J.H., V.S., L.Z., G.Z., L.P.-B., S.D., S.S., C.M., P.W., V.J.: critical revision of manuscript for important intellectual content.

Financial support: None to report.

Potential competing interests: J.H. has received speaker's fees from AbbVie, Janssen, and Takeda, and consulting fees from Alimentiv Inc. V.S. has no conflict of interest. L.Z. has no conflict of interest. G.Z. has received consulting fees from Alimentiv. L.P.-B. consulting fees from Galapagos, AbbVie, Janssen, Genentech, Alimentiv, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSE Immunotherapeutics, Enthera, Theravance, Pandion Therapeutics, Gossamer Bio, Viatris, Thermo Fisher, ONO Pharma, Mopac, Cytoki Pharma, Morphic, Prometheus, and Applied Molecular Transport; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Galapagos, Janssen, Ferring, Tillots, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Arena, Gilead, Amgen, Vifor, and Viatris; support for attending meetings and/or travel from AbbVie, Galapagos, Janssen, Ferring, Tillots, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Arena, Gilead, Amgen, and Vifor; participation on a Data Safety Monitoring Board or Advisory Board from Galapagos, AbbVie, Janssen, Genentech, Alimentiv, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSE Immunotherapeutics, Enthera, Theravance, Pandion Therapeutics, Gossamer Bio, Viatris, Thermo Fisher, ONO Pharma, Mopac, Cytoki Pharma, Morphic, Prometheus, and Applied Molecular Transport; and stocks from CTMA. S.D. has received consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, 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 lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, and Takeda. S.S. has received personal fees from Pfizer for ad hoc grant review and research funding from Pfizer and AbbVie. C.M. has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, BioJAMP, 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, and Takeda; royalties from Springer Publishing; and research support from Ferring and Pfizer. P.W. has no conflict of interest. V.J. has received consulting/advisory board fees from AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, Second Genome, Sorriso Pharmaceuticals, Takeda, Teva, TopiVert, Ventyx, and Vividion and speaker's fees from AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen, Pfizer, Shire, Takeda, and Fresenius Kabi. All authors have approved the final version of the manuscript, including the authorship list.

Figures

Figure 1.
Figure 1.
Study flow diagram for Crohn's disease (a) and ulcerative colitis (b).
Figure 2.
Figure 2.
Pooled treatment effect sizes (expressed as risk ratios between the active treatment arm and the placebo arm) for the primary endpoint in phase 2 trials for Crohn's disease (a), phase 3 trials for Crohn's disease (b), phase 2 trials for ulcerative colitis (c), and phase 3 trials for ulcerative colitis (d). DL, DerSimonian-Laird estimator.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Sedgwick P. What are the four phases of clinical research trials? BMJ 2014;348(1):g3727. - PubMed
    1. Robuck PR, Wurzelmann JI. Understanding the drug development process. Inflamm Bowel Dis 2005;11(Suppl 1):S13–6. - PubMed
    1. Harris MS, Wichary J, Zadnik M, et al. . Competition for clinical trials in inflammatory bowel diseases. Gastroenterology 2019;157(6):1457–61.e2. - PubMed
    1. Morgan P, Van Der Graaf PH, Arrowsmith J, et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving phase II survival. Drug Discov Today 2012;17(9-10):419–24. - PubMed
    1. Halpern SD, Karlawish JH, Berlin JA. The continuing unethical conduct of underpowered clinical trials. JAMA 2002;288(3):358–62. - PubMed

MeSH terms