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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1461-1469 |
| Number of pages | 9 |
| Journal | Gastroenterology |
| Volume | 143 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 2012 |
Keywords
- Clinical Trials
- Crohn's Disease
- Inflammatory Bowel Disease
- Trial Design
- Ulcerative Colitis
ASJC Scopus subject areas
- Gastroenterology
- Hepatology
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In: Gastroenterology, Vol. 143, No. 6, 12.2012, p. 1461-1469.
Research output: Contribution to journal › Review article › peer-review
TY - JOUR
T1 - Challenges to the design, execution, and analysis of randomized controlled trials for inflammatory bowel disease
AU - D'Haens, Geert
AU - Feagan, Brian
AU - Colombel, Jean Frédéric
AU - Sandborn, William J.
AU - Reinisch, Walter
AU - Rutgeerts, Paul
AU - Carbonnel, Frank
AU - Mary, Jean Yves
AU - Danese, Silvio
AU - Fedorak, Richard N.
AU - Hanauer, Steven
AU - Lémann, Marc
N1 - Funding Information: Conflicts of interest G. D'Haens has received consultancy fees from Abbott Laboratories, ActoGeniX, Centocor, Cosmo, enGene, Ferring Pharmaceuticals, GlaxoSmithKline, Janssen Biologics, Millennium Pharmaceuticals, MSD, Novo Nordisk, PDL BioPharma, Pfizer, SetPoint, Shire, Takeda, Teva, and UCB; research grants from Abbott Laboratories , Janssen Biologics , Given Imaging , MSD , Falk Pharma , and PhotoPill ; and speaking honoraria from Abbott Laboratories, Tillotts Pharma AG, Tramedico, Ferring Pharmaceuticals, MSD, UCB, Norgine, Shire, and Vifor Pharma. B. Feagan has received consultancy fees from Synta Pharmaceuticals, Millennium Pharmaceuticals, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Protein Design Labs, Isis Pharmaceuticals, Teva Pharmaceuticals, Santarus, Schering-Plough, Bristol-Myers Squibb, Celgene, CombinatoRx, UCB Pharma, Napo Pharma, Abbott Laboratories, Procter & Gamble, Osiris, Berlex, AstraZeneca, Gene Logic, Cerimon Pharmaceuticals, Tioga Pharmaceuticals, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging, Salix Pharmaceuticals, Ore Pharmaceuticals (previously Gene Logic), Novo Nordisk, GlaxoSmithKline, ActoGeniX, Prometheus Therapeutics and Diagnostics, Athersys, Alba Therapeutics, Axcan, Funxional Therapeutics, Gilead Sciences, Nektar, Pfizer, Shire, Wyeth, and Zealand Pharma; has received research grants from Merck , Otsuka , Millennium Pharmaceuticals , Tillotts Pharma AG , Abbott Laboratories , Protein Design Labs , Boehringer Ingelheim , Novartis , Centocor , Berlex , Synta Pharmaceuticals , Schering Canada , Elan/Biogen , UCB Pharma , Bristol-Myers Squibb , Procter & Gamble , Osiris , Genentech , CombinatoRx , ActoGeniX , and Wyeth ; has received speaking honoraria from UCB, Abbott Laboratories, and J&J/Janssen; and is a member of the scientific advisory board for Protein Design Labs, AstraZeneca, Elan/Biogen, Celltech, Synta Pharmaceuticals, Merck, Celgene, Novartis, Given Imaging, UCB Pharma, Salix Pharmaceuticals, Abbott Laboratories, Centocor, Pfizer, Axcan, Tillotts Pharma AG, and Prometheus Laboratories. J-F Colombel has served as a speaker, a consultant, and/or an advisory board member for Abbott Laboratories, ActoGeniX, Affilogic, Albireo Pharma, AstraZeneca, Bayer Schering Pharma, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix SL, ChemoCentryx, Centocor, Cosmo Technologies, Danone France, Elan Pharmaceuticals, Falk Pharma, Ferring Pharmaceuticals, Genentech, Giuliani SPA, Given Imaging, GlaxoSmithKline, Merck, Millennium Pharmaceuticals, Neovacs SA, Ocera Therapeutics, Otsuka, PDL BioPharma, Pfizer, RiboVacs Biotech, Schering-Plough, Shire Pharmaceuticals, Synta Pharmaceuticals, Takeda, Teva Pharmaceuticals, Therakos, UCB Pharma, and Wyeth; has received research grants from AstraZeneca , Ferring Pharmaceuticals , Schering-Plough , UCB Pharma , Lesaffre , Giuliani SPA , Danisco , Ocera Therapeutics , Danone , Roquette Pharma , Mapi-Naxis , and Disphar ; and holds stock/stock options in Intestinal Biotech Development. W. J. Sandborn has received consulting fees from Abbott Laboratories, ActoGeniX, AGI Therapeutics, Alba Therapeutics, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas, Athersys, Atlantic Healthcare, Aptalis, BioBalance, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine PharmaSciences, Eagle Pharmaceuticals, enGene, Eli Lilly, EnteroMedics, Exagen Diagnostics, Ferring Pharmaceuticals, Flexion Therapeutics, Funxional Therapeutics, Genzyme, Gilead Sciences, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood Pharmaceuticals, KaloBios Pharmaceuticals, Lexicon Pharmaceuticals, Lycera, Meda Pharmaceuticals, Merck Research Laboratories, Merck Serono, Millennium Pharmaceuticals, Nisshin Kyorin Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, PDL BioPharma, Pfizer, Procter & Gamble, Prometheus Laboratories, ProtAb, PurGenesis Technologies, Relypsa, Roche, Salient Pharmaceuticals, Salix Pharmaceuticals, Santarus, Schering-Plough, Shire Pharmaceuticals, Sigmoid Pharma, Sirtris Pharmaceuticals, SLA Pharma UK, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG, TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics, Warner Chilcott UK, and Wyeth; has received research grants from Abbott Laboratories , Bristol-Myers Squibb , Genentech , GlaxoSmithKline , Janssen , Millennium Pharmaceuticals , Novartis , Pfizer , Procter & Gamble , Shire Pharmaceuticals , and UCB Pharma ; has received payments for lectures/speaker bureaus from Abbott Laboratories, Bristol-Myers Squibb, and Janssen; and holds stock/stock options in EnteroMedics. W. Reinisch has served as a speaker, a consultant, and/or an advisory board member for Abbott Laboratories, Aesca, Amgen, AstraZeneca, Biogen Idec, Bristol-Myers Squibb, Cellerix, ChemoCentryx, Centocor, Danone Austria, Elan, Ferring Pharmaceuticals, Genentech, Lipid Therapeutics, Millennium Pharmaceuticals, Mitsubishi Tanabe Pharma, MSD, Novartis, Ocera, Otsuka, PDL BioPharma, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Schering-Plough, Shire, Takeda, Therakos, TiGenix, UCB, Vifor, Yakult Austria, and 4SC. P. Rutgeerts received consulting fees from Millennium/Takeda, Genentech/Hoffman-La Roche, Neovacs, Merck/Serono, Bristol-Myers Squibb, Robarts, Tillotts Pharma AG, Pfizer, and Falk Pharma and has served as a speaker and a consultant and received payments for lectures/research support from Centocor, Merck, UCB, and Abbott Laboratories. F. Carbonnel discloses no conflicts. J-Y Mary discloses no conflicts. S. Danese has received consulting fees from Schering-Plough, AstraZeneca, Abbott Laboratories, Novo Nordisk, and Millennium/Takeda and lecture fees, including fees for service on speaker bureaus, from UCB Pharma, Ferring Pharmaceuticals, Vifor, and Merck Sharp & Dohme. R. N. Fedorak has served as an advisory board member for Abbott Laboratories, Ferring Pharmaceuticals, Merck, Shire, and VSL#3; is a recipient of clinical/basic research grants from Abbott Laboratories , Alba , Axcan , Bristol-Myers Squibb , Centocor , Ferring Pharmaceuticals , GlaxoSmithKline , Genentech , Merck , Millennium Pharmaceuticals , Novartis , Otsuka , Procter & Gamble , Roche , and VSL#3 ; and is owner/shareholder of Metabolomic Technologies.
PY - 2012/12
Y1 - 2012/12
N2 - 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.
AB - 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.
KW - Clinical Trials
KW - Crohn's Disease
KW - Inflammatory Bowel Disease
KW - Trial Design
KW - Ulcerative Colitis
UR - http://www.scopus.com/inward/record.url?scp=84869846163&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84869846163&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2012.09.031
DO - 10.1053/j.gastro.2012.09.031
M3 - Review article
C2 - 23000597
AN - SCOPUS:84869846163
SN - 0016-5085
VL - 143
SP - 1461
EP - 1469
JO - Gastroenterology
JF - Gastroenterology
IS - 6
ER -