Abstract
Background & Aims: There is no consensus on the best way to integrate biomarkers into inflammatory bowel disease (IBD) research and clinical practice. The International Organization for the Study of Inflammatory Bowel Disease aimed to outline biomarker definitions, categories, and operating properties required for their use in registration trials and clinical practice. Using fecal calprotectin as an example, we provide a framework for biomarker development and validation in patients with IBD. Methods: We reviewed international society guidelines, regulatory agency guidance documents, and standardized reporting guidelines for biomarkers, in combination with publications on fecal calprotectin levels in patients with IBD. We assessed the validity of fecal calprotectin to serve as a surrogate biomarker of IBD activity and outlined a framework for further validation and development of biomarkers. Results: No endpoints have been fully validated as surrogates of risk of disease complications; mucosal healing is the most valid endpoint used to determine risk of disease complications. Fecal level of calprotectin has not been validated as a biomarker for IBD activity because of lack of technical and clinical reliability, assessment of performance when used as a replacement for endoscopy, and assessment of responsiveness to changes in disease states. The level of fecal calprotectin can be used only as a prognostic factor for disease recurrence in patients in remission after medical or surgical treatment. Conclusions: We reviewed guidelines, regulatory documents, and publications to identify properties required for the development of biomarkers of IBD activity and areas in need of clarification from regulatory agencies and societies. We propose a path forward for research of biomarkers for IBD.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1032-1043.e1 |
| Journal | Gastroenterology |
| Volume | 157 |
| Issue number | 4 |
| DOIs | |
| State | Published - Oct 2019 |
Funding
Author contributions: Parambir S. Dulai: guarantor of article, review of literature, drafting of the manuscript. All authors: critical review and editing of the manuscript, final approval of the manuscript. Parambir S. Dulai is supported by a Research Scholar Award from the American Gastroenterology Association. Author contributions: Parambir S. Dulai: guarantor of article, review of literature, drafting of the manuscript. All authors: critical review and editing of the manuscript, final approval of the manuscript. Parambir S. Dulai is supported by a Research Scholar Award from the American Gastroenterology Association. Conflicts of interest These authors disclose the following: Parambir S. Dulai has received research support from AbbVie, Pfizer, Janssen, Takeda, Bulhmman, Alpco, and Polymedco; consulting or honoraria from Janssen and Takeda; and travel support from Janssen and Takeda. Laurent Peyrin-Biroulet has received honoraria from Merck, AbbVie, Janssen, Genentech, Ferring, Tillots, Vifor, Pharmacosmos, Celltrion, Takeda, Biogaran, Boerhinger Ingelheim, Lilly, Pfizer, Index Pharmaceuticals, Amgen, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma, Sterna, Nestlé, Enterome, Mylan, and HAC-Pharma. Silvio Danese reports consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring Pharmaceuticals, Gilead, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB, and Vifor. Bruce E. Sands has received consulting fees and research grants from AbbVie, Pfizer, Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda and has received consulting fees from 4D Pharma, Boehringer Ingelheim, Arena Pharmaceuticals, Forward Pharma, Gilead, Immune Pharmaceuticals, Lilly, Otsuka, Synergy Pharmaceuticals, Theravance, Receptos, TiGenix, TopiVert Pharma, MedImmune, Allergan, UCB Pharma, EnGene, Target PharmaSolutions, Lycera, Lyndra, Vivelix Pharmaceuticals, and Oppilan Pharma. Axel Dignass served as a consultant for AbbVie, Celgene, MSD, Roche, Sandoz/Hexal, Pfizer, Takeda, Tillots, Janssen, and Vifor; received payment for development of educational presentations from Ferring and Tillots; received speaker fees from Falk Foundation, AbbVie, Ferring, Pfizer, Janssen, MSD, Vifor, Celgene, Tillots and Takeda; received manuscript fees from Thieme and Wiley; and received research grants from Institut für Gemeinwohl, Deutsche Morbus Crohn und Colitis ulcerosa Vereinigung and Stiftung Leben mit Krebs. Dan Turner received consultation fees, research grants, royalties, or honoraria from Janssen, Pfizer, Hospital for Sick Children, Ferring, AstraZeneca, AbbVie, Takeda, Boehringer Ingelheim, Biogen, Atlantic Health, Shire, Celgene, and Lilly. Gerassimos Mantzaris is an advisory board member for AbbVie, Astellas, Celgene, Danone, Ferirng, Genesis, Hospira, Janssen, Millennium Pharmaceuticals, MSD, Otsuka, Pharmacosmos, Pfizer, Sandoz, Takeda, and UCB; is a speaker for AbbVie, Angelini, Astellas, Danone, Falk Pharma, Ferring, Galenica, Hospira, Janssen, MSD, Omega Pharma, and Takeda; is a consultant for MSD and Takeda; and provides research support for AbbVie, Galenica, Genesis, Menarini Group, MSD, and Pharmathen. Walter Reinisch has served as a speaker for Abbott Laboratories, AbbVie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, and Yakult; as a consultant for Abbott Laboratories, AbbVie, Aesca, Amgen, AM Pharma, AOP Orphan, Arena Pharmaceuticals, Astellas, AstraZeneca, Avaxia, Roland Berger, Bioclinica, Biogen IDEC, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, Elan, Eli Lilly, Ernest & Young, Falk Pharma, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, Setpointmedical, Sigmoid, Takeda, Therakos, Tigenix, UCB, Vifor, Zealand, Zyngenia, and 4SC; as an advisory board member for Abbott Laboratories, AbbVie, Aesca, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Biogen IDEC, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, SetPoint Medical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia, and 4SC; and has received research funding from Abbott Laboratories, AbbVie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnsotik, and MSD. William J. Sandborn reports research grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, AbbVie, Janssen, Takeda, Lilly, and Celgene/Receptos; consulting fees from AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Avexegen Therapeutics, BeiGene, Boehringer Ingelheim, Celgene, Celltrion, Conatus, Cosmo, Escalier Biosciences, Ferring, Forbion, Genentech, Gilead Sciences, Gossamer Bio, Incyte, Janssen, Kyowa Kirin Pharmaceutical Research, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pfizer, Precision IBD, Progenity, Prometheus Laboratories, Reistone, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust, HART), Series Therapeutics, Shire, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tigenix, Tillotts Pharma, UCB Pharma, Ventyx Biosciences, Vimalan Biosciences, and Vivelix Pharmaceuticals; and stock or stock options from BeiGene, Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Precision IBD, Progenity, Ritter Pharmaceuticals, Ventyx Biosciences, Vimalan Biosciences; his spouse has relationships with Opthotech (consultant, stock options), Progenity (consultant, stock), Oppilan Pharma (employee, stock options), Escalier Biosciences (employee, stock options), Precision IBD (employee, stock options), Ventyx Biosciences (employee, stock options), and Vimalan Biosciences (employee, stock options). The remaining authors disclose no conflicts.
Keywords
- Crohn's Disease
- Outcome
- Response to Treatment
- Ulcerative Colitis
ASJC Scopus subject areas
- Hepatology
- Gastroenterology