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Pediatric Crohn Disease Clinical Outcome Assessments and Biomarkers: Current State and Path Forward for Global Collaboration

Sun, Haihao*; Vesely, Richard; Lee, Kerry Jo*; Klein, Agnes; Ikima, Mutsuhiro§; Mulberg, Andrew E.*

Journal of Pediatric Gastroenterology and Nutrition: March 2017 - Volume 64 - Issue 3 - p 368–372
doi: 10.1097/MPG.0000000000001284
Original Articles: Gastroenterology: Inflammatory Bowel Disease

Objective: There is a pressing need for drug development in pediatric Crohn disease (CD). Our aim was to provide strategic approaches toward harmonization of current thinking about clinical outcome assessments (COAs) and biomarkers to facilitate drug development in pediatric CD.

Methods: Scientists from the United States Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan had monthly teleconferences from January 2014 through May 2015. A literature review was conducted to assess the measurement properties of all existing COA tools and to evaluate the current landscape of biomarkers used in pediatric CD. Based on the findings of literature review, we reached the consensus on the strategic approaches for evaluating outcomes in pediatric CD trials.

Results: The pediatric Crohn's Disease Activity Index, Crohn's Disease Activity Index, and Harvey-Bradshaw's index were used in pediatric CD clinical studies. But they lack adequate measurement properties (validity, reliability, and ability to detect change of the treatment) that are required to support approval of products intended to treat pediatric CD. Biomarkers (ie, fecal lactoferrin, osteoprotegerin, and calprotectin) have shown some promise for their potential as noninvasive surrogate endpoints in CD.

Conclusions: Lack of well-defined and reliable COAs presents a hurdle for global drug development in pediatric CD. It is essential to develop well-defined and reliable COAs that can measure meaningful clinical benefit for patients in terms of how they feel, function, and survive. Development of noninvasive biomarkers as reliable surrogate endpoints needs to be further explored.

*United States Food and Drug Administration, Silver Spring, MD

European Medicines Agency, London, UK

Health Canada, Ottawa, Ontario, Canada

§Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.

Address correspondence and reprint requests to Andrew E. Mulberg, MD, FAAP, Division of Gastroenterology and Inborn Errors Products, OND/CDER, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993 (e-mail:

Received 15 January, 2016

Accepted 26 May, 2016

Views expressed in this manuscript are those of the authors and do not necessarily reflect official positions or policies of the FDA, EMA, Health Canada and PMDA. This work is not funded by any organizations or grants.

This work is neither supported by pharmaceutical industry nor supported by National Institutes of Health, Wellcome Trust, and Howard Hughes Medical Institute.

Members of the i-IBD working group include Primary Authors and Donna Griebel, MD; Jessica J. Lee, MD; Anil Rajpal, MD; Juli Tomaino, MD; Aisha Peterson Johnson, MD; Wes Ishihara, BS and Kevin Bugin, MS, RAC of the Division of Gastroenterology and Inborn Error Product in the FDA; Joachim Musaus; Peter Szitanyi; Frank Petavy and Jan Taminiau of EMA; Kader Kourad, MD, PhD; Catherine Njue PhD; Cora Chen, MD PhD; Talia De Laurentis of Health Canada; Yosuke Kobayashi; Shinobu Uzu; Yumiko Nomura; Kazuishi Sekino, MS; Rieko Yamazaki; Junichi Asano, PhD of PMDA; Other members from the FDA: E. Papadopoulos, MD, MPH (Clinical Outcome Assessments Staff); Renan A. Bonnel, Pharm D. MPH; Jean Temeck, MD; Suzanne Malli of the Office of Pediatric Therapeutics; Yeh-Fong Chen, PhD; and Insook Kim, PhD.

The authors report no conflicts of interest.

© 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,