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Steps Toward Harmonization for Clinical Development of Medicines in Pediatric Ulcerative Colitis—A Global Scientific Discussion, Part 1: Efficacy Endpoints and Disease Outcome Assessments

Sun, Haihao*; Vesely, Richard; Taminiau, Jan; Szitanyi, Peter; Papadopoulos, Elektra J.*; Isaac, Maria; Klein, Agnes; Uzu, Shinobu§; Griebel, Donna*; Mulberg, Andrew E.*

Journal of Pediatric Gastroenterology and Nutrition: June 2014 - Volume 58 - Issue 6 - p 679–683
doi: 10.1097/MPG.0000000000000306
Special Feature

Objectives: There is a pressing need for drug development in pediatric ulcerative colitis (UC). Lack of scientific consensus on efficacy endpoints and disease outcome assessments presents a hurdle for global drug development in pediatric UC. Scientists from 4 regulatory agencies convened an International Inflammatory Bowel Disease Working Group (i-IBD Working Group) to harmonize present thinking about various aspects of drug development in pediatric UC globally.

Methods: The i-IBD Working Group was convened in 2012 by scientists from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan. The members of this group considered reasons for differences in their acceptance of efficacy endpoints and disease activity indices used in pediatric UC, reviewed the available literature, and developed consensus opinions regarding approaches for evaluating outcomes in pediatric UC trials.

Results: There is lack of harmonization in using efficacy endpoint and outcome assessments including disease activity indices to assess clinical benefit in pediatric UC trials. Many disease activity indices have been developed, but their biometric properties, such as responsiveness, reliability, and validity, have not been properly validated. Biomarkers, such as fecal calprotectin and lactoferrin, are being investigated for their potential as noninvasive surrogate endpoints in UC.

Conclusions: Consensus on the efficacy endpoints, disease activity indices, and outcome assessments is needed for globalization of pediatric UC trials. The i-IBD Working Group offers several perspectives to facilitate harmonization across regions. The development of noninvasive biomarkers as reliable surrogate endpoints needs to be explored further.

*US 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, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993 (e-mail:

Received 5 September, 2013

Accepted 6 January, 2014

Members of the i-IBD Working Group include primary authors and Jessica Lee, MD; Anil Rajpal, MD; Robert Fiorentino, MD; Klaus Gottlieb, MD; Aisha Peterson Johnson, MD; Zana Handy Marks, MD; Wes Ishihara, BS; Kevin Bugin, MS, RAC of the Division of Gastroenterology and Inborn Error Product in the FDA; Kader Kourad; Catherine Njue; Cora Chen; Talia De Laurenti of Health Canada; Mutsuhiro Ikuma, MD; Yosuke Kobayashi; Keiko Ueda, MD; Hana Sugai; and Akiko Nitta of PMDA. Other members from the FDA are Jean Temeck, MD; William Rodriguez, MD, PhD; Robert M Nelson, MD, PhD; and Suzanne Malli of the Office of Pediatric Therapeutics.

The views expressed in this article are those of the authors and do not necessarily reflect official positions or policies of the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan.

The authors report no conflicts of interest.

© 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,