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Steps Toward Harmonization for Clinical Development of Medicines in Pediatric Ulcerative Colitis—A Global Scientific Discussion, Part 2: Data Extrapolation, Trial Design, and Pharmacokinetics

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

Journal of Pediatric Gastroenterology and Nutrition: June 2014 - Volume 58 - Issue 6 - p 684–688
doi: 10.1097/MPG.0000000000000322
Special Feature

Objectives: To facilitate global drug development, the International Pediatric Inflammatory Bowel Disease Working Group (i-IBD Working Group) discussed data extrapolation, trial design, and pharmacokinetic (PK) considerations for drugs intended to treat pediatric ulcerative colitis (UC), and considered possible approaches toward harmonized drug development.

Methods: Representatives from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan convened monthly to explore existing regulatory approaches, reviewed the results of a literature search, and provided perspectives on pediatric UC drug development based on the available medical literature.

Results: Although pediatric UC, when compared with UC in adults, has a similar disease progression and response to intervention, the similarity of the exposure-response relation has not been adequately established. Consequently, clinical endpoints should be selected to optimally assess efficacy in children. The inclusion of a placebo control in pediatric trials to assure assay sensitivity may be appropriate under limited circumstances. In clinical studies, although the drug under investigation could provide possible direct benefit, placebo treatment should present no more than a minor increase over minimal risk to children with UC.

Conclusions: Partial extrapolation of efficacy from informative adult studies may be appropriate. Placebo-controlled efficacy trials are scientifically and ethically appropriate for pediatric UC given appropriate patient selection and the use of early escape. Clinical studies in pediatric UC may include initial dose-finding studies and exposure-response modeling followed by an efficacy and safety study to further explore the exposure-response relation.

*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 Ave, Silver Spring, MD 20993 (e-mail:

Received 5 September, 2013

Accepted 22 January, 2014

Members of the i-IBD Working Group include primary authors and Jessica J. Lee, MD; Anil Rajpal, MD; Robert Fiorentino, MD; Klaus Gottlieb, MD; Aisha Peterson Johnson, MD; Zana Handy Marks, MD; Wes Ishihara, BS, and 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; Akiko Nitta of PMDA; other members from the FDA—E. Papadopoulos, MD, MPH (Study Endpoints and Labeling Development), and Jean Temeck, MD; William Rodriguez, MD, PhD; 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,