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Pediatric UC Drug Development: A GREAT Idea Now Needs a GRAND Conversation

Rosh, Joel R.*; Hyams, Jeffrey S.

Journal of Pediatric Gastroenterology and Nutrition: June 2014 - Volume 58 - Issue 6 - p 677–678
doi: 10.1097/MPG.0000000000000367
Invited Commentaries

*Pediatric Gastroenterology, Goryeb Children's Hospital, Atlantic Health, Morristown, NJ

Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford.

Address correspondence and reprint requests to Joel R. Rosh, MD, Director, Pediatric Gastroenterology, Goryeb Children's Hospital, Atlantic Health, 100 Madison Ave, Morristown, NJ 07962 (e-mail:

Received 25 February, 2014

Accepted 2 March, 2014

J.R.R. has received grant/research support from Abbvie, AstraZeneca, and Janssen Biotech; has been a consultant to/served on the advisory boards of Abbvie, Aptalis, Given Imaging, Janssen Biotech, Prometheus, and Soligenix; and has served on the speakers’ bureau of/received honoraria from Abbott Nutrition and Prometheus Laboratories. J.S.H. has been a consultant to Janssen Biotech, Abbvie, UCB, Soligenix, and TNI Biotech; has served on the advisory boards of Janssen Biotech and Abbvie; and has received research support/served on the speakers’ bureau of Janssen Biotech.

It is the long history of humankind that those who learned to collaborate and improvise most effectively have prevailed.

Charles Darwin

See “Steps Toward Harmonization for Clinical Development of Medicines in Pediatric UC—A Global Scientific Discussion, Part 1: Efficacy Endpoints and Disease Outcome Assessments” and “Steps Toward Harmonization for Clinical Development of Medicines in Pediatric UC—A Global Scientific Discussion, Part 2: Data Extrapolation, Trial Design, and Pharmacokinetics” by Mulberg et al on page 684.

Rapid advancement in the understanding of the biology of the inflammatory bowel diseases (IBDs) has occurred in the last 2 decades (1). These advancements have resulted in unbridled enthusiasm over the potential for treatments that can change the natural history of these diseases by healing the bowel and providing true and durable clinical remission. The approval process of treatments that can offer such powerful biological impact demands rigorous clinical trials with meaningful and well-validated endpoints. The simple demonstration of a short-term improvement in gastrointestinal symptoms is no longer an acceptable outcome for a disease whose duration may be measured in a lifetime (2).

In the present issue of the journal, 4 global regulatory agencies provide a consensus discussion of their goals when evaluating potential medications for pediatric ulcerative colitis (UC). Such cohesiveness is critical to moving the process forward because pediatric IBD drug development carries its own specific challenges. Although the impact of disease in this vulnerable population is great, the number of affected patients is not and historically pediatric IBD trials have languished behind trials in adults. Consequently, this regulatory framework is “must reading” for anyone working to improve the therapy for pediatric UC.

Now that the global regulatory agencies are coming together, it is essential that the discussion be broadened to include the other essential parties in the discussion: patients and their physicians. The Food and Drug Administration took important first steps to achieve such a goal by holding its Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics (GREAT) workshops in 2012 and 2013. By bringing together regulators, industry members, clinicians, academics, and patients along with their families, a Gathering Reports from All Needed Domains (GRAND) conversation has begun. Only such a GRAND conversation will deliver the needed specifics to enable the rapid and appropriate approval of new agents for pediatric IBD.

Looking at the specific challenges posed by pediatric UC, it is most notable that the condition meets criteria of an orphan disease (3). Having so few affected patients means a small pool of potential participants for clinical trials. This demographic, combined with a professional sense of paternalism and other factors, has prompted traditional IBD drug development to start with adult patients. With pediatric trials starting long after drug approval in adults, enrollment has been made difficult. Why would a parent or physician want to enter a sick child into a placebo-controlled trial of a medication that has already shown significant efficacy in adults? On the contrary, when a pediatric physician prescribes such a drug “off-label,” they invariably do so with little knowledge of appropriate pediatric dosing. Practice is “extrapolated” from adult experience, not evidence based. Clearly, change is needed. Pediatric pharmacokinetic studies need to occur early enough in the overall drug development process (ie, early phase III of adult trials) so that drug metabolism data in children are known and can facilitate the start of pediatric trials as adult efficacy becomes clear.

As we have learned over and over, efficacy can be extrapolated but pharmacokinetics and safety cannot. The global regulatory consensus statement lays a helpful framework, and the GRAND conversation is now needed for the details. Everyone agrees that both symptom relief and evidence of bowel healing are critically important short- and long-term outcomes. What is not agreed upon is who the best reporter for clinical improvement is: patients alone, physicians alone, or, most likely, a combination of the 2. Working with the involved parties seems to be the most efficacious plan for developing this end point. For example, could patient diaries be used to help fill the domains of the Pediatric Ulcerative Colitis Activity Index (4)? What is the best scoring system for endoscopic healing? Should gross or histological healing be used? What is the criterion standard for mucosal assessment? Recent pediatric data from the NIH-funded PROTECT study clearly show that consensus central reading of endoscopic mucosal appearance is superior to that of a single physician performing the colonoscopy (5). This same prospective, translational, multicenter study of newly diagnosed pediatric patients with UC also holds promise to define specific and useful biomarkers that may, someday, serve as meaningful noninvasive surrogate markers. Other specific pediatric IBD drug development issues are listed in Table 1.



The pediatric IBD community has made great strides in the last decade, and so much of this has been through multicenter collaboration. A GRAND conversation that is multidisciplinary is now needed to deliver what the global regulators state that they need.

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1. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009; 361:2066–2078.
2. Mahadevan U, Cucchiara S, Hyams JS, et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organisation: pregnancy and pediatrics. Am J Gastroenterol 2011; 106:214–222.
3. National Center for Advancing Translational Science, Office of Rare Diseases Research, National Institutes of Health Diseases. Accessed February 24, 2014.
4. Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology 2007; 133:423–432.
5. Walters T, Mack DR, Markowitz J, et al. Endoscopic assessment of mucosal activity in pediatric ulcerative colitis: are current methods reliable? Oral abstract presented at Digestive Disease Week, New Orleans, May 2014.
© 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,