ORIGINAL ARTICLE: GASTROENTEROLOGY: INFLAMMATORY BOWEL DISEASE
Pediatric Crohn Disease Clinical Outcome Assessments
and Biomarkers: Current State and Path Forward for
Global Collaboration

Haihao Sun, yRichard Vesely, Kerry Jo Lee, zAgnes Klein, §Mutsuhiro Ikima, Andrew E. Mulberg,
on behalf of the International Inflammatory Bowel Disease (i-IBD) Working Group
ABSTRACT
Downloaded from https://journals.lww.com/jpgn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3Gamkn0m7hy6Mhb8DYgpUeqLgT2Ue6dY4JJBnXyUM1N4= on 08/26/2018
Objective: There is a pressing need for drug development in pediatric Crohn
disease (CD). Our aim was to provide strategic approaches toward harmo-
nization 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.
Key Words: biomarkers, clinical outcome assessments, endpoints,
pediatric Crohn disease, surrogate endpoint
(JPGN 2017;64: 368–372)
Received January 15, 2016; accepted May 26, 2016.
From the United States Food and Drug Administration, Silver Spring, MD,
the yEuropean Medicines Agency, London, UK, the zHealth Canada,
Ottawa, Ontario, Canada, and the §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: Andrew.Mulberg@fda.hhs.gov).
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;
368
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
What Is Known
 The Pediatric Crohn’s Disease Activity Index was used
as the primary endpoint to support the approval of
Remicade and Humira.
 Biomarkers, such as fecal lactoferrin, osteoprotegerin,
and calprotectin, have shown some promise for their
potential as noninvasive surrogate endpoints in
Crohn Disease.
What Is New
 The Pediatric Crohn’s Disease Activity Index lacks
adequate measurement properties for use as a primary
endpoint for phase III trials intended to support
approval of products for the indication of pediatric
Crohn Disease. It is essential to develop well-defined
and reliable clinical outcome assessments that can
measure meaningful clinical benefit for patients in
terms of how they feel, function, and survive.
 The global consensus is reached that development
of noninvasive biomarkers as reliable surrogate
endpoints needs to be further explored.
A critical need for additional therapies for pediatric Crohn
disease (CD) exists globally. CD is a chronic, recurrent
disease characterized by patchy, transmural inflammation involving
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.
Copyright # 2016 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0000000000001284
JPGN  Volume 64, Number 3, March 2017
JPGN  Volume 64, Number 3, March 2017 Pediatric Crohn Disease Clinical Outcome Assessments and Biomarkers
any segment of the gastrointestinal tract from mouth to the anus (1).
The annual overall incidence of CD was registered at 20.2, 12.7, and
5 per 100,000 person-years in North America, Europe, and Asia,
respectively (2). Although CD incidence rates in the general
population seem to have stabilized in most industrialized countries
since 1980s, it shows an increase in the childhood-onset CD (2).
Currently, 2 products, Remicade (Janssen Biotech, Inc., Horsham,
PA) and Humira (AbbVie Inc., North Chicago, IL), have been
approved by the United States Food and Drug Administration
(FDA), European Medicines Agency (EMA), Health Canada,
and the Pharmaceuticals and Medical Devices Agency of Japan,
along with 2 bio-similar products to Remicade (infliximab), Inflec-
tra (Hospira UK Limited) and Remsima (Celltrion Healthcare
Hungary Kft. Budapest, Hungary), approved only by the EMA,
for a pediatric CD indication. Other drugs in various classes are
used off-label for this indication.
A strategic approach toward the global regulatory harmoni-
zation can facilitate future pediatric CD trials and drug develop-
ment. The International Inflammatory Bowel Disease (i-IBD)
Working Group (WG), which consists of multidisciplinary scien-
tists from the FDA, EMA, Health Canada, and the Pharmaceuticals
and Medical Devices Agency of Japan, is an international collab-
oration developed to advance scientific knowledge on efficacy
endpoints, trial design, data extrapolation, and pharmacokinetics
(PK) supporting drug development in pediatric IBD including
ulcerative colitis (UC) and CD. The i-IBD WG seeks to improve
the likelihood that clinical development of safe and effective
therapies for the treatment of IBD is successful. The WG intends
to focus on the immediate need for consensus on efficacy endpoints,
biomarkers, trial design, and how to use extrapolation and PK data
in pediatric IBD among regulatory authorities as well as in the
scientific and medical community. We have previously reported the
scientific discussions of pediatric UC (3,4). This article summarizes
scientific discussions of pediatric CD among members of the i-IBD
WG and provides possible approaches to consider for working
toward harmonization of current thinking about drug development
in pediatric CD. The views of the i-IBD WG expressed in this article
are only individual personal opinions or suggestions for drug
development in pediatric CD and do not represent regulatory
consensus or official guidelines of the individual agencies.
Due to the limitation set by the journal in word count, part 1
of this article, presented here, focuses only on the discussion of
clinical outcome assessments, biomarkers, and surrogate endpoints
in pediatric CD trials. Part 2 of the article, related to discussions of
data extrapolation, trial designs, and PK studies, will be reported in
a separate paper.
METHODS
The members of the i-IBD WG convened monthly via
teleconferences from January 2014 through June 2015. We dis-
cussed the current positions and practices at each agency based on
our evaluations of applications received for drugs intended to treat
pediatric CD. All attempts were made to understand individual
approaches of agencies and opinions of experts. We also brought up
the issues that need to be addressed with an effort to formulate the
suggestions for the path forward. Among many other issues, we
identified clinical outcome assessments and biomarkers as one of
the priorities to be discussed. Clinical outcome assessment (COA) is
any assessment that may be influenced by human choices, judg-
ment, or motivation and may support, either directly or indirectly,
evidence of treatment benefit (5). COAs depend on the implementa-
tion, interpretation, and reporting by a patient, a clinician, or an
observer (5). For these reasons, a well-defined and reliable COA is
critical to document the full spectrum of signs and symptoms
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important to patients and to assess treatment benefit in patients
in pediatric CD trials. Biomarkers are measurable characteristics
that reflect physiological, pharmacological, or disease processes in
animals or humans. Changes in biomarkers following treatment
may reflect the clinical response to the product and may predict or
identify safety problems related to a drug candidate or reveal a
pharmacological activity expected to predict an eventual benefit
from treatment (6). Surrogate endpoint is a biomarker that is
intended to substitute for a clinical endpoint and is expected to
predict clinical benefit (or harm, or lack of benefit or harm) based on
epidemiological, therapeutic, pathophysiological, or other scientific
evidence. ‘‘Surrogate endpoints’’ are a subset of pharmacodynamic
biomarkers; while all surrogate endpoints can be considered bio-
markers, it is likely that only a few biomarkers will be appropriate
for use as surrogate endpoints (6).
As a result, clinical outcome assessment and biomarker
subgroups from within the overall i-IBD WG were formed to focus
on the key topics in each specific area. Each group conducted a
literature review relevant to the specific area and subsequently
presented the results of the literature review and analysis to the
overall i-IBD WG monthly teleconference for discussion. The
suggestions provided in this article are based, wherever possible,
on the evidence published in the medical literature.
A literature review was conducted to assess COAs, bio-
markers, and surrogate endpoints that have been used in pediatric
CD trials. The electronic database, PubMed/Medline, EMBASE,
and Web of Science were searched. The phrase ‘‘pediatric Crohn’s
disease/AND (disease activity indices OR endpoints)’’ was used
for the literature search on the topic of pediatric endpoints and
clinical outcome assessments. The phrase ‘‘inflammatory bowel
disease/AND (disease activity indices or instrument) AND
(biomarkers or surrogate endpoints)’’ was used for the literature
search for biomarkers. No language and time restrictions were
applied during the search. The last search was conducted on
May 31, 2015. The literature were reviewed and discussed among
all 5 to 6 members within each subgroup.
RESULTS
Current State of Clinical Outcome Assessments
Used in Pediatric Crohn Disease Trials
Five clinical outcome assessment tools, designed specifically
for the pediatric CD assessment were identified in the literature
search. They included the Pediatric Crohn’s Disease Activity Index
(PCDAI), abbreviated PCDAI, short PCDAI, modified PCDAI, and
weighted PCDAI. Although designed for adult patients, the Crohn’s
Disease Activity Index (CDAI) and partial Harvey Bradshaw index
(HBI) were also adapted for use in a few clinical trials with pediatric
patients with CD (7,8). The PCDAI was used as the primary
endpoint to support the approval of Remicade (infliximab) and
Humira (adalimumab) for the indication of pediatric CD in USA,
European Union, Canada, and Japan.
The measurement properties of the clinical outcome assess-
ment tools include the content validity, reliability, and ability to
detect changes. In general, clinical outcome assessment tools
should be reliable, valid, and able to detect clinically meaningful
change in the concept of interest based on the principles described
in the ‘‘Guidance for Industry Patient-Reported Outcome
Measures: Use in Medical Product Development to Support Label-
ing Claims’’ (9). In addition to this, any measurement used for
outcome assessment should be standardized. Sun et al (10) at the US
FDA analyzed the measurement properties of all existing COA
tools for pediatric CD in literature and published registration trials
of approved drugs for pediatric CD based on criteria described in
369
Sun et al
FDA guidance for patient-reported outcome (PRO) development.
The CDAI, HBI, PCDAI, and its derivatives (abbreviated, short,
modified, and weighted PCDAIs) were reviewed. Common issues
in measurement properties of COA tools included absence of direct
patient or caregivers’ input to generate the items measuring signs
and symptoms, absence of evidence demonstrating correlation with
clinically relevant inflammation observed with endoscopic
measures, and lack of standardization in measurement, age-appro-
priate interviewer script and response rating criteria for the phys-
ician interviewer (10).
Particularly, the PCDAI was developed in 1990 by a group of
30 pediatric gastroenterologists as a research tool to facilitate
standardization of disease activity assessment in the course of
clinical trials (11). Although the PCDAI has become the standard
measurement for disease activity in pediatric CD during the last 20
years, a few variations of PCDAI have been developed to address
the limitations (eg, poor feasibility, item redundancy, etc) that the
original PCDAI revealed in the course of research and clinical trials
(12–16). Hyams et al (17) studied the relation of common labora-
tory parameters to the PCDAI in 133 children with CD. They found
that no single laboratory test in PCDAI was adequate to reflect
disease activity in all 133 pediatric patients studied (17). Hyams
et al (18) also conducted a longitudinal assessment to develop cut
scores reflecting disease activities as determined by physician
global assessment and to evaluate the responsiveness of the PCDAI
to changes in patient condition after therapeutic intervention. They
concluded in this study that the PCDAI could reflect disease activity
as assessed by physician global assessment and a DPCDAI score of
12.5 points following therapeutic intervention could reflect a
clinically significant response (18). Several reviews have compared
the strength and weakness of various disease activity index used in
pediatric CD trials (19,20). The PCDAI was used as the primary
endpoint to support the approval of infliximab and adalimumab.
The current regulatory landscape continues to foster identification
of improved outcome measures of pediatric IBD disease activity.
The PCDAI, however, lacks adequate content validity thus
presents a concern (10). The PCDAI performance record in clinical
trials is not clear, although various thresholds have been established
in the past using the data from registry studies. The available data in
the literature have not adequately and consistently demonstrated the
PCDAI’s ability to detect a moderate treatment difference in the
clinical trials and test-retest reliability (10). Furthermore, growth
parameters including weight gain/loss and height/height velocity
account for 20% of the PCDAI score, while Turner and colleagues
identified that height, hematocrit, and abdominal examination were
redundant and insensitive to the change of disease activities (16,21).
It should also be noted, although inconsistent with these reports, that
abdominal exams and hematocrit are important to clinicians in the
patient care setting. It is not uncommon for children to have marked
anemia in the absence of any signs or symptoms secondary to the
effect of proinflammatory cytokines on red blood cell production
(10). Although height may not be responsive in a short-term trial, it
is relevant in a 1-year maintenance trial for children who still have
growth potential. The potential for changes in hematocrit together
with changes in albumin to reflect clinically significant changes
may be considered potentially relevant in the construct of a primary
endpoint model. Understanding the importance of clinically
relevant biomarkers, that is, hematocrit and albumin, in construct-
ing an endpoint model that reflects the clinical condition may yield
clarity from a clinical and regulatory perspective (10).
In addition, although remission and response has been
characterized in children with CD using PCDAI, evolving manage-
ment of CD is now focusing on complications of CD related to
structural damage and mucosal injury and the predominating signs
and symptoms indicating the presence of disease (10,22,23). Both
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JPGN  Volume 64, Number 3, March 2017
signs and symptoms of disease and effects on mucosal injury could
be relevant targets for novel therapies. Mucosal healing has been
increasingly recognized as an important outcome of medical treat-
ment as it is associated with longer remission periods and reduced
risk for surgeries and hospitalization (24–26). Thus, endoscopic or
radiological mucosal and histological examination may need to be
considered as 1 outcome measurement. Given the nature of this
disease, it would be helpful to explore the relation of intestinal
damage as demonstrated from imaging studies to mucosal inflam-
mation observed during endoscopy and histologically in pediatric
patients with CD (10). Meanwhile, we acknowledge that there are
many challenges to assessing mucosal healing in children with CD:
reluctance to repeat endoscopies, inability to pass the scope to the
disease site, need for standardization of endoscopic interpretation,
and others (10). We also acknowledge that interobserver variability
in endoscopic scoring may exist during endoscopic assessments.
Primarily, the mucosal healing definition remains elusive to the
adult and pediatric IBD communities and to regulatory agencies.
For these reasons, CDAI, HBI, and the 5 versions of the
PCDAI lack adequate measurement properties for use as a primary
endpoint for phase III trials intended to support approval of products
intended to treat pediatric CD (10). A well-defined, reliable,
sensitive, and globally recognized PRO that measures signs and
symptoms indicating the presence of disease in children with CD,
and that can be used in conjunction with endoscopic endpoints
and/or serum biomarkers is sorely needed to facilitate pediatric drug
development (10). To date, collaborative efforts to identify these
key signs and symptoms and correlate them with response and
remission are underway (27).
Review of Noninvasive Biomarkers
The literature search yielded 32 articles, 2 of which cited
pediatric data. All 32 articles were reviewed and discussed among
the members in the biomarker subgroup. Candidates include serum
and stool markers, and, uniquely in CD, magnetic resonance
enterography (MRE). Newer modalities involving mucosal markers
from the microbiome or RNAseq may also be useful in the future
and are further described below. At this time, none of these
biomarkers can replace current standards utilized in clinical trials
of biopsy or disease activity indices used to measure improvement
in endpoints or disease progression of CD, although some are closer
than others, particularly fecal biomarkers.
Serum biomarkers discussed included C-reactive protein
(CRP) as a measure of inflammation. CRP has yielded mixed
results. In a recent analysis of data involving a subset of patients
from the Study of Biologic and Immunomodulator Naive Patients in
Chrohn Disease trial, of the 118 who had CRP elevation and
mucosal ulcerations, 37% had a normalization of both at 26 weeks
with treatment, which is lower than those that showed mucosal
healing altogether (48%) (28). The FDA’s internal analysis of 3968
patients in clinical trials looking at the relation between CDAI and
CRP found a weak correlation with positive predictive value of CRP
in determining remission based on CDAI of 28.4% and negative
predictive value for CRP of 61.2% (unpublished data). Gottlieb et al
(29) reviewed recent CD trials evaluating TNFa antagonists which
CRP subgroup data were reanalyzed. In these study-level data, it
was not convincing that the level of CRP can discriminate between
patients who responded to biologics or went into sustained remis-
sion from those who did not. Further work may include an analysis
of patient level data using CRP and other biomarkers, alone or
in combination with different cutoff values. Deficiencies of
various vitamins and minerals were also discussed given that CD
affects absorption at multiple places throughout the small intestine.
Levels of vitamins such as vitamin D, and nutrients, such as zinc and
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JPGN  Volume 64, Number 3, March 2017 Pediatric Crohn Disease Clinical Outcome Assessments and Biomarkers
iron, while identified as abnormal in inflammatory bowel disease,
still await further structured studies to determine change with
disease activity (30).
Fecal markers appear more promising. Currently fecal cal-
protectin, lactoferrin, and osteoprotegerin (OPG) are all under
investigation. The merits of lactoferrin correlation to clinical dis-
ease activity indices and serum biomarkers (31) and calprotectin
correlation to mucosal healing (32) were discussed in the previous i-
IBD paper on pediatric UC endpoints (4). A pediatric trial in 37
children with IBD (20 with CD) found higher spot calprotectin
levels in children with IBD relative to control patients. In addition,
it found those with higher disease activity had higher calprotectin
levels (33). Another pediatric trial in 56 children with suspected
IBD (UC and CD) found that those with intestinal inflammation
from IBD had significantly elevated fecal lactoferrin levels as
compared to control patients who did not have IBD. This observa-
tional study also demonstrated that patients with IBD with elevated
fecal lactoferrin and normal CRP levels had active intestinal
inflammation on colonoscopy (34). OPG has recently been shown
in a pediatric study to be elevated in mucosal, fecal, and serum
levels of children with CD as compared to controls. These elevated
levels in serum and fecal OPG dropped significantly after treatment
with enteral therapy (35).
Newer modalities that may eventually serve as biomarkers
for disease activity include microbiome studies that appear to be
able to detect IBD (36) as well as RNAseq studies that show
miRNAs that are specific to IBD in colonic mucosal tissue (37).
Much more work, however, remains to be done to validate these
modalities with respect to disease activity. Genetic markers were
discussed, however, while useful to diagnose disease or estimate the
likelihood of disease occurrence, are not optimal as biomarkers to
indicate the course of the disease state (38).
The use of MRE may elucidate the nature of disease in all
affected areas of the intestine in CD. To date, there are a few small
studies that have sought to validate MRE against biopsy, but none
conducted in pediatric patients. One recent study looked at 48
patients comparing baseline ileocolonoscopy to MRE at 2 time
points on treatment in which healing was identified as the disap-
pearance of ulcers in endoscopic evaluation. Additional analyses in
the study established the accuracy of MRE in determining endo-
scopic remission (a Crohn’s Disease Endoscopic Index of Severity
[CDEIS] score <3.5) and change in severity based on consideration
of all segments. MRE determined ulcer healing with 90% accuracy
and endoscopic remission with 83% accuracy (39). Meanwhile, we
acknowledge that there are some challenges to perform MRE in
children with CD. For instance, many young children cannot
undergo MRE because they are not able to drink the contrast or
stay still enough for optimal images (10).
DISCUSSION
Lack of well-defined and reliable clinical outcome assess-
ments presents a hurdle for global drug development in pediatric
CD. The goals of clinical treatment for pediatric CD are to improve
how a child with CD feels and functions (eg, reduction of diarrhea,
bleeding, and abdominal pain, which would be expected to increase
school attendance and function within the family and with friends)
and to prevent complications (strictures, abscess, growth failure,
and colon cancer). With that in mind, it is essential to develop well-
defined and reliable COAs that can measure meaningful clinical
benefit for patients in terms of how they feel and function to
facilitate drug development. Before we use the application of PROs
for studies in pediatric CD, these clinical outcome assessments
should be developed and validated against other outcome measures,
including the criterion standard if identified by the community in
agreement with the regulatory agencies.
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The beneficial impact of a drug on the complications of the
disease seems directly linked to its impact on improvement of signs
of mucosal inflammation (24–26,40). At this time, the best meth-
odology for directly documenting this impact is visualization of the
mucosa via endoscopy. It would be helpful to maximize endoscopic
evaluations and encourage patients with CD to undergo baseline
and follow-up endoscopy in clinical trials. Currently, evaluation of
mucosal inflammation has been requested by some regulatory
authorities in agreed upon pediatric study plans for new medicines.
To reduce the interobserver variability in endoscopic scoring, the
central reading is recommended in the pediatric CD trials.
Additional points considered by the i-IBD WG included whether
biopsy indicating mucosal improvement always needs to be per-
formed. In CD, many of the changes may occur in areas that we are
unable to biopsy; therefore, other methods of assessment may
be considered.
The WG also discussed the lack of utility of using growth
indices as short-term measures of disease activity. Growth is
difficult to measure, requires standardization of methodology,
and the FDA has opined on these issues in other chronic pediatric
diseases related to the use of corticosteroids for management (41). It
is accepted that well-conducted growth assessments represent one
of the most sensitive indicators of systemic effects of a disease and
potentially drug therapy. Effects on growth should be interpreted as
a pharmacodynamic effect of a disease process and may well
represent an outcome measure in a 1-year maintenance trial for
children who still may manifest growth potential. Utility in demon-
strating growth changes in a short-term clinical trial seems
unviable.
The i-IBD WG agreed that while there is no one biomarker
that is adequately sensitive to treatment, and correlates with clinical
endpoints and disease progression for CD, there are many candi-
dates currently being researched that hold promise. Biomarkers and
their potential role as surrogate endpoints for efficacy should
continue to be investigated for their utility and potential role
in expediting pediatric drug development. The qualification
procedures from the FDA and EMA can aid in presenting clear
guidelines for a regulatory acceptance via a formal validation
process (42,43).
Acknowledgments: The authors wish to recognize and thank
Dr Julie Beitz at the United States Food and Drug Administration
for her valuable editing and insightful input during the manuscript
preparation.
REFERENCES
1. Kenneth RM. Alimentary tract. In: Lawrence Jr M, Stephen JM,
Maxine AP, eds. Current Medical Diagnosis and Treatment. Vol 43.
Lange Medical Books/McGraw-Hill Medical Publishing Division;
2004:603–7.
2. Gasparetto M, Guariso G. Highlights in IBD epidemiology and its
natural history in the paediatric age. Gastroenterol Res Pract
2013;2013:829040.
3. Sun H, Vesely R, Nelson RM, et al. Steps toward harmonization for
clinical development of medicines in pediatric ulcerative colitis—a
global scientific discussion, part 2: data extrapolation, trial
design, and pharmacokinetics. J Pediatr Gastroenterol Nutr
2014;58:684–8.
4. Sun H, Vesely R, Taminiau J, et al. Steps toward harmonization for
clinical development of medicines in pediatric ulcerative colitis—a
global scientific discussion, part 1: efficacy endpoints and disease
outcome assessments. J Pediatr Gastroenterol Nutr 2014;58:679–83.
5. Clinical Outcome Assessment (COA): Glossary of Terms. Available at
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDeve-
lopmentToolsQualificationProgram/ucm370262.htm. Accessed June
10, 2016.
371
Sun et al
6. Biomarker definition. Available at http://inside.fda.gov:9003/CDER/
OfficeofTranslationalSciences/BiomarkerQualifications/
ucm229855.htm. Accessed January 25, 2016.
7. Escher JC. Budesonide versus prednisolone for the treatment of active
Crohn’s disease in children: a randomized, double-blind, controlled,
multicentre trial. Eur J Gastroenterol Hepatol 2004;16:47–54.
8. Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-
mercaptopurine and prednisone in children with newly diagnosed
Crohn’s disease. Gastroenterology 2000;119:895–902.
9. Guidance for industry, patient-reported outcome measures: use in
medical product development to support labeling claims. Available at
http://www.fda.gov/downloads/drugs/guidancecomplianceregulator-
yinformation/guidances/ucm193282.pdf. Accessed June 10, 2016.
10. Sun H, Papadopoulos EJ, Hyams JS, et al. Well-defined and reliable
clinical outcome assessments for pediatric Crohn’s disease: a critical
need for drug development. J Pediatr Gastroenterol Nutr 2015;60:
729–36.
11. Hyams JS, Ferry GD, Mandel FS, et al. Development and validation of a
Pediatric Crohn’s Disease Activity Index. J Pediatr Gastroenterol Nutr
1991;12:439–47.
12. Kappelman MD, Crandall WV, Colletti RB, et al. Short Pediatric
Crohn’s Disease Activity Index for quality improvement and observa-
tional research. Inflamm Bowel Dis 2011;17:112–7.
13. Leach ST, Nahidi L, Tilakaratne S, et al. Development and assessment
of a modified Pediatric Crohn Disease Activity Index. J Pediatr
Gastroenterol Nutr 2010;51:232–6.
14. Loonen HJ, Griffiths AM, Merkus MP, et al. A critical assessment of
items on the Pediatric Crohn’s Disease Activity Index. J Pediatr
Gastroenterol Nutr 2003;36:90–5.
15. Shepanski MA, Markowitz JE, Mamula P, et al. Is an abbreviated
Pediatric Crohn’s Disease Activity Index better than the original? J
Pediatr Gastroenterol Nutr 2004;39:68–72.
16. Turner D, Griffiths AM, Walters TD, et al. Mathematical weighting of
the Pediatric Crohn’s Disease Activity Index (PCDAI) and comparison
with its other short versions. Inflamm Bowel Dis 2012;18:55–62.
17. Hyams JS, Mandel F, Ferry GD, et al. Relationship of common
laboratory parameters to the activity of Crohn’s disease in children. J
Pediatr Gastroenterol Nutr 1992;14:216–22.
18. Hyams J, Markowitz J, Otley A, et al. Evaluation of the pediatric Crohn
disease activity index: a prospective multicenter experience. J Pediatr
Gastroenterol Nutr 2005;41:416–21.
19. Griffiths AM, Otley AR, Hyams J, et al. A review of activity indices and
end points for clinical trials in children with Crohn’s disease. Inflamm
Bowel Dis 2005;11:185–96.
20. Otley A, Loonen H, Parekh N, et al. Assessing activity of pediatric
Crohn’s disease: which index to use? Gastroenterology 1999;116:
527–31.
21. Kundhal PS, Critch JN, Zachos M, et al. Pediatric Crohn Disease
Activity Index: responsive to short-term change. J Pediatr Gastroenterol
Nutr 2003;36:83–9.
22. D’Haens G, Baert F, Van AG, et al. Early combined immunosuppression
or conventional management in patients with newly diagnosed Crohn’s
disease: an open randomised trial. Lancet 2008;371:660–7.
23. Levesque BG, Sandborn WJ, Ruel J, et al. Converging goals of treatment
for inflammatory bowel disease, from clinical trials and practice.
Gastroenterology 2014;148:37–51.
24. Shah SC, Colombel JF, Sands BE, et al. Systematic review with meta-
analysis: mucosal healing is associated with improved long-term out-
comes in Crohn’s disease. Aliment Pharmacol Ther 2016;43:317–33.
25. De Cruz P, Kamm MA, Prideaux L, et al. Mucosal healing in Crohn’s
disease: a systematic review. Inflamm Bowel Dis 2013;19:429–44.
372
Copyright © ESPGHAN and NASPGHAN. All rights reserved.
JPGN  Volume 64, Number 3, March 2017
26. Schnitzler F, Fidder H, Ferrante M, et al. Mucosal healing predicts long-
term outcome of maintenance therapy with infliximab in Crohn’s
disease. Inflamm Bowel Dis 2009;15:1295–301.
27. Gastroenterological regulatory endpoints and therapeutics. Available
at http://www.ema.europa.eu/docs/en_GB/document_library/Regula-
tory_and_procedural_guideline/2009/10/WC500004201.pdf. Accessed
June 10, 2016.
28. Peyrin-Biroulet L, Reinisch W, Colombel JF, et al. Clinical disease
activity, C-reactive protein normalisation and mucosal healing in
Crohn’s disease in the SONIC trial. Gut 2014;63:88–95.
29. Gottlieb KK, Lisa; Rajpal, Anil; Mulberg, Andrew. Modernizing clin-
ical trial design: Could C-Reactive Protein (CRP) serve as an enrich-
ment biomarker in Crohn’s disease trials? 2011 IBD Annual Meeting
2011.
30. Santucci NR, Alkhouri RH, Baker RD, et al. Vitamin and zinc status
pretreatment and posttreatment in patients with inflammatory bowel
disease. J Pediatr Gastroenterol Nutr 2014;59:455–7.
31. Walker TR, Land ML, Kartashov A, et al. Fecal lactoferrin is a sensitive
and specific marker of disease activity in children and young adults with
inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007;44:
414–22.
32. Ricanek P, Brackmann S, Perminow G, et al. Evaluation of disease
activity in IBD at the time of diagnosis by the use of clinical, bio-
chemical, and fecal markers. Scand J Gastroenterol 2011;46:1081–91.
33. Bunn SK, Bisset WM, Main MJ, et al. Fecal calprotectin as a measure of
disease activity in childhood inflammatory bowel disease. J Pediatr
Gastroenterol Nutr 2001;32:171–7.
34. Buderus S, Boone JH, Lentze MJ. Fecal lactoferrin: reliable biomarker
for intestinal inflammation in pediatric IBD. Gastroenterol Res Pract
2015;2015:578527.
35. Nahidi L, Leach ST, Sidler MA, et al. Osteoprotegerin in pediatric
Crohn’s disease and the effects of exclusive enteral nutrition. Inflamm
Bowel Dis 2011;17:516–23.
36. Papa E, Docktor M, Smillie C, et al. Non-invasive mapping of the
gastrointestinal microbiota identifies children with inflammatory bowel
disease. PLoS One 2012;7:e39242.
37. Lin J, Welker NC, Zhao Z, et al. Novel specific microRNA biomarkers
in idiopathic inflammatory bowel disease unrelated to disease activity.
Mod Pathol 2014;27:602–8.
38. Economou M, Pappas G. New global map of Crohn’s disease: Genetic,
environmental, and socioeconomic correlations. Inflamm Bowel Dis
2008;14:709–20.
39. Ordas I, Rimola J, Rodriguez S, et al. Accuracy of magnetic resonance
enterography in assessing response to therapy and mucosal healing in
patients with Crohn’s disease. Gastroenterology 2014;146:374–82.
40. Zubin G, Peter L. Predicting endoscopic Crohn’s disease activity before
and after induction therapy in children: a comprehensive assessment
of PCDAI, CRP, and fecal calprotectin. Inflamm Bowel Dis 2015;21:
1386–91.
41. Guidance for Industry Orally Inhaled and Intranasal Corticosteroids:
Evaluation of the Effects on Growth in Children U.S. Department of
Health and Human Services Food and Drug Administration Center for
Drug Evaluation and Research (CDER) March 2007. Available at http://
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor-
mation/Guidances/UCM071968.pdf. Accessed June 10, 2016.
42. European medicines agency guidance for companies requesting quali-
fication of novel methodologies 2013.
43. Guidance for Industry: Qualification Process for Drug Development
Tools. Available at http://inside.fda.gov:9003/downloads/CDER/Offi-
ceofTranslationalSciences/BiomarkerQualifications/UCM232136.pdf.
Accessed June 10, 2016.
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