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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 What Is Known
disease (CD). Our aim was to provide strategic approaches toward harmo-
nization of current thinking about clinical outcome assessments (COAs) and  The Pediatric Crohn’s Disease Activity Index was used
biomarkers to facilitate drug development in pediatric CD. as the primary endpoint to support the approval of
Methods: Scientists from the United States Food and Drug Administration, Remicade and Humira.
European Medicines Agency, Health Canada, and the Pharmaceuticals and  Biomarkers, such as fecal lactoferrin, osteoprotegerin,
Medical Devices Agency of Japan had monthly teleconferences from and calprotectin, have shown some promise for their
January 2014 through May 2015. A literature review was conducted to potential as noninvasive surrogate endpoints in
assess the measurement properties of all existing COA tools and to evaluate Crohn Disease.
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.
What Is New
Results: The pediatric Crohn’s Disease Activity Index, Crohn’s Disease
 The Pediatric Crohn’s Disease Activity Index lacks
Activity Index, and Harvey-Bradshaw’s index were used in pediatric CD
clinical studies. But they lack adequate measurement properties (validity, adequate measurement properties for use as a primary
reliability, and ability to detect change of the treatment) that are required to endpoint for phase III trials intended to support
support approval of products intended to treat pediatric CD. Biomarkers (ie, approval of products for the indication of pediatric
fecal lactoferrin, osteoprotegerin, and calprotectin) have shown some Crohn Disease. It is essential to develop well-defined
promise for their potential as noninvasive surrogate endpoints in CD. and reliable clinical outcome assessments that can
Conclusions: Lack of well-defined and reliable COAs presents a hurdle for measure meaningful clinical benefit for patients in
global drug development in pediatric CD. It is essential to develop well- terms of how they feel, function, and survive.
 The global consensus is reached that development
defined and reliable COAs that can measure meaningful clinical benefit for
patients in terms of how they feel, function, and survive. Development of of noninvasive biomarkers as reliable surrogate
noninvasive biomarkers as reliable surrogate endpoints needs to be further endpoints needs to be further explored.
explored.
Key Words: biomarkers, clinical outcome assessments, endpoints,
pediatric Crohn disease, surrogate endpoint

(JPGN 2017;64: 368–372) 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

Received January 15, 2016; accepted May 26, 2016. Aisha Peterson Johnson, MD; Wes Ishihara, BS and Kevin Bugin, MS,
From the United States Food and Drug Administration, Silver Spring, MD, RAC of the Division of Gastroenterology and Inborn Error Product in the
the yEuropean Medicines Agency, London, UK, the zHealth Canada, FDA; Joachim Musaus; Peter Szitanyi; Frank Petavy and Jan Taminiau of
Ottawa, Ontario, Canada, and the §Pharmaceuticals and Medical Devices EMA; Kader Kourad, MD, PhD; Catherine Njue PhD; Cora Chen, MD
Agency, Tokyo, Japan. PhD; Talia De Laurentis of Health Canada; Yosuke Kobayashi; Shinobu
Address correspondence and reprint requests to Andrew E. Mulberg, MD, Uzu; Yumiko Nomura; Kazuishi Sekino, MS; Rieko Yamazaki; Junichi
FAAP, Division of Gastroenterology and Inborn Errors Products, OND/ Asano, PhD of PMDA; Other members from the FDA: E. Papadopoulos,
CDER, Food and Drug Administration, 10903 New Hampshire Ave, MD, MPH (Clinical Outcome Assessments Staff); Renan A. Bonnel,
Silver Spring, MD 20993 (e-mail: Andrew.Mulberg@fda.hhs.gov). Pharm D. MPH; Jean Temeck, MD; Suzanne Malli of the Office of
Views expressed in this manuscript are those of the authors and do not Pediatric Therapeutics; Yeh-Fong Chen, PhD; and Insook Kim, PhD.
necessarily reflect official positions or policies of the FDA, EMA, Health The authors report no conflicts of interest.
Canada and PMDA. This work is not funded by any organizations or grants. Copyright # 2016 by European Society for Pediatric Gastroenterology,
This work is neither supported by pharmaceutical industry nor supported by Hepatology, and Nutrition and North American Society for Pediatric
National Institutes of Health, Wellcome Trust, and Howard Hughes Gastroenterology, Hepatology, and Nutrition
Medical Institute. DOI: 10.1097/MPG.0000000000001284
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 JPGN  Volume 64, Number 3, March 2017

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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). important to patients and to assess treatment benefit in patients
The annual overall incidence of CD was registered at 20.2, 12.7, and in pediatric CD trials. Biomarkers are measurable characteristics
5 per 100,000 person-years in North America, Europe, and Asia, that reflect physiological, pharmacological, or disease processes in
respectively (2). Although CD incidence rates in the general animals or humans. Changes in biomarkers following treatment
population seem to have stabilized in most industrialized countries may reflect the clinical response to the product and may predict or
since 1980s, it shows an increase in the childhood-onset CD (2). identify safety problems related to a drug candidate or reveal a
Currently, 2 products, Remicade (Janssen Biotech, Inc., Horsham, pharmacological activity expected to predict an eventual benefit
PA) and Humira (AbbVie Inc., North Chicago, IL), have been from treatment (6). Surrogate endpoint is a biomarker that is
approved by the United States Food and Drug Administration intended to substitute for a clinical endpoint and is expected to
(FDA), European Medicines Agency (EMA), Health Canada, predict clinical benefit (or harm, or lack of benefit or harm) based on
and the Pharmaceuticals and Medical Devices Agency of Japan, epidemiological, therapeutic, pathophysiological, or other scientific
along with 2 bio-similar products to Remicade (infliximab), Inflec- evidence. ‘‘Surrogate endpoints’’ are a subset of pharmacodynamic
tra (Hospira UK Limited) and Remsima (Celltrion Healthcare biomarkers; while all surrogate endpoints can be considered bio-
Hungary Kft. Budapest, Hungary), approved only by the EMA, markers, it is likely that only a few biomarkers will be appropriate
for a pediatric CD indication. Other drugs in various classes are for use as surrogate endpoints (6).
used off-label for this indication. As a result, clinical outcome assessment and biomarker
A strategic approach toward the global regulatory harmoni- subgroups from within the overall i-IBD WG were formed to focus
zation can facilitate future pediatric CD trials and drug develop- on the key topics in each specific area. Each group conducted a
ment. The International Inflammatory Bowel Disease (i-IBD) literature review relevant to the specific area and subsequently
Working Group (WG), which consists of multidisciplinary scien- presented the results of the literature review and analysis to the
tists from the FDA, EMA, Health Canada, and the Pharmaceuticals overall i-IBD WG monthly teleconference for discussion. The
and Medical Devices Agency of Japan, is an international collab- suggestions provided in this article are based, wherever possible,
oration developed to advance scientific knowledge on efficacy on the evidence published in the medical literature.
endpoints, trial design, data extrapolation, and pharmacokinetics A literature review was conducted to assess COAs, bio-
(PK) supporting drug development in pediatric IBD including markers, and surrogate endpoints that have been used in pediatric
ulcerative colitis (UC) and CD. The i-IBD WG seeks to improve CD trials. The electronic database, PubMed/Medline, EMBASE,
the likelihood that clinical development of safe and effective and Web of Science were searched. The phrase ‘‘pediatric Crohn’s
therapies for the treatment of IBD is successful. The WG intends disease/AND (disease activity indices OR endpoints)’’ was used
to focus on the immediate need for consensus on efficacy endpoints, for the literature search on the topic of pediatric endpoints and
biomarkers, trial design, and how to use extrapolation and PK data clinical outcome assessments. The phrase ‘‘inflammatory bowel
in pediatric IBD among regulatory authorities as well as in the disease/AND (disease activity indices or instrument) AND
scientific and medical community. We have previously reported the (biomarkers or surrogate endpoints)’’ was used for the literature
scientific discussions of pediatric UC (3,4). This article summarizes search for biomarkers. No language and time restrictions were
scientific discussions of pediatric CD among members of the i-IBD applied during the search. The last search was conducted on
WG and provides possible approaches to consider for working May 31, 2015. The literature were reviewed and discussed among
toward harmonization of current thinking about drug development all 5 to 6 members within each subgroup.
in pediatric CD. The views of the i-IBD WG expressed in this article
are only individual personal opinions or suggestions for drug RESULTS
development in pediatric CD and do not represent regulatory
consensus or official guidelines of the individual agencies. Current State of Clinical Outcome Assessments
Due to the limitation set by the journal in word count, part 1 Used in Pediatric Crohn Disease Trials
of this article, presented here, focuses only on the discussion of Five clinical outcome assessment tools, designed specifically
clinical outcome assessments, biomarkers, and surrogate endpoints for the pediatric CD assessment were identified in the literature
in pediatric CD trials. Part 2 of the article, related to discussions of search. They included the Pediatric Crohn’s Disease Activity Index
data extrapolation, trial designs, and PK studies, will be reported in (PCDAI), abbreviated PCDAI, short PCDAI, modified PCDAI, and
a separate paper. weighted PCDAI. Although designed for adult patients, the Crohn’s
Disease Activity Index (CDAI) and partial Harvey Bradshaw index
METHODS (HBI) were also adapted for use in a few clinical trials with pediatric
The members of the i-IBD WG convened monthly via patients with CD (7,8). The PCDAI was used as the primary
teleconferences from January 2014 through June 2015. We dis- endpoint to support the approval of Remicade (infliximab) and
cussed the current positions and practices at each agency based on Humira (adalimumab) for the indication of pediatric CD in USA,
our evaluations of applications received for drugs intended to treat European Union, Canada, and Japan.
pediatric CD. All attempts were made to understand individual The measurement properties of the clinical outcome assess-
approaches of agencies and opinions of experts. We also brought up ment tools include the content validity, reliability, and ability to
the issues that need to be addressed with an effort to formulate the detect changes. In general, clinical outcome assessment tools
suggestions for the path forward. Among many other issues, we should be reliable, valid, and able to detect clinically meaningful
identified clinical outcome assessments and biomarkers as one of change in the concept of interest based on the principles described
the priorities to be discussed. Clinical outcome assessment (COA) is in the ‘‘Guidance for Industry Patient-Reported Outcome
any assessment that may be influenced by human choices, judg- Measures: Use in Medical Product Development to Support Label-
ment, or motivation and may support, either directly or indirectly, ing Claims’’ (9). In addition to this, any measurement used for
evidence of treatment benefit (5). COAs depend on the implementa- outcome assessment should be standardized. Sun et al (10) at the US
tion, interpretation, and reporting by a patient, a clinician, or an FDA analyzed the measurement properties of all existing COA
observer (5). For these reasons, a well-defined and reliable COA is tools for pediatric CD in literature and published registration trials
critical to document the full spectrum of signs and symptoms of approved drugs for pediatric CD based on criteria described in

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Sun et al JPGN  Volume 64, Number 3, March 2017

FDA guidance for patient-reported outcome (PRO) development. signs and symptoms of disease and effects on mucosal injury could
The CDAI, HBI, PCDAI, and its derivatives (abbreviated, short, be relevant targets for novel therapies. Mucosal healing has been
modified, and weighted PCDAIs) were reviewed. Common issues increasingly recognized as an important outcome of medical treat-
in measurement properties of COA tools included absence of direct ment as it is associated with longer remission periods and reduced
patient or caregivers’ input to generate the items measuring signs risk for surgeries and hospitalization (24–26). Thus, endoscopic or
and symptoms, absence of evidence demonstrating correlation with radiological mucosal and histological examination may need to be
clinically relevant inflammation observed with endoscopic considered as 1 outcome measurement. Given the nature of this
measures, and lack of standardization in measurement, age-appro- disease, it would be helpful to explore the relation of intestinal
priate interviewer script and response rating criteria for the phys- damage as demonstrated from imaging studies to mucosal inflam-
ician interviewer (10). mation observed during endoscopy and histologically in pediatric
Particularly, the PCDAI was developed in 1990 by a group of patients with CD (10). Meanwhile, we acknowledge that there are
30 pediatric gastroenterologists as a research tool to facilitate many challenges to assessing mucosal healing in children with CD:
standardization of disease activity assessment in the course of reluctance to repeat endoscopies, inability to pass the scope to the
clinical trials (11). Although the PCDAI has become the standard disease site, need for standardization of endoscopic interpretation,
measurement for disease activity in pediatric CD during the last 20 and others (10). We also acknowledge that interobserver variability
years, a few variations of PCDAI have been developed to address in endoscopic scoring may exist during endoscopic assessments.
the limitations (eg, poor feasibility, item redundancy, etc) that the Primarily, the mucosal healing definition remains elusive to the
original PCDAI revealed in the course of research and clinical trials adult and pediatric IBD communities and to regulatory agencies.
(12–16). Hyams et al (17) studied the relation of common labora- For these reasons, CDAI, HBI, and the 5 versions of the
tory parameters to the PCDAI in 133 children with CD. They found PCDAI lack adequate measurement properties for use as a primary
that no single laboratory test in PCDAI was adequate to reflect endpoint for phase III trials intended to support approval of products
disease activity in all 133 pediatric patients studied (17). Hyams intended to treat pediatric CD (10). A well-defined, reliable,
et al (18) also conducted a longitudinal assessment to develop cut sensitive, and globally recognized PRO that measures signs and
scores reflecting disease activities as determined by physician symptoms indicating the presence of disease in children with CD,
global assessment and to evaluate the responsiveness of the PCDAI and that can be used in conjunction with endoscopic endpoints
to changes in patient condition after therapeutic intervention. They and/or serum biomarkers is sorely needed to facilitate pediatric drug
concluded in this study that the PCDAI could reflect disease activity development (10). To date, collaborative efforts to identify these
as assessed by physician global assessment and a DPCDAI score of key signs and symptoms and correlate them with response and
12.5 points following therapeutic intervention could reflect a remission are underway (27).
clinically significant response (18). Several reviews have compared
the strength and weakness of various disease activity index used in Review of Noninvasive Biomarkers
pediatric CD trials (19,20). The PCDAI was used as the primary
endpoint to support the approval of infliximab and adalimumab. The literature search yielded 32 articles, 2 of which cited
The current regulatory landscape continues to foster identification pediatric data. All 32 articles were reviewed and discussed among
of improved outcome measures of pediatric IBD disease activity. the members in the biomarker subgroup. Candidates include serum
The PCDAI, however, lacks adequate content validity thus and stool markers, and, uniquely in CD, magnetic resonance
presents a concern (10). The PCDAI performance record in clinical enterography (MRE). Newer modalities involving mucosal markers
trials is not clear, although various thresholds have been established from the microbiome or RNAseq may also be useful in the future
in the past using the data from registry studies. The available data in and are further described below. At this time, none of these
the literature have not adequately and consistently demonstrated the biomarkers can replace current standards utilized in clinical trials
PCDAI’s ability to detect a moderate treatment difference in the of biopsy or disease activity indices used to measure improvement
clinical trials and test-retest reliability (10). Furthermore, growth in endpoints or disease progression of CD, although some are closer
parameters including weight gain/loss and height/height velocity than others, particularly fecal biomarkers.
account for 20% of the PCDAI score, while Turner and colleagues Serum biomarkers discussed included C-reactive protein
identified that height, hematocrit, and abdominal examination were (CRP) as a measure of inflammation. CRP has yielded mixed
redundant and insensitive to the change of disease activities (16,21). results. In a recent analysis of data involving a subset of patients
It should also be noted, although inconsistent with these reports, that from the Study of Biologic and Immunomodulator Naive Patients in
abdominal exams and hematocrit are important to clinicians in the Chrohn Disease trial, of the 118 who had CRP elevation and
patient care setting. It is not uncommon for children to have marked mucosal ulcerations, 37% had a normalization of both at 26 weeks
anemia in the absence of any signs or symptoms secondary to the with treatment, which is lower than those that showed mucosal
effect of proinflammatory cytokines on red blood cell production healing altogether (48%) (28). The FDA’s internal analysis of 3968
(10). Although height may not be responsive in a short-term trial, it patients in clinical trials looking at the relation between CDAI and
is relevant in a 1-year maintenance trial for children who still have CRP found a weak correlation with positive predictive value of CRP
growth potential. The potential for changes in hematocrit together in determining remission based on CDAI of 28.4% and negative
with changes in albumin to reflect clinically significant changes predictive value for CRP of 61.2% (unpublished data). Gottlieb et al
may be considered potentially relevant in the construct of a primary (29) reviewed recent CD trials evaluating TNFa antagonists which
endpoint model. Understanding the importance of clinically CRP subgroup data were reanalyzed. In these study-level data, it
relevant biomarkers, that is, hematocrit and albumin, in construct- was not convincing that the level of CRP can discriminate between
ing an endpoint model that reflects the clinical condition may yield patients who responded to biologics or went into sustained remis-
clarity from a clinical and regulatory perspective (10). sion from those who did not. Further work may include an analysis
In addition, although remission and response has been of patient level data using CRP and other biomarkers, alone or
characterized in children with CD using PCDAI, evolving manage- in combination with different cutoff values. Deficiencies of
ment of CD is now focusing on complications of CD related to various vitamins and minerals were also discussed given that CD
structural damage and mucosal injury and the predominating signs affects absorption at multiple places throughout the small intestine.
and symptoms indicating the presence of disease (10,22,23). Both 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, The beneficial impact of a drug on the complications of the
still await further structured studies to determine change with disease seems directly linked to its impact on improvement of signs
disease activity (30). of mucosal inflammation (24–26,40). At this time, the best meth-
Fecal markers appear more promising. Currently fecal cal- odology for directly documenting this impact is visualization of the
protectin, lactoferrin, and osteoprotegerin (OPG) are all under mucosa via endoscopy. It would be helpful to maximize endoscopic
investigation. The merits of lactoferrin correlation to clinical dis- evaluations and encourage patients with CD to undergo baseline
ease activity indices and serum biomarkers (31) and calprotectin and follow-up endoscopy in clinical trials. Currently, evaluation of
correlation to mucosal healing (32) were discussed in the previous i- mucosal inflammation has been requested by some regulatory
IBD paper on pediatric UC endpoints (4). A pediatric trial in 37 authorities in agreed upon pediatric study plans for new medicines.
children with IBD (20 with CD) found higher spot calprotectin To reduce the interobserver variability in endoscopic scoring, the
levels in children with IBD relative to control patients. In addition, central reading is recommended in the pediatric CD trials.
it found those with higher disease activity had higher calprotectin Additional points considered by the i-IBD WG included whether
levels (33). Another pediatric trial in 56 children with suspected biopsy indicating mucosal improvement always needs to be per-
IBD (UC and CD) found that those with intestinal inflammation formed. In CD, many of the changes may occur in areas that we are
from IBD had significantly elevated fecal lactoferrin levels as unable to biopsy; therefore, other methods of assessment may
compared to control patients who did not have IBD. This observa- be considered.
tional study also demonstrated that patients with IBD with elevated The WG also discussed the lack of utility of using growth
fecal lactoferrin and normal CRP levels had active intestinal indices as short-term measures of disease activity. Growth is
inflammation on colonoscopy (34). OPG has recently been shown difficult to measure, requires standardization of methodology,
in a pediatric study to be elevated in mucosal, fecal, and serum and the FDA has opined on these issues in other chronic pediatric
levels of children with CD as compared to controls. These elevated diseases related to the use of corticosteroids for management (41). It
levels in serum and fecal OPG dropped significantly after treatment is accepted that well-conducted growth assessments represent one
with enteral therapy (35). of the most sensitive indicators of systemic effects of a disease and
Newer modalities that may eventually serve as biomarkers potentially drug therapy. Effects on growth should be interpreted as
for disease activity include microbiome studies that appear to be a pharmacodynamic effect of a disease process and may well
able to detect IBD (36) as well as RNAseq studies that show represent an outcome measure in a 1-year maintenance trial for
miRNAs that are specific to IBD in colonic mucosal tissue (37). children who still may manifest growth potential. Utility in demon-
Much more work, however, remains to be done to validate these strating growth changes in a short-term clinical trial seems
modalities with respect to disease activity. Genetic markers were unviable.
discussed, however, while useful to diagnose disease or estimate the The i-IBD WG agreed that while there is no one biomarker
likelihood of disease occurrence, are not optimal as biomarkers to that is adequately sensitive to treatment, and correlates with clinical
indicate the course of the disease state (38). endpoints and disease progression for CD, there are many candi-
The use of MRE may elucidate the nature of disease in all dates currently being researched that hold promise. Biomarkers and
affected areas of the intestine in CD. To date, there are a few small their potential role as surrogate endpoints for efficacy should
studies that have sought to validate MRE against biopsy, but none continue to be investigated for their utility and potential role
conducted in pediatric patients. One recent study looked at 48 in expediting pediatric drug development. The qualification
patients comparing baseline ileocolonoscopy to MRE at 2 time procedures from the FDA and EMA can aid in presenting clear
points on treatment in which healing was identified as the disap- guidelines for a regulatory acceptance via a formal validation
pearance of ulcers in endoscopic evaluation. Additional analyses in process (42,43).
the study established the accuracy of MRE in determining endo-
scopic remission (a Crohn’s Disease Endoscopic Index of Severity Acknowledgments: The authors wish to recognize and thank
[CDEIS] score <3.5) and change in severity based on consideration Dr Julie Beitz at the United States Food and Drug Administration
of all segments. MRE determined ulcer healing with 90% accuracy for her valuable editing and insightful input during the manuscript
and endoscopic remission with 83% accuracy (39). Meanwhile, we preparation.
acknowledge that there are some challenges to perform MRE in
children with CD. For instance, many young children cannot
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