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Pediatric Crohn Disease Clinical Outcome Assessments and Biomarkers: Current State and Path Forward for Global
Haihao Sun1, Richard Vesely, Kerry Jo Lee
1*United States Food and Drug Administration, Silver Spring, MD †European Medicines Agency, London, UK ‡Health Canada, Ottawa, Ontario, Canada §Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
Insights
Developing reliable clinical outcome assessments (COAs) and biomarkers is crucial for advancing drug development in pediatric Crohn disease (CD). Harmonizing these tools will accelerate the approval of new treatments for children with CD.
Area of Science:
- Pediatric gastroenterology
- Drug development
- Clinical trial methodology
Background:
- Pediatric Crohn disease (CD) lacks effective drug development due to inadequate clinical outcome assessments (COAs).
- Existing COA tools like the pediatric Crohn's Disease Activity Index, Crohn's Disease Activity Index, and Harvey-Bradshaw's index lack the necessary measurement properties for regulatory approval.
- Noninvasive biomarkers such as fecal lactoferrin, osteoprotegerin, and calprotectin show promise as surrogate endpoints in CD.
Framework:
- International collaboration among regulatory agencies (FDA, EMA, Health Canada, PMDA) to harmonize COAs and biomarkers.
- Systematic literature review to assess measurement properties of existing COA tools and current biomarker landscape in pediatric CD.
- Consensus reached on strategic approaches for evaluating outcomes in pediatric CD trials.
Implementation:
- Monthly teleconferences held by scientists from major global regulatory agencies from January 2014 to May 2015.
- Literature review focused on evaluating measurement properties of COA tools and assessing biomarkers for pediatric CD.
- Development of consensus-based strategic approaches for pediatric CD clinical trials.
Implications:
- Addressing the lack of well-defined and reliable COAs is essential to overcome hurdles in global drug development for pediatric CD.
- Development of robust COAs is needed to measure meaningful clinical benefit in pediatric CD patients.
- Further exploration and validation of noninvasive biomarkers as reliable surrogate endpoints are critical for advancing pediatric CD therapeutics.
Objective:
There is a pressing need for drug development in pediatric Crohn disease (CD). Our aim was to provide strategic approaches toward harmonization 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.
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