Necrotizing Enterocolitis: Using Regulatory Science and Drug Development to Improve Outcome

Caplan MS, Underwood MA, Modi N, Patel R, Gordon PV, Sylvester KG, McElroy S, Manzoni P, Gephart S, Chwals WJ, Turner MA, Davis JM; Necrotizing Enterocolitis Workgroup of the International Neonatal Consortium. Necrotizing Enterocolitis: Using Regulatory Science and Drug Development to Improve Outcomes. J Pediatr. 2019 Sep;212:208-215.e1. doi: 10.1016/j.jpeds.2019.05.032. Epub 2019 Jun 22. PMID: 31235383.

Necrotizing enterocolitis (NEC) is the most common intestinal pathology and cause of death between 2 and 8 weeks of life in neonates born extremely preterm. NEC has an unpredictable and often sudden onset with a rapidly progressive clinical course.1 The diagnosis is currently made through a constellation of clinical observations and radiographic findings (eg, abdominal distention, bloody stool, pneumatosis intestinalis). NEC is likely triggered by a variety of insults resulting in a final pathway of intestinal dysfunction, inflammation, injury, and necrosis. Although clinical associations (eg, enteral feeding, blood transfusion), predisposing risk factors (eg, prematurity, altered intestinal microbiome, growth restriction), and specific molecular pathway involvement (eg, Toll-like receptor-4 signaling) are well established, the interactions between each of these factors and exposures are not fully understood.2, 3 There are currently no licensed drugs or biologics for the prevention and/or treatment of NEC.

The Critical Path Institute is an independent, nonprofit organization committed to transformational improvement of the drug development process. The Food and Drug Administration working with the Critical Path Institute established the International Neonatal Consortium (INC) in 2015 to advance regulatory science for neonates. A working group for NEC was established to identify challenges associated with the development and licensing of products for the prevention and/or treatment of NEC. In this review, the INC NEC working group addresses key issues that relate to the diagnosis, prevention, and treatment of NEC while suggesting a path forward to evaluate the safety and efficacy of each product. Despite years of clinical investigation, additional key data elements are needed to meet the requirements of regulatory agencies and evidence-based medicine.4
These include reliable diagnostic criteria, biomarkers predictive of risk and prognosis, and criteria for the design and conduct of clinical trials with consistent and clinically meaningful outcome measures for therapeutic trials.

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