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Using real-world data in pediatric clinical trials: Lessons learned and future applications in studies of persistent pulmonary hypertension of the newborn

Published:April 07, 2022DOI:https://doi.org/10.1016/j.siny.2022.101331

      Abstract

      Persistent pulmonary hypertension of the newborn (PPHN) is a complication of term birth, characterized by persistent hypoxemia secondary to failure of normal postnatal reduction in pulmonary vascular resistance, with potential for short- and long-term morbidity and mortality. The primary pharmacologic goal for this condition is reduction of the neonate's elevated pulmonary vascular resistance with inhaled nitric oxide, the only approved treatment option. Various adjunctive, unapproved therapeutics have been trialed with mixed results, likely related to challenges with recruiting the full, intended patient population into clinical studies. Recently, real-world data and subsequent derived evidence have been utilized to improve the efficiency of various pediatric clinical trials. We aim to provide recent perspectives regarding the use of real-world data in the planning and execution of pediatric clinical trials and how this may facilitate more streamlined assessment of future therapeutics for the treatment of PPHN and other neonatal conditions.

      Keywords

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      References

        • Davis J.M.
        • Connor E.M.
        • Wood A.J.
        The need for rigorous evidence on medication use in preterm infants: is it time for a neonatal rule?.
        JAMA. 2012; 308: 1435-1436https://doi.org/10.1001/jama.2012.12883
        • Mulugeta Y.L.
        • Zajicek A.
        • Barrett J.
        • Sachs H.C.
        • Mccune S.
        • Sinha V.
        • et al.
        Development of drug therapies for newborns and children: the scientific and regulatory imperatives.
        Pediatr Clin. 2017; 64: 1185-1196https://doi.org/10.1016/j.pcl.2017.08.015
        • U.S. Food and Drug Administration U.S. Food and Drug Administration
        General clinical pharmacology considerations for neonatal studies for drugs and biological products.
        2019
        • March of Dimes
        March of dimes report card.
        2019
        • Stiers J.L.
        • Ward R.M.
        Newborns, one of the last therapeutic orphans to be adopted.
        JAMA Pediatr. 2014; 168: 106-108https://doi.org/10.1001/jamapediatrics.2013.4604
        • Thompson G.
        • Barker C.I.
        • Folgori L.
        • Bielicki J.A.
        • Bradley J.S.
        • Lutsar I.
        • et al.
        Global shortage of neonatal and paediatric antibiotic trials: rapid review.
        BMJ Open. 2017; 7e016293https://doi.org/10.1136/bmjopen-2017-016293
      1. Inomax, U.S. Prescribing Information, https://www.inomax.com/wp-content/themes/inomax-website/dist/downloads/Inomax-PI.pdf Accessed:.

      2. Clinical Trials. Gov, PPHN neonates, https://clinicaltrials.gov/ct2/results?cond=PPHN&term=neonates+vasodilator&cntry=&state=&city=&dist= Accessed: 25 February 2022.

        • Us Congress
        21st Century Cures Act.
        in: HR 34, 114th congress, enacted on dec 13. 2016
        • U.S. Food and Drug Administration Department of Health and Human Services
        Submitting documents using real-world data and real-world evidence to FDA for drugs and biologics.
        2019
      3. U.S. Food and Drug Administration, Consideration on use of RWD and RWE, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-use-real-world-data-and-real-world-evidence-support-regulatory-decision-making-drug 2021 Accessed: 25 February 2022.

      4. European Medicines Agency, Use of Real World Evidence, https://www.ema.europa.eu/en/news/vision-use-real-world-evidence-eu-medicines-regulation Accessed: 25 February 2022.

        • Flynn R.
        • Plueschke K.
        • Quinten C.
        • Strassmann V.
        • Duijnhoven R.G.
        • Gordillo-Marañon M.
        • et al.
        Marketing authorization applications made to the European Medicines agency in 2018-2019: what was the contribution of real-world evidence?.
        Clin Pharmacol Ther. 2022; 111: 90-97https://doi.org/10.1002/cpt.2461
        • Salaets T.
        • Turner M.A.
        • Short M.
        • Ward R.M.
        • Hokuto I.
        • Ariagno R.L.
        • et al.
        Development of a neonatal adverse event severity scale through a Delphi consensus approach.
        Arch Dis Child. 2019; 104: 1167-1173https://doi.org/10.1136/archdischild-2019-317399
        • Jung B.
        • Adeli K.
        Clinical laboratory reference intervals in pediatrics: the CALIPER initiative.
        Clin Biochem. 2009; 42: 1589-1595https://doi.org/10.1016/j.clinbiochem.2009.06.025
        • Christensen R.D.
        • Henry E.
        • Jopling J.
        • Wiedmeier S.E.
        The CBC: reference ranges for neonates.
        Semin Perinatol. 2009; 33: 3-11https://doi.org/10.1053/j.semperi.2008.10.010
        • Christensen R.D.
        • Henry E.
        • Bennett S.T.
        • Yaish H.M.
        Reference intervals for reticulocyte parameters of infants during their first 90 days after birth.
        J Perinatol. 2016; 36: 61-66https://doi.org/10.1038/jp.2015.140
        • Mukherjee D.
        • Konduri G.G.
        Pediatric pulmonary hypertension: definitions, mechanisms, diagnosis, and treatment.
        Compr Physiol. 2021; 11: 2135-2190https://doi.org/10.1002/cphy.c200023
      5. IBM, IBM Explorys EHR database, https://www.ibm.com/watson-health/about/explorys Accessed:.

      6. Optum Clinformatics, Clinformatics Data Mart https://www.optum.com/content/dam/optum/resources/productSheets/Clinformatics_for_Data_Mart.pdf Accessed: 25 February 2022.

        • Nagamine T.
        • Gillette B.
        • Pakhomov A.
        • Kahoun J.
        • Mayer H.
        • Burghaus R.
        • et al.
        Multiscale classification of heart failure phenotypes by unsupervised clustering of unstructured electronic medical record data.
        Sci Rep. 2020; 10: 21340https://doi.org/10.1038/s41598-020-77286-6
        • Thorlund K.
        • Dron L.
        • Park J.J.H.
        • Mills E.J.
        Synthetic and external controls in clinical trials - a primer for researchers.
        Clin Epidemiol. 2020; 12: 457-467https://doi.org/10.2147/clep.S242097
        • Hellström A.L.D.
        • Hansen-Pupp I.
        • Hallberg B.
        • Ramenghi L.A.
        • Löfqvist C.
        • Smith L.E.H.
        • Hård A.L.
        IGF-I in the clinics: use in retinopathy of prematurity.
        Growth Hormone IGF Res. 2016; 30–31: 75-80https://doi.org/10.1016/j.ghir.2016.09.005
        • Hellström A.S.L.E.H.
        • Dammann O.
        Retinopathy of prematurity.
        Lancet. 2013; 382: 1445-1457https://doi.org/10.1016/S0140-6736(13)60178-6
        • Mutlu F.M.
        • Sarici S.U.
        Treatment of retinopathy of prematurity: a review of conventional and promising new therapeutic options.
        Int J Ophthalmol. 2013; 6: 228-236https://doi.org/10.3980/j.issn.2222-3959.2013.02.23
        • Pertl L.S.G.
        • Mayer C.
        • Hausberger S.
        • Pöschl E.-M.
        • Wackernagel W.
        • Wedrich a
        • El-Shabrawi Y.
        • Haas A.
        A systematic review and meta-analysis on the safety of vascular endothelial growth factor (VEGF) inhibitors for the treatment of retinopathy of prematurity.
        PLoS One. 2015; 10: 1-16https://doi.org/10.1371/journal.pone.0129383
        • Salman A.G.
        • Said A.M.
        Structural, visual and refractive outcomes of intravitreal aflibercept injection in high-risk prethreshold type 1 retinopathy of prematurity.
        Ophthalmic Res. 2015; 53: 15-20https://doi.org/10.1159/000364809
        • Stahl A.
        • Lepore D.
        • Fielder A.
        • Fleck B.
        • Reynolds J.D.
        • Chiang M.F.
        • et al.
        Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial.
        Lancet. 2019; 394: 1551-1559https://doi.org/10.1016/s0140-6736(19)31344-3
        • Neuenschwander B.
        • Capkun-Niggli G.
        • Branson M.
        • Spiegelhalter D.J.
        Summarizing historical information on controls in clinical trials.
        Clin Trials. 2010; 7: 5-18https://doi.org/10.1177/1740774509356002
        • Day C.L.
        • Ryan R.M.
        Bronchopulmonary dysplasia: new becomes old again.
        Pediatr Res. 2017; 81: 210-213https://doi.org/10.1038/pr.2016.201
        • Isayama T.
        • Lee S.K.
        • Yang J.
        • Lee D.
        • Daspal S.
        • Dunn M.
        • et al.
        Revisiting the definition of bronchopulmonary dysplasia: effect of changing panoply of respiratory support for preterm neonates.
        JAMA Pediatr. 2017; 171: 271-279https://doi.org/10.1001/jamapediatrics.2016.4141
        • Ofman G.
        • Caballero M.T.
        • Alvarez Paggi D.
        • Marzec J.
        • Nowogrodzki F.
        • Cho H.Y.
        • et al.
        The discovery BPD (D-BPD) program: study protocol of a prospective translational multicenter collaborative study to investigate determinants of chronic lung disease in very low birth weight infants.
        BMC Pediatr. 2019; 19: 227https://doi.org/10.1186/s12887-019-1610-8