Article Text
Abstract
Background Assessment of the seriousness, expectedness and causality are necessary for any adverse event (AE) in a clinical trial. In addition, assessing AE severity helps determine the importance of the AE in the clinical setting. Standardisation of AE severity criteria could make safety information more reliable and comparable across trials. Although standardised AE severity scales have been developed in other research fields, they are not suitable for use in neonates. The development of an AE severity scale to facilitate the conduct and interpretation of neonatal clinical trials is therefore urgently needed.
Methods A stepwise consensus process was undertaken within the International Neonatal Consortium (INC) with input from all relevant stakeholders. The consensus process included several rounds of surveys (based on a Delphi approach), face-to-face meetings and a pilot validation.
Results Neonatal AE severity was classified by five grades (mild, moderate, severe, life threatening or death). AE severity in neonates was defined by the effect of the AE on age appropriate behaviour, basal physiological functions and care changes in response to the AE. Pilot validation of the generic criteria revealed κ=0.23 and guided further refinement. This generic scale was applied to 35 typical and common neonatal AEs resulting in the INC neonatal AE severity scale (NAESS) V.1.0, which is now publicly available.
Discussion The INC NAESS is an ongoing effort that will be continuously updated. Future perspectives include further validation and the development of a training module for users.
- adverse event
- severity grading
- drug safety
- neonate
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Footnotes
Collaborators The International Neonatal Consortium would like to acknowledge the following people who participated in the process: Marilee Allen, Johns Hopkins; Albert Allen, Eli Lilly; Dina Apele Freimane, PDCO, P. Stradins, Clinical University Hospital; Judy Aschner, The Joseph M Sanzari Children’s Hospital at Hackensack Meridian Health School of Medicine and Albert Einstein College of Medicine; Roberta Ballard, UCSF School of Medicine; Yodit Belew, FDA; Ralph Bax, EMA; Bobby Bellflower, The University of Tennessee; Varsha Bhatt-Mehta, University of Michigan; Mike Blum, FDA; Chiara Bonardi, Chiesi Pharmaceuticals; Patti Bondurant, Greenwood Solutions; Geraldine Boylan, INFANT Research Centre & Department of Paediatrics and Child Health; Teresa Buracchio, FDA; Gilbert Burckart, FDA; Amber Burnett, Baxter International; Janelle Burnham, FDA; Cheryl Carlson, UNC; Alice Chen, NIH; Bob Clay, Highbury Regulatory Science Ltd; Alan Cohen, Bayer; Eamonn Connolly, Infant Bacterial Therapeutics; Edward Connor, Institute for Advanced Clinical Trials for Children; Edress Darsey, Pfizer Inc; Roberto De Lisa, EMA; Jennifer Degl, Speaking for Moms and Babies, Inc.; Eugene Dempsey, INFANT Research Centre & Department of Paediatrics and Child Health; Tom Diacovo, Children's Hospital of Pittsburgh; Janis Dionne, BC Children's Hospital; Jennifer Duchon, Tufts Medical Center; Wakako Eklund, National Association of Neonatal Nurses; Laura Fabbri, Chiesi Pharmaceuticals; Alistair Fielder, City University; Emily Freilich, FDA; Sabine Fürst-Recktenwald, Hoffmann-La Roche LTD; Tamorah Graham, Quorum Health Corporation; Dionna Green, FDA; Cristal Grogan, Preemie Parent Alliance; Darell Heiselman, Eli Lilly; Ann Hellström, University of Gothenburg; Ralf Herold, Bayer; Anna Maria Hibbs, Case Western Reserve University School of Medicine; Steven Hirschfeld, NIH; Mary Hise Brown, Baxter International; Jim Holberton, Mercy Health Foundation; Pablo Iveli, Hospital Quirónsalud Barcelona; Alan Jobe, Cincinnati Children's Hospital; Allyson Kayton, National Association of Neonatal Nurses; Carole Kenner, Council of International Neonatal Nurses; Walter Kraft, Thomas Jefferson University; Satoshi Kusuda, Tokyo Women's Medical University; Thierry Lacaze, The Pediatric Network in Canada; Tamorah Lewis, Children’s Mercy Kansas City; Kei Lui, Australian & New Zealand Neonatal Network; Irja Lutsar, University of Tartu, Estonia; Alexandra Mangili, Takeda; Barry Mangum, Paidion Research, Inc.; Susan McCune, FDA; Karen McDonald, Barton and Associates, Inc.; Courtney McGuire, FDA; Christopher McPherson, St. Louis Children's Hospital; Washington University; Thomas Miller, Bayer; Jeffrey Ming, Sanofi Pharmaceuticals; Alison Mitzner, Pfizer; Neena Modi, Imperial College London; Maya Morrison, Baxter International; Eva Morsing, Lund University; Lily Mulugeta, FDA; Hide Nakamura, Nagano Children's Hospital; Skip Nelson, J and J Services, Inc.; Gary Noel, J and J Services, Inc.; Miki Olshansky, ELGAN; Alex Oschman, Children's Mercy Hospital and Clinics; Hulya Ozsahin, Centre Médical Qorpus; Mike Padula, Children's Hospital of Philadelphia; Vasum Peiris, FDA; Luana Pesco Koplowitz, DUCK FLATS Pharma; Josh Pham, Baxter International; Aprile Pilon, Trove Therapeutics; Ron Portman, Novartis pharmaceuticals; Ronit Pressler, Great Ormond Street Hospital; Heike Rabe, Brighton & Sussex Medical School; Tonse Raju, NIH; Douglas Andrew Roepke, Eli Lilly; Rashmin Savani, University of Texas Southwestern Medical Center; Patrick Schnell, Pfizer; Robert Segal, Windtree Therapeutics; Thibault Senterre, Baxter International; Prakesh Shah, Canadian Neonatal Network/University of Toronto; Philip Sheridan, FDA; Catherine Sherwin, University of Utah; Rajendra Singh, GlaxoSmithkline; Roger Soll, Vermont Oxford Network; Janet Soul, Harvard University; Kaye Spence, Children's Hospital at Westmead; Linda Storari, Chiesi Pharmaceuticals; Jan Taminiau, Emma Children's Hospital; Brian Tseng, Novartis Pharmaceuticals; John Van Den Anker, Sophia Children’s Hospital (the Netherlands) and Children's National Medical Center, Washington, D.C.; Judy Varga, Windtree Therapeutics; Preeti Venkataraman, FDA; Norma Vivas, Sanofi; Karen Walker, Australian College of Neonatal Nurses; Janice Wilson, University of Maryland; Anne Zajicek, NICHD; Gary Zaloga, Baxter International; and Stav Zeldis, ELGAN.
Contributors TS and KA designed and guided the development process and drafted the manuscript. MAT, JD and RMW helped supervise and guide the entire process. SB, GB, IH, RLA, AK, MS, KW and MT participated in every step of the development process. JH linked the terminology to MedDRA; TQ created the concepts and links in the National Cancer Institute Thesaurus. ER designed and provided the case descriptions for the validation exercise. All authors were involved in reviewing and rewriting the manuscript.
Funding The International Neonatal Consortium (INC) is supported in part by grant number U18FD005320-01 from the US Food and Drug Administration (FDA) to the Critical Path Institute (http://c-path.org) and through annual dues of member companies. The first and last author are supported by the SafePedrug project (IWT SBO 130033).
Disclaimer The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the US Food and Drug Administration, the position of Health Canada or the position of the National Institutes of Health.
Competing interests One coauthor is an employee of a pharmaceutical company, as noted in the list of affiliations. MT has performed paid consultancy work for Chiesi Farmaceutici S.p.A, Italy. No products are discussed in this article. The consortium aims to improve methods that can be applied to evaluating the safety and effectiveness of any medical product for neonates and is consequently drug agnostic.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.