Requirements and Special Considerations for Drug Trials with Children Across Six Jurisdictions: 1. Clinical Trial Application Review in the Regulatory Approval Process

Breanne Stewart ¹ Pirkko Lepola ² Gunter Florian Egger ³ Fahimeda Ali ⁴ Albert John Allen ^5,6 Alysha Kristine Croker ⁷ Andrew John Davidson ⁸ Pamela Dicks ⁹ Saul Nicholas Faust ^10,11 Dionna Jeter Green ¹² Collins Hovinga ^5,6 Agnes Victoria Klein ⁷ Robyn Langham ¹³ Hidefumi Nakamura ¹⁴ Laura Pioppo ³ Shiva Ramroop ⁴ Michiyo Sakiyama ¹⁵ Isabel Sánchez Vigil de la Villa ³ Junko Sato ¹⁶ Donna Louise Snyder ¹⁷ Mark Augustine Turner ^18,19 Sarah Zaidi ¹² Kanecia Zimmerman ^20,21 Thierry Lacaze-Masmonteil ^1*

• ¹ MICYRN, Vancouver, Canada
• ² University of Helsinki and Helsinki University Hospital, Helsinki, Uusimaa, Finland
• ³ Pediatric Medicines Office and Data Analytics and Methods Task Force, European Medicines Agency (EMA), Amsterdam, Netherlands
• ⁴ Paediatrics – Innovative Medicines, Healthcare Quality & Access, MHRA, London, United Kingdom
• ⁵ Institute for Advances Clinical Trials for Children, Rockville, California, United States
• ⁶ Critical Path Institute, Tucson, Arizona, United States
• ⁷ Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada,, Ottawa, Canada
• ⁸ Melbourne Children’s Trials Centre, Murdoch Children’s Research Institute, Melbourne, Australia
• ⁹ NHS Scottish Children’s Research Network, Royal Aberdeen Children’s Hospital, Scotland, United Kingdom
• ¹⁰ NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
• ¹¹ Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
• ¹² Office of Pediatric Therapeutics, Office of the Commissioner, United States Food and Drug Administration, Silver Spring, Maryland, United States
• ¹³ Therapeutic Goods Administration, Australian Government Department of Health and Aged Care, Woden, Australia
• ¹⁴ National Centre for Child Health and Development – Department of Research and Development Supervision, Tokyo, Japan
• ¹⁵ Pediatric Drug Working Group, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan
• ¹⁶ Pediatric Drug Working Group, Pharmaceuticals and Medical Devices Agency,, Tokyo, Japan
• ¹⁷ WCG Clinical, Princeton, United States
• ¹⁸ Department of Women’s and Children’s Health, University of Liverpool, Liverpool, United Kingdom
• ¹⁹ conect4children Stichting, Utrecht, Netherlands
• ²⁰ Duke Clinical Research Institute, School of Medicine, Duke University, Durham, North Carolina, United States
• ²¹ Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina, United States

Background: Conducting clinical trials (CTs) with children presents several challenges. A major challenge is the need to enrol participants at multiple sites across different jurisdictions. Regardless of whether the trials involve children, adults, or both, CTs need to meet separate Competent Authority (CA) requirements to proceed in each participating country. This work, undertaken by the Working Group (WG) on International Collaborations at the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA) aims to describe the regulatory requirements including any specific to pediatrics, as well as current or upcoming changes across six jurisdictions – the European Union (EU), United Kingdom (UK), United States of America (USA), Canada, Japan, and Australia. Methods: An open questionnaire developed by the WG and directed at both the CA and the national pediatric clinical trial networks arranged by jurisdictions. Results: A synopsis of the current legislative and regulatory requirements for CTs applications, application submission processes and application requirements is presented for each of the six jurisdictions. Requirements were found to be mostly consistent across jurisdictions. No difference was found in processes for CTs submission, review, and authorization for pediatric CTs versus CTs in adults. However, there are additional Ethics Committee/Institutional Review Board requirements for clinical trials including children. Some jurisdictions are considering adopting a risk-based approach, inspired by the Organization of Economic Co-operation and Development (OECD) recommendations on Governance. Changes currently or soon to be implemented in some jurisdictions are also described. Conclusions: Regulators from the jurisdictions represented in this WG are collaborating to facilitate regulatory harmonization and foster international alignment of pediatric CTs. By interacting with their respective regulatory bodies and developing expertise in their jurisdiction’s regulatory requirements, national pediatric networks can support both academic and industry sponsors in navigating the regulatory process for CTs.