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Ethical and procedural issues for applying researcher-driven multi-national paediatric clinical trials in and outside the European Union: the challenging experience of the DEEP project
Open accessAbstract
Background: We describe our experience from a multi-national application of a European Union-funded research-driven paediatric trial (DEEP-2, EudraCT 2012-000353-31; NCT01825512). This paper aims to evaluate the impact of the local and national rules on the trial authorisation process in European and non-European countries. National/local provisions and procedures, number of Ethics Committees and Competent Authorities to be addressed, documentation required, special provisions for the paediatric population, timelines for completing the authorisation process and queries received were collected; compliance with the European provisions were evaluated. Descriptive analysis, Wilcoxon Rank-Sum test and General Linear Model analysis were used to determine factors potentially influencing the timelines. The Cluster Analysis procedure was used to identify homogenous groups of cases. Result: The authorisation process was completed in 7.7 to 53.8 months in European countries and in 17.1 to 27.1 months in non-European countries. The main factors influencing these timelines were the requests for changes/clarifications in European countries and the different national legislations in non-European countries. Conclusion: This work confirms that the procedures and requirements for the clinical trial application of a paediatric trial are different. In the European Union, the timeframes for submission were generally harmonised but longer. In non-European countries, delays were caused by national dispositions but the entire authorisation process resulted faster with less requests from ECs/CAs. The upcoming application of Regulation (EU) 536/2014 is expected to harmonise practices in Europe and possibly outside. Networks on paediatric research acting at international level will be crucial in this effort.
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![Fig. 1 Number of additional documents required by Competent Authorities and Ethics Committees. This scatter-plot shows the number of documents required by each country in addition to those required by the EC guidance [5, 6] for each country and the means of EU and non-EU countries. For Italy, the numbers vary according to the 12 sites. For Egypt, the 3 ECs were considered. The numbers behind the country name are the site numbers](/paper-figures/dc05f7f031ba49cf853d98b658fe1c01/ethical-and-procedural-issues-for-applying-researcher-driven-multi-national-figure-1.jpg)
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“Furthermore, this review did not include paediatric studies, where enablers and barriers of trial participation might differ considerably from those of adults [80].”
From Enablers and barriers of clinical trial participation in adult patients from minority ethnic groups: a systematic review (2025) · cites this paper as [80]
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“The present review also underscored the value of patient navigators [41], community liaisons [40] and cultural ambassadors [80] in the recruitment of patients from minority ethnic groups into clinical trials.”
From Enablers and barriers of clinical trial participation in adult patients from minority ethnic groups: a systematic review (2025) · cites this paper as [80]
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Citations
Cites
Filibeck, U., & Sanzi, E. (2017) · Microchemical Journal · doi:10.1016/j.microc.2017.08.003 · Cited by 83
Maggio, A., Kattamis, A., Felisi, M., Reggiardo, G., El-Beshlawy, A. M., Béjaoui, M., Sherief, L. M., Christou, S., Cosmi, C., Pasqua, O. E. D., et al. (2020) · The Lancet Haematology · doi:10.1016/s2352-3026(20)30100-9 · Cited by 74
Self-citationClinical Trial Application in Europe: What Will Change with the New Regulation?
Giannuzzi, V., Altavilla, A., Ruggieri, L., & Ceci, A. (2015) · Science and Engineering Ethics · doi:10.1007/s11948-015-9662-0 · Cited by 27
Self-citationThe ethical framework for performing research with rare inherited neurometabolic disease patients
Giannuzzi, V., Devlieger, H., Margari, L., Odlind, V., Ragab, L., Bellettato, C. M., D’Avanzo, F., Lampe, C., Cassis, L., Cortès‐Saladelafont, E., et al. (2017) · European Journal of Pediatrics · doi:10.1007/s00431-017-2852-9 · Cited by 22
Self-citationBottoni, R., & Tirabassi, M. (2013) · Quaderni di diritto e política ecclesiastica · Cited by 16
Altavilla, A., Giaquinto, C., Giocanti, D., Manfredi, C., Aboulker, J.-P., Bartoloni, F., Cattani, E., Giudice, M. L., Mellado, M. J., Nagler, R. M., et al. (2009) · Pharmaceuticals Policy and Law · doi:10.3233/ppl-2009-0208 · Cited by 11
Self-citationMatheson, L. A., Huber, A. M., Warner, B. A., & Rosenberg, A. M. (2012) · Paediatrics & Child Health · doi:10.1093/pch/17.6.313 · Cited by 10
Ceci, A., Conte, R., Didio, A., Bonifazi, D., Felisi, M., Giannuzzi, V., & Bonifazi, F. (2019) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2019.1613977 · Cited by 8
Self-citationReihart, D., & Platonov, P. G. (2005) · International Journal of Pharmaceutical Medicine · doi:10.2165/00124363-200519020-00002 · Cited by 6
Research works printed but not linked: 2
- Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92. European Parliament, Council of the European Union (2006) Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. Official Journal of the European Union L 378:1–19
- DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2020–N–0837] Rare Disease Clinical Trial Networks; Request for Information and Comments. Federal Register / Vol. 85, No. 105 / Monday, June 1, 2020 / Notices.
Cited by
Ru, Q., Li, Y., Zhang, F., Chen, L., Wu, Y., Min, J., & Wang, F. (2025) · Bone Research · doi:10.1038/s41413-024-00398-6 · Cited by 64
Alarcón Garavito, G. A., Gilchrist, K., Ciurtin, C., Khanna, S., Chambers, P., McNally, N., Merivale, E., Carr, E., Yu, R., & Vindrola-Padros, C. (2025) · Trials · doi:10.1186/s13063-025-08769-y · Cited by 42
“These cultural ambassadors acted as the bridge between the medical school and communities, supporting the development of protocols, recruitment plans, translation services and planning community engagement activities [80].”
InfluentialSalmanton‐García, J., Stewart, F. A., Heringer, S., Koniordou, M., Álvarez-Barco, E., Argyropoulos, C. D., Themistocleous, S., Valle-Simón, P., Spivak, O., Součková, L., et al. (2022) · Vaccine · doi:10.1016/j.vaccine.2022.05.022 · Cited by 30
VACCELERATE Site Network: Real-time definition of clinical study capacity in Europe
Salmanton‐García, J., Wipfler, P., Valle-Simón, P., Merakou, C., Kopsidas, I., Bethe, U., Steinbach, A., Spivak, O., Součková, L., Mendonça, M. A., et al. (2023) · Vaccine · doi:10.1016/j.vaccine.2023.05.006 · Cited by 10
Effects of the Paediatric Regulation funding on the development of off-patent medicines in children
Ruggieri, L., Torretta, S., Giannuzzi, V., Natale, A., Felisi, M., Ceci, A., & Bonifazi, F. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2024.1473862 · Cited by 7
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Metadata
- Authors
- Giannuzzi, V., Felisi, M., Bonifazi, D., Devlieger, H., Papanikolaou, G., Ragab, L., Fattoum, S., Tempesta, B., Reggiardo, G., & Ceci, A.
- Affiliations
- Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus (IT)
- Consorzio per Valutazioni Biologiche e Farmacologiche (IT)
- KU Leuven (BE)
- Harokopio University of Athens (GR)
- Cairo University (EG)
- Tunis El Manar University (TN)
- Corresponding author
- Giannuzzi, Viviana
- ORCID
- Venue
- BMC Medical Ethics
- Published
- 2021-04-29
- Volume
- 22
- Issue
- 1
- Pages
- 49-49
- ISSN
- 1472-6939 (ISSN-L)
- PMC
- PMC8086274
- OpenAlex
- W3133161322
- Cited by
- 11
- References
- 10
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 1
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- BMC Medical Ethics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- European Commission (261483)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ethics in Clinical Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Health Sciences › Nursing › Issues, ethics and legal aspects › Biomedical Ethics and Regulation
- Keywords
- pediatric clinical trials, regulatory timelines, competent authorities, national legislation, EU harmonization, international research networks, non-European countries
- MeSH terms
- Child, Europe, European Union, Humans, Morals, Research Personnel
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- CoChat. (2026). Citation check: Ethical and procedural issues for applying researcher-driven multi-national paediatric clinical trials in and outside the European Union: the challenging experience of the DEEP project. https://app.cochat.ai/papers/10.1186/s12910-021-00618-2
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- Giannuzzi, V., Felisi, M., Bonifazi, D., Devlieger, H., Papanikolaou, G., Ragab, L., Fattoum, S., Tempesta, B., Reggiardo, G., & Ceci, A. (2021). Ethical and procedural issues for applying researcher-driven multi-national paediatric clinical trials in and outside the European Union: the challenging experience of the DEEP project. BMC Medical Ethics. https://doi.org/10.1186/s12910-021-00618-2
