Abstract
Purpose
Despite representing a fundamental step towards the efficacious and safe utilisation of drugs in the paediatric population, the conduct of clinical trials in children poses several problems. Methodological issues and ethical concerns represent the major obstacles that have traditionally limited paediatric research. The randomised clinical trial, mainstay of clinical studies to assess the effects of any therapeutic intervention, shows some weaknesses that make it scarcely applicable to the paediatric population. Alternative and innovative approaches to clinical trial design in small populations have been developed in the last few decades with the aim of overcoming the limits related to small samples and to the acceptability of the trial.
Methods
This systematic review describes a variety of alternative designs to assess efficacy and safety in the paediatric population, including their applicability, advantages, disadvantages and real case examples. Approaches include sequential and adaptive designs, Bayesian methods and other innovative approaches.
Results
By limiting the sample size and increasing acceptability, these methods may rationally limit the amount of experimentation in children to what is achievable, necessary and ethical
Conclusion
Thanks to their features, these methods represent a reliable way of ultimately improving paediatric care.
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References
European Parliament and the Council of the European Union (2001) Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Off J Eur Communities L121:34–44
European Parliament and the Council of the European Union (2006) Regulation (EC) No 1901/2006, 12 December 2006, on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. Off J Eur Union L378:1–19
European Parliament and the Council of the European Union (2006) Regulation (EC) No 1902/2006 of the European Parliament and of the Council of 20 December 2006 amending Regulation 1901/2006 on medicinal products for paediatric use. Off J Eur Union L378:20–21
European Medicines Agency (2001) ICH/Topic E11. Clinical Investigation of Medicinal Products in the Paediatric Population. Step 5—Note for guidance on clinical investigation of medicinal products in the paediatric population. CPMP/ICH/2711/99. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002926.pdf. Accessed 24 December 2010
Committee for Medicinal Products for Human Use—CHMP (2006) Guideline on clinical trials in small populations. Doc. Ref. CHMP/EWP/83561/2005. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003615.pdf. Accessed 24 December 2010
Committee for Medicinal Products for Human Use—CHMP (2009) Guideline on the clinical development of medicinal products for the treatment of cystic fibrosis. Doc. Ref. EMEA/CHMP/EWP/9147/2008. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/12/WC500017055.pdf. Accessed 24 December 2010
Committee for Medicinal Products for Human Use—CHMP (2009) Guideline on the requirements for clinical documentation for orally inhaled products (OIP) including the requirements for demonstration of therapeutic equivalence between two inhaled products for use in the treatment of asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of asthma in children and adolescents. Doc. Ref. CPMP/EWP/4151/00 Rev. 1. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003504.pdf. Accessed 24 December 2010
Committee for Medicinal Products for Human Use—CHMP (2010) Paediatric addendum to CHMP guideline on the clinical investigations of medicinal products for the treatment of pulmonary arterial hypertension. Draft. EMA/CHMP/EWP/213972/2010. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/06/WC500091628.pdf. Accessed 24 December 2010
Committee for Medicinal Products for Human Use—CHMP (2010) Paediatric addendum to CHMP note for guidance on clinical investigation of medicinal products in the treatment of lipid disorders. Draft. EMA/CHMP/213057/2010. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/07/WC500094340.pdf. Accessed 24 December 2010
Committee for Proprietary Medicinal Products—CPMP (2003) Note for guidance on evaluation of anticancer medicinal products in man. Addendum on paediatric oncology. EMEA/CPMP/EWP/569/02. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/10/WC500003969.pdf. Accessed 24 December 2010
Committee for Medicinal Products for Human Use—CHMP (2008) Guideline on the clinical development of medicinal products for the treatment of HIV infection. Doc. Ref. EMEA/CPMP/EWP/633/02. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003460.pdf. Accessed 24 December 2010
Goodman SN (2005) Ethics and evidence in clinical trials. Clin Trials 2(3):195–196
Palmer CR, Rosenberger WF (1999) Ethics and practice: alternative designs for phase III randomized clinical trials. Control Clin Trials 20(2):172–186
Della Pasqua O, Zimmerhackl L, Rose K (2007) Study and protocol design for paediatric patients of different ages. In: Rose K, van den Anker JN (eds) Guide to paediatric clinical research. Karger, Basel, pp 87–107
Goodman SN (2009) Stopping trials for efficacy: an almost unbiased view. Clin Trials 6(2):133–135
Van der Lee JH, Wesseling J, Tanck MW, Offringa M (2010) Sequential design with boundaries approach in pediatric intervention research reduces sample size. J Clin Epidemiol 63(1):19–27
Chow SC, Chang M (2008) Adaptive design methods in clinical trials—a review. Orphanet J Rare Dis 3:11
Schoenfeld DA, Zheng H, Finkelstein DM (2009) Bayesian design using adult data to augment pediatric trials. Clin Trials 6(4):297–304
Goodman SN, Sladky JT (2005) A Bayesian approach to randomized controlled trials in children utilizing information from adults: the case of Guillain-Barré syndrome. Clin Trials 2(4):305–310
Honkanen VE, Siegel AF et al (2001) A three-stage clinical trial design for rare disorders. Stat Med 20(20):3009–3021
Chiron C, Dulac O, Pons G (2008) Antiepileptic drug development in children: considerations for a revisited strategy. Drugs 68(1):17–25
Chiron C, Dulac O, Gram L (1996) Vigabatrin withdrawal randomized study in children. Epilepsy Res 25(3):209–215
Chiron C, Tonnelier S, Rey E, Brunet ML, Tran A, d’Athis P, Vincent J, Dulac O, Pons G (2006) Stiripentol in childhood partial epilepsy: randomized placebo-controlled trial with enrichment and withdrawal design. J Child Neurol 21(6):496–502
Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Pérez N, Silva CA, Abud-Mendoza C, Burgos-Vargas R, Gerloni V, Melo-Gomes JA, Saad-Magalhães C, Sztajnbok F, Goldenstein-Schainberg C, Scheinberg M, Penades IC, Fischbach M, Orozco J, Hashkes PJ, Hom C, Jung L, Lepore L, Oliveira S, Wallace CA, Sigal LH, Block AJ, Covucci A, Martini A, Giannini EH, Paediatric Rheumatology International Trials Organization, Pediatric Rheumatology Collaborative Study Group (2008) Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet 372(9636):383–391
Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, Nemcova D, Mouy R, Sandborg C, Bohnsack J, Elewaut D, Foeldvari I, Gerloni V, Rovensky J, Minden K, Vehe RK, Weiner LW, Horneff G, Huppertz HI, Olson NY, Medich JR, Carcereri-De-Prati R, McIlraith MJ, Giannini EH, Martini A, Pediatric Rheumatology Collaborative Study Group, Pediatric Rheumatology International Trials Organisation (2008) Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med 359(8):810–820
Feldman B, Wang E, Willan A, Szalai JP (2001) The randomized placebo-phase design for clinical trials. J Clin Epidemiol 54(6):550–557
Acknowledgements
This report is part of the Task-force in Europe for Drug Development for the Young (TEDDY) Network of Excellence supported by the European Commission’s Sixth Framework Program (Contract n. 0005216 LSHBCT- 2005-005126).
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Baiardi, P., Giaquinto, C., Girotto, S. et al. Innovative study design for paediatric clinical trials. Eur J Clin Pharmacol 67 (Suppl 1), 109–115 (2011). https://doi.org/10.1007/s00228-011-0990-y
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DOI: https://doi.org/10.1007/s00228-011-0990-y