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Children Are Not Just Small Adults: The Urgent Need for High-Quality Trial Evidence in Children
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Terry Klassen and colleagues discuss a new study examining whether children and adults with drug-resistant partial epilepsy respond differently to antiepileptic drugs.
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“Of the included studies, 5 were pilot trials,37,38,39,40,43 with insufficient power to detect small treatment effect sizes.”
From Safety Planning Interventions for Suicide Prevention in Children and Adolescents: A Systematic Review and Meta-Analysis (2025) · cites this paper as [38]
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“A differential effectiveness of treatment by patient age has similarly been noted for other interventions, including pharmacological treatments, with potentially harmful effects for pediatric populations48,49”
From Safety Planning Interventions for Suicide Prevention in Children and Adolescents: A Systematic Review and Meta-Analysis (2025) · cites this paper as [49]
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“SI was designated as a primary outcome in zero studies and designated as a secondary outcome in 3 studies.35,38,40”
From Safety Planning Interventions for Suicide Prevention in Children and Adolescents: A Systematic Review and Meta-Analysis (2025) · cites this paper as [38]
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“In controlled trials with children and adolescents,35,38,39,40,42,43,44 control conditions were often vaguely defined and sometimes involved elements of safety planning to varying degrees, although results were consistent whether these studies were removed (Figure 2) or included (eFigure in Supplement 1).”
From Safety Planning Interventions for Suicide Prevention in Children and Adolescents: A Systematic Review and Meta-Analysis (2025) · cites this paper as [38]
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“There is an urgent need for high-quality research in children, to ensure that drugs used in the pediatric setting are both safe and effective [63].”
Standard 6: Age Groups for Pediatric Trials
Williams, K. J., Thomson, D., Seto, I., Contopoulos‐Ioannidis, D. G., Ioannidis, J. P. A., Curtis, S. J., Constantin, E., Batmanabane, G., Hartling, L., & Klassen, T. P. (2012) · PEDIATRICS · doi:10.1542/peds.2012-0055i · Cited by 555
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The evolution of a new publication type: Steps and challenges of producing overviews of reviews
Thomson, D., Russell, K. F., Becker, L. A., Klassen, T. P., & Hartling, L. (2010) · Research Synthesis Methods · doi:10.1002/jrsm.30 · Cited by 110
“To take only a few reasons for this: children may have differing etiologies for the same condition, they often metabolize medications differently, and, moreover, children experience a different range of diseases than adults (Caldwell et al., 2004; Klassen et al., 2008; Shaddy et al., 2007).”
BackgroundSelf-citationFernandes, R. M., van der Lee, J. H., & Offringa, M. (2009) · BMC Pediatrics · doi:10.1186/1471-2431-9-77 · Cited by 43
“There is consensus that DMCs should be a standard requirement for trials with vulnerable populations, such as children[1,4,5,7,20-22] In a recent review of pediatric trials performed until 2002, only 2% of the trials were reported to have a safety committee[23] Recent US and EU regulations that require research on med…”
Self-citationMoncrieffe, H., Ursu, S., Holzinger, D., Patrick, F., Kassoumeri, L., Wade, A., Roth, J., & Wedderburn, L. (2013) · Rheumatology · doi:10.1093/rheumatology/ket152 · Cited by 102
Machine Learning in Pediatric Healthcare: Current Trends, Challenges, and Future Directions
Ganatra, H. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14030807 · Cited by 93
Analysis of pediatric adverse reactions to transfusions
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“Immunologic Allergic 843 (323) 689 (72) FNHTR 445 (171) 1,063 (110) AHTR 13 (5) 8 (1) DSTR 13 (5) 248 (26) TRALI 4 (2) 7 (1) DHTR 1 (<0.”
Ethical considerations in AI for child health and recommendations for child-centered medical AI
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The development of medicines for children
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“However, most paediatric specialties have historically had low levels of clinical trial activity [1,2].”
BackgroundHamm, M. P., Hartling, L., Milne, A., Tjosvold, L., Vandermeer, B., Thomson, D., Curtis, S. J., & Klassen, T. P. (2010) · BMC Pediatrics · doi:10.1186/1471-2431-10-96 · Cited by 73
“appropriate outcome selection, data and safety monitoring committees, sample size, ROB), StaR Child Health aims to be an important contributor to a methodologically strong evidence base for pediatric care [33].”
BackgroundSelf-citationCohen, E., Goldman, R., Ragone, A., Uleryk, E., Atenafu, E., Siddiqui, U., Mahmoud, N., & Parkin, P. (2010) · Archives of Pediatrics & Adolescent Medicine · doi:10.1001/archpediatrics.2009.291 · Cited by 69
Thomson, D., Hartling, L., Cohen, E., Vandermeer, B., Tjosvold, L., & Klassen, T. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013106 · Cited by 63
“Driven by concern about the potential impact of this poor reporting on the quality and applicability of child health trials, a group of pediatric clinicians, methodologists and policy makers, including some of the authors of this article, have formed the StaR Child Health initiative, which is aimed at promoting the us…”
BackgroundSelf-citationStaR Child Health: an initiative for RCTs in children.
Klassen, T., Hartling, L., Hamm, M. P., van der Lee, J. H., Ursum, J., & Offringa, M. (2009) · The Lancet · doi:10.1016/s0140-6736(09)61803-1 · Cited by 59
Self-citationOff-Label Prescribing in Pediatric Population—Literature Review for 2012–2022
Petkova, V., Georgieva, D., Dimitrov, M., & Nikolova, I. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15122652 · Cited by 54
“It is widely acknowledged that children constitute a diverse and heterogeneous population, encompassing preterm neonates to post-pubertal adolescents, and are not simply miniature versions of adults [13].”
BackgroundNanomedicines in the future of pediatric therapy.
Sosnik, A., & Carcaboso, A. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.05.004 · Cited by 54
Standard 1: Consent and Recruitment
Caldwell, P., Dans, L. F., de Vries, M. D., Newman, J., Sammons, H., Spriggs, M., Tambe, P., Hoff, W., Woolfall, K., Young, B., et al. (2012) · Pediatrics · doi:10.1542/peds.2012-0055d · Cited by 54
“ploitation: (1) socioeconomic inequal-”
BackgroundSelf-citationLevetiracetam Monotherapy in Children with Epilepsy: A Systematic Review
Weijenberg, A., Brouwer, O., & Callenbach, P. (2015) · CNS Drugs · doi:10.1007/s40263-015-0248-9 · Cited by 51
“Children, however, have a different developmental physiology, disease pathophysiology, pharmacokinetics and/or pharmacodynamics, resulting in treatment responses that are unpredictably different from those in adults [60, 61].”
BackgroundAdvances in biomarkers for paediatric rheumatic diseases
Consolaro, A., Varnier, G., Martini, A., & Ravelli, A. (2015) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2014.208 · Cited by 49
Zarbock, A., Forni, L. G., Koyner, J. L., Bell, S., Reis, T. D. A., Meersch, M., Bagshaw, S. M., Fuhmann, D. Y., Liu, K. D., Pannu, N., et al. (2024) · Intensive Care Medicine · doi:10.1007/s00134-024-07560-y · Cited by 49
“Importantly, children are a heterogeneous group, ranging from preterm neonates to post-pubertal adolescents [44].”
BackgroundEffects of botulinum toxin A on calf muscles in children with cerebral palsy: a systematic review
Koog, Y., & Min, B. (2010) · Clinical Rehabilitation · doi:10.1177/0269215510367557 · Cited by 46
Pharmacokinetics of nanotechnology-based formulations in pediatric populations
Yellepeddi, V., Joseph, A., & Nance, E. A. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.08.008 · Cited by 67
“In particular, relying on adult safety and efficacy data has resulted in unpredictable and tragic outcomes in children [167].”
BackgroundDeterminants of reduced health-related quality of life in pediatric inherited neuropathies
Burns, J., Ramchandren, S., Ryan, M., Shy, M., & Ouvrier, R. (2010) · Neurology · doi:10.1212/wnl.0b013e3181eee496 · Cited by 43
Current Developments in the Use of Biomarkers for Juvenile Idiopathic Arthritis
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Quantifying Bias in Randomized Controlled Trials in Child Health: A Meta-Epidemiological Study
Hartling, L., Hamm, M. P., Fernandes, R., Dryden, D., & Vandermeer, B. (2014) · PLoS ONE · doi:10.1371/journal.pone.0088008 · Cited by 39
“[6,7] A meta-epidemiological study to quantify bias in a sample of pediatric trials would better inform the design, conduct, reporting, and interpretation of research in child health.”
BackgroundSelf-citationRandomized trial of adjunctive topiramate therapy in infants with refractory partial seizures
Novotny, E., Renfroe, B., Yardi, N., Nordli, D., Ness, S., Wang, S., Weber, T., Kurland, C. L., Yuen, E., Eerdekens, M., et al. (2010) · Neurology · doi:10.1212/wnl.0b013e3181d1cd4c · Cited by 39
“Black or African American 1 (3) 1 (3) 1 (3) 2 (5)”
Walking and balance in children and adolescents with lower‐limb amputation: A review of literature
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Possible harms of oseltamivir--a call for urgent action.
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Parekh, R., Hammond, B. R., & Divya, C. (2024) · Advances in Therapy · doi:10.1007/s12325-024-02785-1 · Cited by 37
“A common aphorism in pediatrics observes that children are not simply small adults [1].”
BackgroundGolhen, K., Buettcher, M., Kost, J., Huwyler, J., & Pfister, M. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15041033 · Cited by 33
“Pediatric patients are a heterogeneous population ranging from preterm and term neonates, infants, older children to post-pubertal adolescents [60].”
BackgroundComparative effectiveness of medical interventions in adults versus children.
Contopoulos-Ioannidis, D., Baltogianni, M. S., & Ioannidis, J. (2010) · Jornal de Pediatria · doi:10.1016/j.jpeds.2010.02.011 · Cited by 33
Nasser, M., Fedorowicz, Z., Aljufairi, H., & Mckerrow, W. (2010) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd006989.pub2 · Cited by 33
Prevalence, Cost, and Variation in Cost of Pediatric Hospitalizations in Ontario, Canada
Gill, P., Thavam, T., Anwar, M. R., Zhu, J. W., Parkin, P., Cohen, E., To, T., Mahant, S., Buchanan, F., Chen, W.-J., et al. (2022) · JAMA Network Open · doi:10.1001/jamanetworkopen.2021.47447 · Cited by 32
Browne, P. D., Nagelkerke, S. C. J., van Etten‐Jamaludin, F. S., Benninga, M. A., & Tabbers, M. M. (2018) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2018.1540298 · Cited by 40
“However, this approach may bring unintended harm, because efficacy and safety profiles of pharmacological treatments appear significantly different for children compared to adults [47].”
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Clark, R., Locke, M., & Bialocerkowski, A. (2015) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.12803 · Cited by 32
“Current paediatric term variability has thus created confusion throughout the health care setting.(7,9,11,12) Consistent definitions are required to strengthen the communication between departments, facilities, and families.”
BackgroundContopoulos-Ioannidis, D., Seto, I., Hamm, M. P., Thomson, D., Hartling, L., Ioannidis, J., Curtis, S., Constantin, E., Batmanabane, G., Klassen, T., et al. (2012) · Pediatrics · doi:10.1542/peds.2012-0055j · Cited by 32
“These pertained to the following: (1) acyclovir for treating varicella in otherwise healthy children and adolescents58; (2) antibiotics for preventing complications in children with measles62; (3) antibiotics for the prevention of acute and chronic suppurative otitis media in children64; (4) gastroesophageal reflux tr…”
BackgroundMethodInfluentialSelf-citationReview on the current use of antipsychotic drugs in children and adolescents
Almandil, N., & Wong, I. (2011) · Archives of Disease in Childhood - Education and Practice · doi:10.1136/archdischild-2011-300054 · Cited by 32
Standard 2: Containing Risk of Bias
Hartling, L., Hamm, M. P., Klassen, T. P., Chan, A., Meremikwu, M. M., Moyer, V. A., Scott, S. D., Moher, D., & Offringa, M. (2012) · PEDIATRICS · doi:10.1542/peds.2012-0055e · Cited by 29
Self-citationQuality of Reporting of Neonatal and Infant Trials in High-Impact Journals
DeMauro, S., Giaccone, A., Kirpalani, H., & Schmidt, B. (2011) · Pediatrics · doi:10.1542/peds.2011-0377 · Cited by 31
Core Outcome Sets in Child Health
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Is the perceived placebo effect comparable between adults and children? A meta-regression analysis
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Trends in Antiepileptic Drug Use in Children and Adolescents With Epilepsy.
Liu, X., Carney, P., Bussing, R., Segal, R., Cottler, L., & Winterstein, A. (2017) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2017.05.016 · Cited by 28
Lack of children in public medical imaging data points to growing age bias in biomedical AIPreprint
Hua, S. B. Z., Heller, N., He, P., Towbin, A., Chen, I. Y., Lu, A. X., & Erdman, L. (2025) · medRxiv · doi:10.1101/2025.06.06.25328913 · Cited by 27
“The neglect of age-related differences mirrors historical patterns in drug 12 and device development 13,14 , where children suffer disparities in quality of care compared to adults 15–17 .”
Shi, L., Chang, J., Liu, X., Zhai, P., Hu, S.-C., Li, P., Hayat, K., Kabba, J., Feng, Z., Yang, C.-J., et al. (2020) · Antibiotics · doi:10.3390/antibiotics9040163 · Cited by 27
“Children are more vulnerable to potential risks of medicines [17], and Chinese guidelines on clinical use of antibiotics explicitly detail the specific requirements of antibiotic use in children.”
BackgroundSierawska, A., Prehn-Kristensen, A., Moliadze, V., Krauel, K., Nowak, R., Freitag, C., Siniatchkin, M., & Buyx, A. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00334 · Cited by 27
“However, in view of the significant health needs of children with ADHD that are not met, and the general importance of providing robust clinical evidence in pediatrics (41), it is urgently required to design studies that consider the complexities of research in such vulnerable study populations.”
BackgroundSafety of Medical Interventions in Children Versus Adults
Lathyris, D., Panagiotou, O., Baltogianni, M. S., Ioannidis, J., & Contopoulos-Ioannidis, D. (2014) · Pediatrics · doi:10.1542/peds.2013-3128 · Cited by 27
Lyons, H., Mollan, S. L. P., Liu, G. T., Bowman, R., Thaller, M., Sinclair, A., & Mollan, S. (2022) · Neuro-ophthalmology (Aeolus Press. 1980) · doi:10.1080/01658107.2022.2153874 · Cited by 26
“There is a greater challenge for paediatric IIH, as it has been documented that there is a lack of high quality designed research in other paediatric conditions(7) and investment in paediatric research is insufficient.(8) There is an unmet clinical need for research to guide the medical and surgical management of paed…”
BackgroundThe Evidence-based Medicine Paradigm: Where are We 20 Years Later? Part 1
Seshia, S. S., & Young, G. B. (2013) · Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques · doi:10.1017/s0317167100014542 · Cited by 30
“99-101 the initiative is relevant for Pediatric clinical neurosciences.”
Bow, S., Klassen, J., Chisholm, A., Tjosvold, L., Thomson, D., Klassen, T., Moher, D., & Hartling, L. (2010) · BMC Pediatrics · doi:10.1186/1471-2431-10-34 · Cited by 26
“This is particularly problematic in situations where the safety and efficacy of interventions for children may differ from adults due to variations in developmental physiology, disease pathophysiology, or developmental pharmacokinetics and pharmacodynamics [7].”
BackgroundSelf-citationNavarro, D. F., Tendal, B., Tingay, D., Vasilunas, N., Anderson, L., Best, J., Burns, P., Cheyne, S., Craig, S., Erickson, S., et al. (2021) · Medical Journal of Australia · doi:10.5694/mja2.51305 · Cited by 25
Randomized controlled trials in children’s heart surgery in the 21st century: a systematic review
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“safety of participants and the integrity of trial data [16].”
BackgroundMartin-Kerry, J., Bower, P., Young, B., Graffy, J., Sheridan, R., Watt, I., Baines, P., Stones, C., Preston, J., Higgins, S., et al. (2017) · Trials · doi:10.1186/s13063-017-1962-z · Cited by 23
“The lack of successful clinical trials leads to many healthcare decisions for children and adolescents being made with inadequate evidence, including evidence extrapolated from trials involving adults [12].”
BackgroundStandard 3: Data Monitoring Committees
Ellenberg, S., Fernandes, R., Saloojee, H., Bassler, D., Askie, L., Vandermeer, B., Offringa, M., van der Tweel, I., Altman, D., & van der Lee, J. H. (2012) · Pediatrics · doi:10.1542/peds.2012-0055f · Cited by 23
“• DMCs should be established for all pediatric trials: (1) addressing major morbidity or mortality end points; (2) with preplanned interim analyses and the possibility of early stopping; (3) in populations with a high risk of severe outcomes; and (4) investigating new interventions with few safety data available • Cri…”
BackgroundSelf-citationBenedetti, F. D., & Ravelli, A. (2000) · BioDrugs · doi:10.2165/00063030-200014020-00003 · Cited by 430
Thomson, D., Foisy, M., Oleszczuk, M., Wingert, A., Chisholm, A., & Hartling, L. (2013) · Evidence-Based Child Health A Cochrane Review Journal · doi:10.1002/ebch.1897 · Cited by 23
“60) (8) (6–12) Treatment failure (excluding studies 47/100 18/100 OR 0.”
BackgroundInfluentialSelf-citationPriority setting in paediatric preventive care research
Lavigne, M., Birken, C., Maguire, J., Straus, S., & Laupacis, A. (2017) · Archives of Disease in Childhood · doi:10.1136/archdischild-2016-312284 · Cited by 22
Impact of standardization of antimicrobial prophylaxis duration in pediatric cardiac surgery.
Bath, S., Lines, J., Loeffler, A. M., Malhotra, A., & Turner, R. B. (2016) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/j.jtcvs.2016.04.091 · Cited by 22
“Median length of stay (d), n (IQR) 7 (5-12) 7 (5-10.”
Sportel, E., Wolcherink, M. O. O., van der Palen, J., Lenferink, A., Thio, B., Movig, K., & Brusse-Keizer, M. (2020) · Trials · doi:10.1186/s13063-020-04694-4 · Cited by 21
Clinical trials: Kids are not just little people.
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“Relevance to previous research Previous studies have suggested that there may be insufficient evidence specific to children in certain topic areas [13,31,32,33], especially non-drug interventions such as counseling and advice [34].”
BackgroundSelf-citationLoss functions in restricted parameter spaces and their Bayesian applications
Mozgunov, P., Jaki, T., & Gasparini, M. (2017) · Journal of Applied Statistics · doi:10.1080/02664763.2019.1586848 · Cited by 20
“There is overwhelmingmedical evidence that children’s response cannoticeably differ from the adults’ response in many diseases [15,32].”
Do systematic reviews on pediatric topics need special methodological considerations?
Farid‐Kapadia, M., Askie, L. M., Hartling, L., Contopoulos‐Ioannidis, D. G., Bhutta, Z. A., Soll, R. F., Moher, D., & Offringa, M. (2017) · BMC Pediatrics · doi:10.1186/s12887-017-0812-1 · Cited by 22
“often excluded, from clinical research [1].”
BackgroundSelf-citationEvidence-based guidelines for pediatric clinical trials: focus on StaR Child Health
Sampson, M., Benjamin, D., & Cohen-Wolkowiez, M. (2012) · Expert Review of Clinical Pharmacology · doi:10.1586/ecp.12.52 · Cited by 20
Data monitoring committees, interim analysis and early termination in paediatric trials
Fernandes, R., van der Lee, J. H., & Offringa, M. (2011) · Acta paediatrica · doi:10.1111/j.1651-2227.2011.02282.x · Cited by 20
“DMCs for paediatric trials should be aware that evaluating harms in paediatrics is challenging and requires attention to child-specific safety issues (1).”
BackgroundSelf-citationA systematic review of paediatric randomised controlled drug trials published in 2007
Aripin, K. N. N., Choonara, I., & Sammons, H. M. (2010) · Archives of Disease in Childhood · doi:10.1136/adc.2009.173591 · Cited by 22
“Another concern was that trials recruiting both children and adults often inadequately describe the characteristics of paediatric participants. This is essential to report because of the potential differences in pharmacokinetics and pharmacodynamics between paediatric and adult participants.”
BackgroundClayton, P., Connelly, J., Ellington, M., Rojas, V., Lorenzo, Y., Trak‐Fellermeier, M. A., & Palacios, C. S. (2021) · Obesity Reviews · doi:10.1111/obr.13335 · Cited by 29
“There is enough evidence showing that early lifestyle interventions positively impact the risk of non-communicable chronic diseases at an early stage, which could have a large impact on public health.(8) Despite this, most intervention studies are on adults, and the results of these studies have been extrapolated to c…”
BackgroundDigra, K. K., Pandita, A., Saini, G., & Bharti, R. (2015) · Clinical Medicine Insights: Pediatrics · doi:10.4137/cmped.s29493 · Cited by 19
Comparison of transfusion reactions in children and adults: A systematic review and meta‐analysis
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Sample size calculations in pediatric clinical trials conducted in an ICU: a systematic review
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“However, there remains a deficit of age-appropriate evidence base (1).”
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“Moreover, it is currently known that children are not similar to small adults (6); as children have a different biochemical profile (7).”
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“However, today, targeting specific age groups in human studies remains rare (1).”
Background
Metadata
- Authors
- Klassen, T. P., Hartling, L., Craig, J. C., & Offringa, M.
- Affiliations
- University of Alberta (CA)
- The University of Sydney (AU)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Klassen, Terry P
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-08-12
- Volume
- 5
- Issue
- 8
- Pages
- e172
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC2504487
- OpenAlex
- W2133984258
- Cited by
- 209
- References
- 17
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 14 · 2023: 17 · 2022: 13 · 2021: 12 · 2020: 9 · 2019: 11 · 2018: 10 · 2017: 19 · 2016: 7 · 2015: 10 · 2014: 13 · 2013: 6 · 2012: 12
- FWCI
- 7.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- pediatric clinical trials, drug-resistant epilepsy, focal epilepsy, antiepileptic drugs, children versus adults, epilepsy treatment
- MeSH terms
- Adult, Child, Clinical Trials as Topic, Epilepsy, Humans, Placebos
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