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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 with insufficient power to detect small treatment effect sizes.
“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]
The 'Where to Go from Here' section warns that inadequately powered pediatric studies can fail to provide valid treatment-effect estimates. It does not identify five included studies as pilot trials or assess whether those trials could detect small treatment effects; its 'Epilepsy as a Case Study' section describes a different set of five pediatric trials. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDifferential effectiveness of treatment by patient age has been noted for other interventions, including pharmacological treatments, with potentially harmful effects for pediatric populations.
“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]
Suicide ideation was designated as a primary outcome in zero studies and as a secondary outcome in 3 studies.
“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]
The Epilepsy as a Case Study section identifies seizure response as the primary outcome of the study it discusses, while Where to Go from Here discusses pediatric trial endpoints and safety monitoring. Searches for suicide or suicidal ideation and for the claimed primary- and secondary-outcome counts found no passage addressing them in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn controlled trials with children and adolescents, 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 or included.
“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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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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“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…”
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“However, most paediatric specialties have historically had low levels of clinical trial activity [1,2].”
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“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].”
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“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
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“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].”
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Standard 1: Consent and Recruitment
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“ploitation: (1) socioeconomic inequal-”
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“Importantly, children are a heterogeneous group, ranging from preterm neonates to post-pubertal adolescents [44].”
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“In particular, relying on adult safety and efficacy data has resulted in unpredictable and tragic outcomes in children [167].”
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“[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.”
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“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 .”
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“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.”
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“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.”
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“safety of participants and the integrity of trial data [16].”
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“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
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“• 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…”
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“60) (8) (6–12) Treatment failure (excluding studies 47/100 18/100 OR 0.”
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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].”
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“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?
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“often excluded, from clinical research [1].”
BackgroundSelf-citationEvidence-based guidelines for pediatric clinical trials: focus on StaR Child Health
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Data monitoring committees, interim analysis and early termination in paediatric trials
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“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
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“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.”
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“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…”
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Comparison of transfusion reactions in children and adults: A systematic review and meta‐analysis
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“If estimation is accurate, it is expected that these discrepancies will take place in both directions (both over-and underestimating), causing no overall effect in the design characteristics of the RCTs reviewed.”
InfluentialGuo, K., Wang, X.-H., Zhang, H., Wang, M., Song, S.-L., & Ma, S. (2021) · Frontiers in Pediatrics · doi:10.3389/fped.2021.660297 · Cited by 17
“However, there remains a deficit of age-appropriate evidence base (1).”
BackgroundIdentification of juvenility-associated genes in the mouse hepatocytes and cardiomyocytes
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“Recently, there has been considerable advocacy for the performance of well-designed trials on children (66,67).”
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Self-citationA Revisited Strategy for Antiepileptic Drug Development in Children
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“The efficacy signals must then be confirmed by high-quality RCTs [42].”
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Baba, A., Aregbesola, A., Caldwell, P. H. Y., Elliott, S. A., Elsman, E. B. M., Fernandes, R. M., Hartling, L., Heath, A., Kelly, L. E., Preston, J., et al. (2024) · PEDIATRICS · doi:10.1542/peds.2024-065799 · Cited by 16
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Joseph, P. D., Caldwell, P. H. Y., Barnes, E. H., Hynes, K., Choong, C. S. Y., Turner, S., Vosk, C., White, J., Richichi, K., & Craig, J. (2018) · Journal of Paediatrics and Child Health · doi:10.1111/jpc.14189 · Cited by 13
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Self-citationPediatric biobanks to enhance clinical and translational research for children
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“As such, with a clearly demonstrated need for high-quality research in these ages [13,14], this finding negates excuses for poor methodology.”
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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).”
BackgroundLarge Pediatric Randomized Clinical Trials in ClinicalTrials.gov
Cho, S. M., Serghiou, S., Ioannidis, J., Klassen, T., & Contopoulos-Ioannidis, D. (2021) · Pediatrics · doi:10.1542/peds.2020-049771 · Cited by 10
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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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