Comparative Effectiveness of Medical Interventions in Adults Versus Children

Contopoulos‐Ioannidis, Despina G.; Baltogianni, Maria; Ioannidis, John P. A.

doi:10.1016/j.jpeds.2010.02.011

Cited by 30 publications

(27 citation statements)

References 128 publications

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“…In this study, 128 meta-analyses from Cochrane reviews, containing data on at least 1 adult and 1 pediatric randomized controlled trial (RCT) with a binary primary efficacy outcome, were reviewed. 1 The authors found that in all except 1 case, the 95% confidence intervals could not exclude a relative difference in treatment efficacy between adults and children of .20%; in two-thirds of these cases, the relative difference in observed point estimates was .50%. The study also highlighted the paucity of RCTs in pediatrics; the median number of children per metaanalysis was 2.5 times smaller than the number of adults.…”

Section: Dilemmamentioning

confidence: 95%

“…In acute traumatic brain injury, corticosteroids did not decrease mortality in adults, but there was a trend for increased mortality in children. 1 In asthma, long-acting b2-agonists decreased exacerbations in adults but tended to increase exacerbations in children. 1 Intravenous lorazepam, when compared with diazepam in status epilepticus, led to significantly more discontinuations of status in adults but not in children.…”

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confidence: 99%

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Standard 6: Age Groups for Pediatric Trials

et al. 2012

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DILEMMAIt has long been an axiom in clinical pediatrics that "children are not just little adults." It has also been recognized that there are many changes from birth through childhood and the adolescent years. However, the full implications of pediatric age groupings for health care and research are still not adequately understood. There is still much to be discovered about children' s biological and psychological development and how these processes affect the effectiveness and efficacy of interventions. Trial design that accounts for age differences and promotes consistency in reporting of age-related data is essential to ensure the validity and clinical usefulness of pediatric trial data.A recent study highlighted variable treatment efficacy in children versus adults. In this study, 128 meta-analyses from Cochrane reviews, containing data on at least 1 adult and 1 pediatric randomized controlled trial (RCT) with a binary primary efficacy outcome, were reviewed. 1 The authors found that in all except 1 case, the 95% confidence intervals could not exclude a relative difference in treatment efficacy between adults and children of .20%; in two-thirds of these cases, the relative difference in observed point estimates was .50%. The study also highlighted the paucity of RCTs in pediatrics; the median number of children per metaanalysis was 2.5 times smaller than the number of adults.Children and adults seem to have distinctive responses to treatments. For example, administration of phenobarbitones is useful for adults with cerebral malaria and is associated with decreased convulsions. However, in children, this drug is associated with increased 6-month mortality. Similarly, corticosteroids may offer survival benefit for adults with bacterial meningitis but not for children with the same condition. In acute traumatic brain injury, corticosteroids did not decrease mortality in adults, but there was a trend for increased mortality in children. 1 In asthma, long-acting b2-agonists decreased exacerbations in adults but tended to increase exacerbations in children. 1 Intravenous lorazepam, when compared with diazepam in status epilepticus, led to significantly more discontinuations of status in adults but not in children. It is not surprising then that although using an algorithm for extrapolation of adult data for use in pediatric drug licensing and development was found to be useful for streamlining drug development and approvals for pediatric use, complete extrapolation from adult data were only appropriate for 6% of drugs reviewed. 2 Beyond the stark contrast in the efficacy of pharmacologic interventions between children and adults, considerable variation of adverse events and morbidity can be anticipated across the pediatric age range. Authors of a recent study of pediatric drug surveillance and adverse event reporting concluded that "suspect drugs and adverse events should be evaluated in the context of age groups" because both drug utilization and the ability to report adverse events vary by age. 3 For example, t...

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confidence: 95%

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et al. 2012

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“…There is growing evidence that interventions may work differently for children than adults due to physiologic and developmental differences and different disease pathophysiology. [60][61][62] Design features may lead to differences in estimates of effect, such as greater response among children to placebo. 63,64 The finding of differences between children and adults in their response to treatment may extend to the influence of bias on estimates of treatment effectiveness.…”

Section: Research Agendamentioning

confidence: 99%

Standard 2: Containing Risk of Bias

et al. 2012

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DILEMMAThere is a crisis of credibility facing the child health research community because of the paucity of reliable estimates of the effects of interventions in children. Associations between risk of bias assessments and treatment effect estimates have important implications, for the clinician, and the families face important challenges as decisionmakers stemming from results that exaggerate treatment effectiveness or safety. Consequently, interventions that are not efficacious and potentially harmful may be prescribed, whereas interventions that truly are efficacious may be withheld. [1][2][3][4][5] Positive trends in pediatric research have been observed since the first trial was published in 1948. Specifically, there has been a substantial increase in the number of trials published over time, the proportion of randomized to nonrandomized controlled trials, and the proportion of child to adult trials. 6 Reporting of methods has also improved; however, methodological quality remains modest. 6 Three studies have specifically examined risk of bias in pediatric trials by using the Cochrane Risk of Bias tool. [7][8][9] The results are summarized in Table 1 by risk of bias domain. In 2 reviews, the overall risk of bias was unclear or high for the vast majority of trials. 7,8 Both of these articles also revealed that trials at high or unclear risk of bias had exaggerated treatment effects compared with those at low risk of bias. Sequence generation and allocation concealment appear to be the domains that are consistently problematic. Importantly, several variables have been found to be associated with risk of bias including source of funding (industry-sponsored research revealing higher risk of bias), nature of the interventions (behavioral/educational interventions having higher risk of bias), and number of authors (higher risk of bias with fewer authors). 9 These analyses demonstrate that there is substantial room for improvement in the methodological and reporting quality of pediatric trials. The association between risk of bias assessments and treatment effect estimates has important implications for decision-making both in terms of false-positive and false-negative results. In practice, this may result in unrealistic expectations of treatment benefit and safety. Inadequate reporting can also have an impact on systematic reviews, which are being used increasingly as a basis for informed decisionmaking. Although systematic reviews aim to be comprehensive and include all relevant studies, the number of studies contributing to various analyses, be they qualitative or quantitative, is often considerably smaller due to inadequate reporting.Ensuring methodological rigor and complete reporting is essential for informed clinical decision-making. It is critical that issues of bias are recognized and addressed by every person who conducts trials, reviews trials, funds trials, or uses trials to guide practice. This standards article was motivated by 2 key factors: (1) emerging evidence demonstrating methodological flaws a...

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“…Children have complex physiological, developmental, psychological and pharmacological characteristics that vary from adults and these features are also different across the newborn to adolescent age range [21]. They may metabolize certain medicines differently from adults resulting in sub-optimal therapy, unexpected responses, adverse drug reactions and toxicity which may affect development and future reproductive capacity [22][23][24].…”

Section: Imperative To Conduct Trials In Childrenmentioning

confidence: 99%

“…Industry may be reluctant to conduct trials in children due to decreased commercial interest, increased cost and greater risk of liability [20,[43][44][45]. The more restrictive regulatory oversight for paediatric trials [23,46] which includes the recommendation for provision of medicines post-trial to participants where there is proven therapeutic benefit [47,48], may further discourage industry from conducting trials in children. Funding for paediatric trials therefore often relies on non-profit organizations, which have limited funding.…”

Section: Imperative To Conduct Trials In Childrenmentioning

confidence: 99%

Clinical trials in children

Joseph

Craig

Caldwell

2015

Brit J Clinical Pharma

307

274

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Safety and efficacy data on many medicines used in children are surprisingly scarce. As a result children are sometimes given ineffective medicines or medicines with unknown harmful side effects. Better and more relevant clinical trials in children are needed to increase our knowledge of the effects of medicines and to prevent the delayed or non-use of beneficial therapies. Clinical trials provide reliable evidence of treatment effects by rigorous controlled testing of interventions on human subjects. Paediatric trials are more challenging to conduct than trials in adults because of the paucity of funding, uniqueness of children and particular ethical concerns. Although current regulations and initiatives are improving the scope, quantity and quality of trials in children, there are still deficiencies that need to be addressed to accelerate radically equitable access to evidence-based therapies in children.

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Comparative Effectiveness of Medical Interventions in Adults Versus Children

Cited by 30 publications

References 128 publications

Standard 6: Age Groups for Pediatric Trials

Standard 6: Age Groups for Pediatric Trials

Standard 2: Containing Risk of Bias

Clinical trials in children

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