Denise Thomson

Standard 6: Age Groups for Pediatric Trials

* Abbreviations: RCT — : randomized controlled trial SSRI — : selective serotonin reuptake inhibitor It 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 meta-analysis 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 β2-agonists decreased … Address correspondence to Martin Offringa, MD, PhD, Senior Scientist and Program Head, Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: martin.offringa{at}sickkids.ca

A Descriptive Analysis of Overviews of Reviews Published between 2000 and 2011

Background Overviews of systematic reviews compile data from multiple systematic reviews (SRs) and are a new method of evidence synthesis. Objectives To describe the methodological approaches in overviews of interventions. Design Descriptive study. Methods We searched 4 databases from 2000 to July 2011; we handsearched Evidence-based Child Health: A Cochrane Review Journal. We defined an overview as a study that: stated a clear objective; examined an intervention; used explicit methods to identify SRs; collected and synthesized outcome data from the SRs; and intended to include only SRs. We did not restrict inclusion by population characteristics (e.g., adult or children only). Two researchers independently screened studies and applied eligibility criteria. One researcher extracted data with verification by a second. We conducted a descriptive analysis. Results From 2,245 citations, 75 overviews were included. The number of overviews increased from 1 in 2000 to 14 in 2010. The interventions were pharmacological (n = 20, 26.7%), non-pharmacological (n = 26, 34.7%), or both (n = 29, 38.7%). Inclusion criteria were clearly stated in 65 overviews. Thirty-three (44%) overviews searched at least 2 databases. The majority reported the years and databases searched (n = 46, 61%), and provided key words (n = 58, 77%). Thirty-nine (52%) overviews included Cochrane SRs only. Two reviewers independently screened and completed full text review in 29 overviews (39%). Methods of data extraction were reported in 45 (60%). Information on quality of individual studies was extracted from the original SRs in 27 (36%) overviews. Quality assessment of the SRs was performed in 28 (37%) overviews; at least 9 different tools were used. Quality of the body of evidence was assessed in 13 (17%) overviews. Most overviews provided a narrative or descriptive analysis of the included SRs. One overview conducted indirect analyses and the other conducted mixed treatment comparisons. Publication bias was discussed in 18 (24%) overviews. Conclusions This study shows considerable variation in the methods used for overviews. There is a need for methodological rigor and consistency in overviews, as well as empirical evidence to support the methods employed.

The evolution of a new publication type: Steps and challenges of producing overviews of reviews

BACKGROUND To date, the Cochrane Child Health Field has published 18 overviews of reviews in our journal, Evidence-based Child Health: A Cochrane Review Journal. In this article, we highlight some of the logistical and methodological challenges of producing such syntheses. As this is a new and evolving publication type, we hope that our experience will benefit others who engage in this process. Current Methods: We discuss the process we have developed to produce overviews of reviews relevant to our mandate, including identification of the research question, establishment of the author team, selection of outcomes and included SRs, and presentation of findings. Ongoing Development: We discuss the lessons we have learned, outstanding challenges for overview authors, and the limitations of overviews. CONCLUSIONS Overviews of reviews are only as good as the SRs and primary studies on which they are based; gaps or lack of currency in this evidence will weaken the overview of reviews. Future directions in this work must address questions of bias and loss of information. Methods for overviews of reviews targeted for specific groups, such as children, need more elaboration. Copyright

Controlled Trials in Children: Quantity, Methodological Quality and Descriptive Characteristics of Pediatric Controlled Trials Published 1948-2006

Background The objective of this study was to describe randomized controlled trials (RCTs) and controlled clinical trials (CCTs) in child health published between 1948 and 2006, in terms of quantity, methodological quality, and publication and trial characteristics. We used the Trials Register of the Cochrane Child Health Field for overall trends and a sample from this to explore trial characteristics in more detail. Methodology/Principal Findings We extracted descriptive data on a random sample of 578 trials. Ninety-six percent of the trials were published in English; the percentage of child-only trials was 90.5%. The most frequent diagnostic categories were infectious diseases (13.2%), behavioural and psychiatric disorders (11.6%), neonatal critical care (11.4%), respiratory disorders (8.9%), non-critical neonatology (7.9%), and anaesthesia (6.5%). There were significantly fewer child-only studies (i.e., more mixed child and adult studies) over time (P = 0.0460). The proportion of RCTs to CCTs increased significantly over time (P<0.0001), as did the proportion of multicentre trials (P = 0.002). Significant increases over time were found in methodological quality (Jadad score) (P<0.0001), the proportion of double-blind studies (P<0.0001), and studies with adequate allocation concealment (P<0.0001). Additionally, we found an improvement in reporting over time: adequate description of withdrawals and losses to follow-up (P<0.0001), sample size calculations (P<0.0001), and intention-to-treat analysis (P<0.0001). However, many trials still do not describe their level of blinding, and allocation concealment was inadequately reported in the majority of studies across the entire time period. The proportion of studies with industry funding decreased slightly over time (P = 0.003), and these studies were more likely to report positive conclusions (P = 0.028). Conclusions/Significance The quantity and quality of pediatric controlled trials has increased over time; however, much work remains to be done, particularly in improving methodological issues around conduct and reporting of trials.

A descriptive analysis of a representative sample of pediatric randomized controlled trials published in 2007

BackgroundRandomized controlled trials (RCTs) are the gold standard for trials assessing the effects of therapeutic interventions; therefore it is important to understand how they are conducted. Our objectives were to provide an overview of a representative sample of pediatric RCTs published in 2007 and assess the validity of their results.MethodsWe searched Cochrane Central Register of Controlled Trials using a pediatric filter and randomly selected 300 RCTs published in 2007. We extracted data on trial characteristics; outcomes; methodological quality; reporting; and registration and protocol characteristics. Trial registration and protocol availability were determined for each study based on the publication, an Internet search and an author survey.ResultsMost studies (83%) were efficacy trials, 40% evaluated drugs, and 30% were placebo-controlled. Primary outcomes were specified in 41%; 43% reported on adverse events. At least one statistically significant outcome was reported in 77% of trials; 63% favored the treatment group. Trial registration was declared in 12% of publications and 23% were found through an Internet search. Risk of bias (ROB) was high in 59% of trials, unclear in 33%, and low in 8%. Registered trials were more likely to have low ROB than non-registered trials (16% vs. 5%; p = 0.008). Effect sizes tended to be larger for trials at high vs. low ROB (0.28, 95% CI 0.21,0.35 vs. 0.16, 95% CI 0.07,0.25). Among survey respondents (50% response rate), the most common reason for trial registration was a publication requirement and for non-registration, a lack of familiarity with the process.ConclusionsMore than half of this random sample of pediatric RCTs published in 2007 was at high ROB and three quarters of trials were not registered. There is an urgent need to improve the design, conduct, and reporting of child health research.

Empirical Evaluation of Age Groups and Age-Subgroup Analyses in Pediatric Randomized Trials and Pediatric Meta-analyses

BACKGROUND: An important step toward improvement of the conduct of pediatric clinical research is the standardization of the ages of children to be included in pediatric trials and the optimal age-subgroups to be analyzed. METHODS: We set out to evaluate empirically the age ranges of children, and age-subgroup analyses thereof, reported in recent pediatric randomized clinical trials (RCTs) and meta-analyses. First, we screened 24 RCTs published in Pediatrics during the first 6 months of 2011; second, we screened 188 pediatric RCTs published in 2007 in the Cochrane Central Register of Controlled Trials; third, we screened 48 pediatric meta-analyses published in the Cochrane Database of Systematic Reviews in 2011. We extracted information on age ranges and age-subgroups considered and age-subgroup differences reported. RESULTS: The age range of children in RCTs published in Pediatrics varied from 0.1 to 17.5 years (median age: 5; interquartile range: 1.8–10.2) and only 25% of those presented age-subgroup analyses. Large variability was also detected for age ranges in 188 RCTs from the Cochrane Central Register of Controlled Trials, and only 28 of those analyzed age-subgroups. Moreover, only 11 of 48 meta-analyses had age-subgroup analyses, and in 6 of those, only different studies were included. Furthermore, most of these observed differences were not beyond chance. CONCLUSIONS: We observed large variability in the age ranges and age-subgroups of children included in recent pediatric trials and meta-analyses. Despite the limited available data, some age-subgroup differences were noted. The rationale for the selection of particular age-subgroups deserves further study.

Overview of reviews in child health: evidence synthesis and the knowledge base for a specific population

BACKGROUND Overviews of reviews are an evolving form of evidence synthesis. The Cochrane Child Health Field has been producing overviews since 2006, during which time the methods that have been used have changed, both due to the development of guidance within The Cochrane Collaboration and to the decisions made by individual author teams. This paper studies the first 29 overviews published in EBCH. OBJECTIVES To describe some aspects of the approaches taken in EBCH overviews to producing evidence syntheses relevant to the healthcare needs of children; to highlight the contribution that overviews can make to the knowledge base for treatment for a particular population. METHODS Data was extracted on: whether the overview included systematic review (SR) data only, or also data from individual trials not present in the included SRs; name(s) of the Cochrane Review Group (CRG) that prepared the included SRs; topics of the overviews as compared to the topics of the included reviews; age-subgroup analyses presented in the overviews. RESULTS In 23 overviews, all published in 2012, the authors included trial data as well as SR data; two overviews addressed conditions not explicitly addressed by the included reviews; three overviews included pre-specified age-subgroup analyses. DISCUSSION The aim of clinical relevance has been achieved by means such as: drawing from reviews produced by multiple CRGs; using SR evidence to explore clinically relevant topics that may not match exactly with the topics covered by the SRs; ensuring that the evidence in overviews is as up to date as possible by redoing searches and including trials not incorporated in the included SRs; and, where permitted by the data, using age-subgroup analyses to present the data in a way which matches the stages of childhood development. CONCLUSION Overview authors are dependent on the nature of the data and methods reported in the included SRs. This suggests a need for further study about how SRs could be conducted in order to facilitate the conduct of overviews.

Cochrane Physical and Rehabilitation Medicine: Current State of Development and Next Steps.

In 2014, the European Society of Physical and Rehabilitation Medicine (ESPRM) in collaboration with the PRM Section and Board of the European Union of Medical Specialists decided to create a Cochrane PRM field (Cochrane PRM). The background and rationale for this initiative has been explained extensively in an editorial in the European Journal of PRM in June 2015. In brief, Cochrane (www.cochrane.org) is a Bglobal independent network of researchers, professionals, patients, carers, and people interested in health[. Cochrane contributors, 37,000 from more than 130 countries, work together to produce credible, accessible health information that is free from commercial sponsorship and other conflicts of interest. Cochrane is organized as a network of groups, distributed at various centers around the world, focused on review production, dissemination, methods, and training. The production of reviews is done by Cochrane review groups (CRGs). Cochrane fields build relationships with stakeholders in focused areas (eg, child health, complementary medicine) with the goal of increasing the use of Cochrane evidence in health care. The specialty of PRM covers a broad medical and scientific domain that includes a large number of health conditions of the musculoskeletal, neurological, and cardiorespiratory systems with an emphasis on function, activity, and participation. Zaina and Negrini reviewedmanuscripts of PRM interest published in the Cochrane Library. They found 242 reviews in more than 28 CRGs. Most of these reviews were performed by the 5 following CRGs: musculoskeletal (40); stroke (38); back (26); bone, joints, and muscle trauma (20); and movement disorders (18). Good quality evidence on the effectiveness of PRM interventions is still relatively scarce. This is due in part to difficult methodological issues in PRM research. For example, randomizing and blinding is often difficult or impossible. Furthermore, clarity on what is usually referred to as Bconventional therapy[ is frequently lacking. In addition, there is often a significant human factor (such as motivation and confidence) interfering with interventions that may affect the patient as well as the therapist. A Cochrane field is the place to encourage a debate on sound research methods and tools that may help us address these shortcomings. Ideally, this debate should take place in close collaboration with related CRGs and other Cochrane fields. This can be accomplishedwith the establishment of a Cochrane PRMfield. Thus, the purpose of this editorial is to report the current state and next steps in the development of Cochrane PRM.

Safe Care for Pediatric Patients: A Scoping Review Across Multiple Health Care Settings

Children are particularly vulnerable to patient safety concerns due to pediatric-specific and general health care challenges. This scoping review identifies and describes the vulnerabilities of those aged 0 to 18 years to iatrogenic harm in various health care settings. Six databases were searched from 1991 to 2012. Primary studies were categorized using predetermined groupings. Categories were tallied and descriptive statistics were employed. A total of 388 primary studies exploring interventions that improved patient safety, deficiencies, or errors leading to safety concerns were included. The most common issues were medication (189 studies, 48.7%) and general medical (81 studies, 20.9%) errors. Sixty studies (15.5%) evaluated or described patient safety interventions, 206 studies (53.1%) addressed health care systems and technologies, 17 studies (4.4%) addressed caregiver perspectives and 20 studies (5.2%) discussed analytic models for patient safety. Further work is needed to ensure consistency of definitions in patient safety research to facilitate comparison and collation of results.

High stakes and high emotions: providing safe care in Canadian emergency departments

Background The high-paced, unpredictable environment of the emergency department (ED) contributes to errors in patient safety. The ED setting becomes even more challenging when dealing with critically ill patients, particularly with children, where variations in size, weight, and form present practical difficulties in many aspects of care. In this commentary, we will explore the impact of the health care providers’ emotional reactions while caring for critically ill patients, and how this can be interpreted and addressed as a patient safety issue. Discussion ED health care providers encounter high-stakes, high-stress clinical scenarios, such as pediatric cardiac arrest or resuscitation. This health care providers’ stress, and at times, distress, and its potential contribution to medical error, is underrepresented in the current medical literature. Most patient safety research is limited to error reporting systems, especially medication-related ones, an approach that ignores the effects of health care provider stress as a source of error, and limits our ability to learn from the event. Ways to mitigate this stress and avoid this type of patient safety concern might include simulation training for rare, high-acuity events, use of pre-determined clinical order sets, and post-event debriefing. Conclusion While there are physiologic and anatomic differences that contribute to patient safety, we believe that they are insufficient to explain the need to address critical life-threatening event-related patient safety issues for both adults and, especially, children. Many factors make patient safety during critical medical events distinct from general patient safety issues, but it is, perhaps, this heightened high-stress, emotional climate that is the most distinct and important part of all. We believe that consideration of this concept is essential when discussing safety improvement in critical medical events.