Design and conduct of early phase drug studies in children: challenges and opportunities

It has historically been very difficult to conduct early phase drug studies in children for a number of reasons related to ethics, acceptability, rarity, standardization, end points, safety, dosing and feasibility. Over the past decade there have been a number of developments including novel clinical trial design, in silico pharmacology and microdosing that have significantly enhanced the ability of investigators to conduct early phase drug studies in children. While the evolution of drug therapy is creating a series of new challenges, there has never been a better time for conducting drug studies in children

Aminophylline Dosage In Asthma Exacerbations in Children: A Systematic Review

<div><p>Background</p><p>Adequate asthma treatment of childhood exacerbations with IV aminophylline depends on appropriate dosage. Recommendations to aim for a target therapeutic range may be inappropriate as serum concentrations correlate poorly with clinical improvement. This review aims to evaluate the evidence for the optimum dosage strategy of intravenous aminophylline in children suffering an exacerbation of asthma.</p><p>Methods</p><p>A systematic review comparing dosage regimens of intravenous aminophylline in children suffering an exacerbation of asthma. Primary outcomes were time until resolution of symptoms, mortality and need for mechanical ventilation. Secondary outcomes were date until discharge criteria are met, actual discharge and adverse effects.</p><p>Data sources</p><p>CENTRAL, CINAHL, MEDLINE and Web of Science. Search performed in March 2016</p><p>Eligibility criteria</p><p>Studies using intravenous aminophylline in children with an acute exacerbation of asthma which reported the dosage and clinical outcomes.</p><p>Findings</p><p>14 RCTs were included. There is a poor relationship between the dosage administered to children and symptom resolution, length of stay or need for mechanical ventilation. This study is limited due to its use of indirect evidence.</p><p>Conclusion</p><p>The currently recommended dosage regimens may not represent the optimum safety and efficacy of intravenous aminophylline. There is a need to develop the evidence base correlating dosage with patient centered clinical outcomes, to improve prescribing practices.</p></div

The Evidence for Intravenous Theophylline Levels between 10-20mg/L in Children Suffering an Acute Exacerbation of Asthma: A Systematic Review

<div><p>Background</p><p>Intravenous theophyllines are a second line treatment for children suffering an acute exacerbation of asthma. Various guidelines and formularies recommend aiming for serum theophylline levels between 10-20mg/l. This review aims to assess the evidence underpinning this recommendation.</p><p>Methods</p><p>A systematic review comparing outcomes of children who achieved serum theophylline concentrations between 10-20mg/l with those who did not. Primary outcomes were time until resolution of symptoms, mortality and need for mechanical ventilation. Secondary outcomes were date until discharge criteria are met, actual discharge, adverse effects and FEV1.</p><p>Data sources</p><p>MEDLINE, CINAHL, CENTRAL and Web of Science. Search performed in October 2015.</p><p>Eligibility criteria</p><p>Interventional or observational studies utilizing intravenous theophyllines for an acute exacerbation of asthma in children where serum theophylline levels and clinical outcomes were measured.</p><p>Findings</p><p>10 RCTs and 2 observational studies were included. Children with serum levels between 10-20mg/l did not have a reduction in duration of symptoms, length of hospital stay or need for mechanical ventilation or better spirometric results compared with levels <10mg/l. Levels above 20mg/l are not associated with higher rates of adverse effects. This study is limited due to heterogeneity in the way theophylline levels were reported and poor surveillance of adverse effects across studies.</p><p>Conclusion</p><p>Dosing strategies aiming for levels between 10-20mg/l are not associated with better outcomes. Clinicians should rely on clinical outcomes and not serum levels when using intravenous theophyllines in children suffering an acute exacerbation of asthma.</p></div

Prioritising neonatal medicines research: UK Medicines for Children Research Network scoping survey

BACKGROUND: The dosing regimen and indications for many medicines in current use in neonatology are not well defined. There is a need to prioritise research in this area, but currently there is little information about which drugs are used in UK neonatal units and the research needs in this area as perceived by UK neonatologists. METHODS: The Neonatal Clinical Studies Group (CSG) of the Medicines for Children Research Network (MCRN) undertook a 2 week prospective scoping survey study to establish which medicines are used in UK neonatal units; how many babies are receiving them; and what clinicians (and other health professionals) believe are important issues for future research. RESULTS: 49 out of 116 units responded to at least one element of the survey (42%). 37 units reported the number of neonates who received medicines over a 2 week period. A total of 3924 medicine-patient pairs were reported with 119 different medicines. 70% of medicine-patient pairs involved medicines that were missing either a license or dose for either term or preterm neonates. 4.3% of medicine-patient pairs involved medicines that were missing both license and dose for any neonate. The most common therapeutic gap in need of additional research identified by UK neonatologists was chronic lung disease (21 responding units), followed by patent ductus arteriosus and vitamin supplements (11 responding units for both) CONCLUSION: The research agenda for neonatal medicines can be informed by knowledge of current medicine use and the collective views of the neonatal community

Improving the quality of written information available at weekends in a paediatric hospital: the TRANSMIT sheet.

The clinical outcomes at weekends are worse than during the week in a hospital setting. There are many potential factors which influence this. High quality communication between the weekday teams and the on call weekend staff could help improve clinical outcomes at weekends, but there are no validated forms of communication that have been established in a paediatric hospital setting. The casenotes of all medical patients (n=119) were prospectively evaluated across all medical wards in a large paediatric hospital over three weekends, to establish the quality of information available to on call teams. Following introduction of structured documentation, known as a TRANSMIT (including Tasks, Respiratory, Anticipated problems, Nutrition, Sepsis, Medication, Intravenous access, Transfer/discharge) sheet, the audit was repeated (n=111). A qualitative survey of junior doctors using TRANSMIT was carried out after introduction. Prior to the introduction of the structured documentation (TRANSMIT sheet) an accurate problem list was present in 56% (67/119), and an adequate written management plan in 63% (75/119). Following introduction, an improvement in the notes was seen, with accurate problem lists in 82% (91/111) and an adequate plan in 76% (84/111). Improvements in the quantity and quality of information available to weekend on call medical staff were noted. The use of a structured documentation (TRANSMIT sheet) can improve the quality of written information available to on-call teams in a paediatric hospital setting. A retrospective qualitative assessment of junior doctors using TRANSMIT sheets showed an improvement in both the quantity and quality of information available to on call staff at weekends

WHAT DOMAINS RELATED TO MEDICINES WERE MEASURED IN STUDIES OF BURDEN OF CARE FOR PAEDIATRIC PATIENTS? A SYSTEMATIC REVIEW

IntroductionMedicines are becoming increasingly common for all populations and polypharmacy has been shown to have numerous risks. Although primary studies and reviews have explored the impact of medical conditions on patients and caregivers, there are no known reviews on the impact of medicines on paediatric patients. This systematic review therefore aimed to determine the domains commonly assessed in studies assessing treatment burden in different conditions for paediatric patients and their caregivers.MethodsSearches were conducted on Medline, CINAHL, EMBASE, Web of Science and Cochrane Database of Systematic Reviews to find relevant papers. Two reviewers independently screened the papers based on the chosen inclusion and exclusion criteria. The quality of the papers was assessed independently by two reviewers using the Newcastle Ottawa Scale. This review was registered with PROSPERO (PROSPERO registration number: CRD42021285097) and conducted according to PRISMA methodology.Results6 papers with 8276 participants were identified in this review. The domains most commonly assessed were the perceived effectiveness of medications (4/6 studies), psychosocial impact (3/6 studies) and the impact on work and school (3/6 studies). Other domains included the ease of use of medicines, side effects from medicines, adherence to medicines, time requirements, costs, using healthcare resources and support from family/friends/organisations.ConclusionsStudies assessing the burden of care due to medicines assessed a range of domains related to the impact of medicines on patients and caregivers. The results from this review will be used create a questionnaire for a cohort study that aims to determine the impact of polypharmacy on paediatric patients and their parents.</jats:sec

DEPRESCRIBING LONG ACTING BETA2 AGONISTS IN CHILDREN AND ADOLESCENTS WITH STABLE ASTHMA: A SYSTEMATIC REVIEW

IntroductionCurrent guidelines recommend step-down of asthma drugs once stable asthma has been achieved but there is no guidance regarding deprescribing long acting beta2 agonists (LABAs) in the paediatric population.AimTo systematically review evidence regarding deprescribing methods of LABAs in the paediatric population.MethodsSearches were undertaken in the following databases: EMBASE, Medline, PubMed and CINAHL regarding reports of deprescription or discontinuation of LABAs in children and adolescents with persistent asthma.ResultsThe search returned 168 papers following deduplication. 4 papers met the eligibility criteria including 3 randomised control trials and 1 retrospective study. Overall, LABA step down was attempted in 365 children and young people (5–18 years old). The studies had variable follow up durations once deprescribing was undertaken, from 2 to 12 weeks. Effects of withdrawal were measured using parameters such as airway hyperresponsiveness tests (3 studies), asthma control test scores (3 studies), use of rescue medication (3 studies) and lung function tests (FeNO, FEV1, FEF25–75%, peak expiratory flow rate (PEFR),% forced expiratory flow at 50% of vital capacity (%V50)) (all studies). Airway responsiveness was unchanged 2 weeks following LABA withdrawal, however decreases in%PEFR and%V50, FEV1 and asthma control test scores were observed. 2 studies assessed changes in LABA related adverse effects after deprescribing.ConclusionThere is limited and short-term evidence regarding stepping down LABAs in paediatrics. To fully implement national and international guidelines, prospective studies in this area are required.</jats:sec