Fewer infants than older patients in paediatric randomised controlled trials

International audienceTo determine whether the youngest age groups are less likely to be included in paediatric randomised controlled trials (PRCTs) than older children, we conducted a PubMed search using the keyword "randomised controlled trial" and the limit "all child: 0-18 years". We retrieved 417 articles published in 2006 in 34 leading journals classified as general medical journals, paediatric medical journals, or specialist medical journals. We arbitrarily selected 144 articles, at random. For each study, we evaluated population age characteristics (central tendency, range, and dispersion), study design, sample size and topic. Of the 144 studies, only 82 were first reports of paediatric randomised controlled trials (PRCTs). Among the other studies, many were done in adults. Of the 82 PRCTs, only 11% included newborns and 26% infants; 59% included children and 39% adolescents. Using the same search strategy to retrieve PRCTs in the same journals in the last 4 months of 2009 retrieved 66 PRCTs, of which 17% included newborns, 24% infants, 61% children and 55% adolescents. The three health conditions most often reported were respiratory diseases, infectious diseases, and mental and behavioural disorders. In 34 leading journals, PRCTs were significantly less likely to include newborns and infants than older paediatric patients. Given the huge impact of PRCTs on paediatric health, additional efforts are needed to promote studies in newborns and infants, as well as studies of the impact of recent European and American regulations designed to encourage paediatric drug trials

Drug Safety Monitoring in Children: Performance of Signal Detection Algorithms and Impact of Age Stratification

Introduction: Spontaneous reports of suspected adverse drug reactions (ADRs) can be analyzed to yield additional drug safety evidence for the pediatric population. Signal detection algorithms (SDAs) are required for these analyses; however, the performance of SDAs in the pediatric population specifically is unknown. We tested the performance of two SDAs on pediatric data from the US FDA Adverse Event Reporting System (FAERS) and investigated the impact of age stratification and age adjustment on the performance of SDAs. Methods: We tested the performance of two established SDAs: the proportional reporting ratio (PRR) and the empirical Bayes geometric mean (EBGM) on a pediatric dataset from FAERS (2004–2012). We compared the performance of the SDAs with a published pediatric-specific reference set by calculating diagnostic test-related statistics, including the area under the curve (AUC) of receiver operating characteristics. Impact of age stratification and age-adjustment on the performance of the SDAs was assessed. Age adjustment was performed by pooling (Mantel-Hanszel) stratum-specific estimates. Results: A total of 115,674 pediatric reports (patients aged 0–18 years) comprising 893,587 drug–event combinations (DECs) were analysed. Crude values of the AUC were similar for both SDAs: 0.731 (PRR) and 0.745 (EBGM). Stratification unmasked four DECs, e.g., ‘ibuprofen and thrombocytopenia’. Age adjustment did not improve performance. Conclusion: The performance of the two tested SDAs was similar in the pediatric population. Age adjustment does not improve performance and is therefore not recommended to be performed routinely. Stratification can reveal new associations, and therefore is recommended when either drug use is age-specific or when an age-specific risk is suspected

Wide intra- and inter-country variability in drug use and dosage in very-low-birth-weight newborns with severe infections

Purpose: To describe the use of ciprofloxacin and fluconazole for the treatment of sepsis in European neonatal intensive care units (NICUs) in order to better orient research aimed at acquiring essential knowledge in this critical area. Methods: The survey consisted of an online questionnaire for all participating NICUs on treatment schemes employed, rationales behind drug choices and interest in participation in research involving the two drugs. Results: A total of 189 level II and III NICUs participated in the survey, representing 25 countries, with Italy, UK and France providing the greatest number of centres (54% of total). Ciprofloxacin is used in 25% of NICUs that responded, although the indications for administering it vary between centres and the dosage ranges vary considerably, with 25% of NICUs giving ≤10 mg/kg/day and another 25 % giving ≥21 mg/kg/day. Factors given as affecting the decision to use ciprofloxacin are uncertainty about its safety and pharmacokinetics and level of penetration in the cerebrospinal fluid. Among the 70% of responding units that use fluconazole to treat fungal infection, 45% administer 6 mg/kg unit doses while 33% administer 12 mg/kg; 41% of NICUs use a 24-h interval between administrations while 20% wait 72h. Among the responding NICUs, 57% were willing to participate in a project on ciprofloxacin and 59% would consider participating in a randomized controlled trial evaluating fluconazole versus micafungin. Conclusions: Great variability in therapies exists within and between countries. Numerous centres are interested in participating in research on these drugs, highlighting the need for further knowledge on sepsis treatment and European centres’ interest in off-patent medicine research

Report on methods of safety signal generation in paediatrics from pharmacovigilance databases

This deliverable is based on the need to develop and test methods for safety signal detection in children. Signal detection is the mainstay of detecting safety issues, but so far very few groups have specifically looked at children. We developed reference sets for positive and negative drugevent combinations and vaccine-event combinations by a systematic literature review on all combinations. We retrieved the FDA AERS database, the CDC VAERS database and EUDRAVIGILANCE database. In order to analyse the datasets we had a stepwise approach from extraction of data, cleaning (e.g. mapping MedDRA and ATC codes) and transformation into a a common data model that we defined for the spontaneous reporting databases. A statistical analysis plan was created for the testing of methods and we provided some descriptive analyses of the FAERS data. Next steps will be to complete the analyses

c4c: Paediatric pharmacovigilance: Methodological considerations in research and development of medicines for children - A c4c expert group white paper

Children frequently respond differently to therapies compared to adults. Differences also exist between paediatric age groups for pharmacokinetics and pharmacodynamics in both efficacy and safety. Paediatric pharmacovigilance requires an understanding of the unique aspects of children with regard to, for example, drug response, growth and development, clinical presentation of adverse drug reactions (ADRs), how they can be detected and population-specific factors (e.g., more frequent use of off-label/unlicensed drugs). In recognition of these challenges, a group of experts has been formed in the context of the conect4children (c4c) project to support paediatric drug development. This expert group collaborated to develop methodological considerations for paediatric drug safety and pharmacovigilance throughout the life-cycle of medicinal products which are described in this article. These considerations include practical points to consider for the development of the paediatric section of the risk management plan (RMP), safety in paediatric protocol development, safety data collection and analysis. Furthermore, they describe the specific details of post-marketing pharmacovigilance in children using, for example, spontaneous reports, electronic health care records, registries and record-linkage, as well as the use of paediatric pharmacoepidemiology studies for risk characterisation. Next the details of the assessment of benefit–risk and challenges related to medicinal product formulation in the context of a Paediatric Investigation Plan (PIP) are presented. Finally, practical issues in paediatric signal detection and evaluation are included. This paper provides practical points to consider for paediatric pharmacovigilance throughout the life-cycle of medicinal products for RMPs, protocol development, safety data collection and analysis and PIPs

Thyrotoxic Vomiting: A Case Report and Possible Mechanisms

The symptoms related to gastrointestinal (GI) tract are sometimes chief complaints in patients with endocrine disease. Thyrotoxicosis is a rare, but notable cause for unexplained and repeated vomiting. Here, we report an adolescent patient with thyrotoxicosis who was initially presented with repeated vomiting and epigastric pain. A 13-year-old female was referred to a GI outpatient department for evaluation of vomiting and abdominal pain from a pediatric clinic. Esophagogastroduodenoscopy revealed acute gastritis with duodenogastric reflux and suspicious reflux esophagitis of minimal change, but there was no significant improvement after treatment and as a result she was admitted to the emergency room. She was subsequently diagnosed as Graves' disease because an initial laboratory test at the GI outpatient department revealed thyroid stimulating hormone < 0.01 µIU/mL and additional blood tests showed elevated thyroid hormones and positive thyroid stimulating hormone receptor antibody. The vomiting and epigastric pain improved remarkably after treatment with antithyroid drugs. Clinicians should consider the possibility of thyrotoxicosis in patient with unexplained and repeated vomiting

Standard Model Extension and Casimir effect for fermions at finite temperature

AbstractLorentz and CPT symmetries are foundations for important processes in particle physics. Recent studies in Standard Model Extension (SME) at high energy indicate that these symmetries may be violated. Modifications in the lagrangian are necessary to achieve a hermitian hamiltonian. The fermion sector of the standard model extension is used to calculate the effects of the Lorentz and CPT violation on the Casimir effect at zero and finite temperature. The Casimir effect and Stefan–Boltzmann law at finite temperature are calculated using the thermo field dynamics formalism

Is there an optimal strategy for real-time continuous glucose monitoring in pediatrics? A 12-month French multi-center, prospective, controlled randomized trial (Start-In!)

AIM: To compare the efficacy of three strategies for real-time continuous glucose monitoring (RT-CGM) over 12 months in children and adolescents with type 1 diabetes. METHODS: A French multicenter trial (NCT00949221) with a randomized, controlled, prospective, open, and parallel-group design was conducted. After 3 months of RT-CGM, patients were allocated to one of three groups: return to self-monitoring of blood glucose, continuous CGM (80% of the time), or discontinuous CGM (40% of the time). The primary outcome was hemoglobin A1c (HbA1c) levels from 3 to 12 months. The secondary outcomes were acute metabolic events, hypoglycemia, satisfaction with CGM and cost. RESULTS: We included 151 subjects, aged 2 to 17 years, with a mean HbA1c level of 8.5% (SD0.7; 69 mmol/mol). The longitudinal change in HbA1c levels was similar in all three groups, at 3, 6, 9 and 12 months. The medical secondary endpoints did not differ between groups. The rate of severe hypoglycemia was significantly lower than that for the pretreatment year for the entire study population. Subjects reported consistent use and good tolerance of the device, regardless of age or insulin treatment. The use of full-time RT-CGM for 3 months costs the national medical insurance system €2629 per patient. CONCLUSION: None of the three long-term RT-CGM strategies evaluated in pediatric type 1 diabetes was superior to the others in terms of HbA1c levels. CGM-use for 3 months decreased rates of severe hypoglycemia. Our results confirm the feasibility of long-term RT-CGM-use and the need to improve educational support for patients and caregivers

'Use of antipsychotics in children and adolescents: a picture from the ARITMO population-based European cohort study'

Aims. Prevalence of the use of antipsychotics (APs) in the paediatric population is globally increasing. The aim of this study was to describe multinational trends and patterns in AP use in children and adolescents in Europe. Methods. This was a dynamic retrospective cohort study comprising all children and adolescents (⩽18 years of age). Data were extracted from five population-based electronic healthcare databases in Europe (Denmark, Germany, Italy, the Netherlands and United Kingdom) from 2000 to 2010. Yearly prevalence and incidence of AP use was expressed per 1000 person-years (PYs). Results. Prevalence increased from 1.44 to 3.41/1000 PYs (2008) in Denmark and from 2.07 to 4.35/1000 PYs in the NL (2009), moderately increased from 2.8 to 3.24/1000 in UK (2009) and from 1.53 to 1.74/1000 PYs in Germany (2008) and remained low from 0.61 to 0.34/1000 PYs in Italy (2010). Similarly, incidence rates increased from 0.69 to 1.52/1000 PYs in Denmark and from 0.86 to 1.49/1000 PYs in the NL, stabilised from 2.29 to 2.37/1000 PYs in the UK and from 0.79 to 0.80/1000 PYs in Germany and remained low from 0.32 to 0.2/1000 PYs in Italy. AP use was highest in 15–18 year olds and in boys compared to girls. Yet, the use observed in the 5–9 year olds was found to be comparatively high in the NL. Prescriptions of second generation APs, especially risperidone, were privileged but the first generation APs were still prescribed in the youngest. Conclusions. A steady increase in AP use in children and adolescents was observed essentially in the NL and Denmark. The use in Germany and Italy was lowest among countries. The use of APs under 9 years of age underlines their off-label use and should be carefully monitored as the risk/benefit ratio of these medications remains unclear in young children. AP use was altogether lower in Europe as compared to that reported in North America

Modalités de recrutement des sujets dans la recherche en pédiatrie : étude prospective multicentrique

Contexte. - Une enquête qualitative exploratoire a montré que le nombre de patients éligibles et sollicités dans les essais en pédiatrie était peu objectivé ainsi que les refus. Objectif. - Estimer le nombre de refus de participation des familles dans les essais en pédiatrie et lier le taux de refus aux caractéristiques protocole, investigateur et patients. Matériel et méthodes. - Étude prospective multicentrique inter-CIC (réseau pédiatrique) d'une cohorte de protocoles. Pour chaque sollicitation à participer, des fiches patient, investigateur et protocole étaient remplies. Résultats. - L'étude a été réalisée de décembre 2005 à septembre 2007 sur quatre centres et a inclus 45 protocoles : 32 à promotion industrielle, 36 multicentriques, 19 essais cliniques, 33 avec prises de sang et six avec examens invasifs, 26 avec des déplacements spécifiques et 14 des hospitalisations supplémentaires. Sur ces protocoles, 170 investigateurs étaient référencés comme recruteurs et 86 (51 %) ont répondu au questionnaire : âge médian 42 ans, sex-ratio de 1, 13 sont investigateurs principal, 32 responsables pour le CIC et 50 investigateurs associés, 20 percevaient une rétribution versée au service dans 80 % des cas. La charge de travail médiane par investigateur était d'une heure par inclusion et 67 (78 %) bénéficiaient d'une aide d'une TEC. Au total, 1022 sollicitations ont été réalisées sur 36 protocoles (neuf protocoles n'ayant eu aucune sollicitation) et 334 refus (33 %) ont été enregistrés soit une médiane de 12 % (Q1Q3 : 0-28 %) de refus par protocole. Parmi les 36 protocoles, 16 n'ont enregistré aucun refus, représentant 147 sollicitations et les 20 autres protocoles ont eu un taux moyen de 38 % de refus. L'analyse explicative est en cours. Conclusion. - Le taux de refus de 12 % n'est pas différent de celui des essais adultes et semble dépendant du type d'étude. L'absence de sollicitation concerne 20 % des études