Challenges in Paediatric Clinical Trials: How to Make It Feasible

The number of paediatric clinical trials in EU has remarkably increased in the last decade in response to the implementation of the new Paediatric Regulation and incentives aiming to define the need of child-specific drug development. Nevertheless, the gap between the number of paediatric and adult-randomised controlled trials is still substantial in almost every major clinical specialty. Economic, ethical, technological, geographical and cultural factors can influence the paediatric drug development and can represent the challenges to be faced for a smooth conduction of a paediatric clinical trial. The need for trials and paediatric patient’s engagement to commensurate with the approved paediatric investigation plans is so high that it is crucial to correctly address key factors. Particular care should be taken to develop well-designed studies, with efficient management plans, experienced administrative and healthcare personnel, awareness of socio-cultural features of the geographic areas involved and good communication with patients and their families in order to ensure ‘trial preparedness’. A case study on a multinational paediatric clinical trial, presented within the recently ended research project ‘DEferiprone Evaluation in Paediatrics (DEEP)’, was reported to exemplify some of the challenges encountered by the authors and the actions taken to overcome them

Chapter Challenges and New Frontiers in the Paediatric Drug Discovery and Development

Drug discovery and development advances in the last decades allowed to find a treatment for many preventable diseases. However, all too often, children are excluded from these progresses since most of the new medicines have been discovered and developed for the adult population. Even if paediatricians routinely give drugs to children ‘off-label’, researchers have demonstrated that children do not respond to medications in the same way as adults. Furthermore, certain specific disorders are unique to children or occur in children differently than in adults. Besides specifically testing medicines in children in proper clinical studies taking into due account the peculiarity of this population, there is a growing recognition of the need to develop paediatric medicines having in mind the specificities of this vulnerable population. In this chapter, we will provide an overview on the drug discovery and development path for children highlighting challenges and new frontiers of each phase from the discovery to the preclinical and clinical development as well as we will provide a slightest hint about paediatric biomarkers discovery, age-appropriate formulation, pregnancy, and perinatal pharmacology and in silico pharmacology. Finally, pricing and reimbursement policies for medicines and new and existing research initiatives in the field will be discussed

Clinical Trials in Paediatrics — Regulatory and Methodological Aspects

The photoautotrophic cyanobacterium Synechocystis PCC6803 has received much attention as a model photosynthetic cell factory for the production of a range of important biotech products. The biomass remaining from this activity may then have further utility in processes such as metal bioremediation. In addition Synechocystis being an inhabitant of many natural aquatic environments is seen as an environmentally friendly alternative to using chemical precipitation methodologies for metal remediation. Synechocystis produces a range of extracellular polysaccharide substances (EPS) that can undergo modification as a function of culture age and growth nutrients which have been implicated in metal biosorption. Many studies have demonstrated that high levels of charged groups present in EPS are important in forming polymeric matrices with metallic ions allowing their biosorption. Genetic studies has revealed genes involved in such metal binding indicating that EPS can be modified for potential enhancement of binding or modification of the types of metals bound. The utility of metal binding to live and dead biomass of Synechocystis has been demonstrated for a range of metals including Cr(VI), Cd(II), Cu(II), Pb(II), Sb, Ni(II), Mn(II), Mn(IV), As(III), As(V), Cs and Hg. The potential of using Synechocystis as a biosorption platform is discussed

Medical Device Development for Children and Young People—Reviewing the Challenges and Opportunities

Development of specific medical devices (MDs) is required to meet the healthcare needs of children and young people (CYP). In this context, MD development should address changes in growth and psychosocial maturation, physiology, and pathophysiology, and avoid inappropriate repurposing of adult technologies. Underpinning the development of MD for CYP is the need to ensure MD safety and effectiveness through pediatric MD-specific regulations. Contrary to current perceptions of limited market potential, the global pediatric healthcare market is expected to generate around USD 15,984 million by 2025. There are 1.8 billion young people in the world today; 40% of the global population is under 24, creating significant future healthcare market opportunities. This review highlights a number of technology areas that have led to successful pediatric MD, including 3D printing, advanced materials, drug delivery, and diagnostic imaging. To ensure the targeted development of MD for CYP, collaboration across multiple professional disciplines is required, facilitated by a platform to foster collaboration and drive innovation. The European Pediatric Translational Research Infrastructure (EPTRI) will be established as the European platform to support collaboration, including the life sciences industrial sector, to identify unmet needs in child health and support the development, adoption, and commercialization of pediatric MDs

Assessment of post-competition peak blood lactate in male and female master swimmers aged 40–79 years and its relationship with swimming performance

The main purpose of this study was to measure the postcompetition blood lactate concentration ([La]b) in master swimmers of both sexes aged between 40 and 79 years in order to relate it to age and swimming performance. One hundred and eight swimmers participating in the World Master Championships were assessed for [La]b and the average rate of lactate accumulation (La’;mmol l-1 s-1) was calculated. In addition, 77 of them were also tested for anthropometric measures. When the subjects were divided into 10-year age groups, males exhibited higher [La]b than women (factorial ANOVA, P < 0.01) and a steeper decline with ageing than female subjects. Overall, mean values (SD) of [La]b were 10.8 (2.8), 10.3 (2.0), 10.3 (1.9), 8.9 (3.2) mmol l-1 in women, and 14.2 (2.5), 12.4 (2.5), 11.0 (1.6), 8.2 (2.0) mmol l-1 in men for, respectively, 40–49, 50–59, 60–69, 70–79 years’ age groups. When, however, [La]b values were normalised for a ‘‘speed index’’, which takes into account swimming speed as a percentage of world record, these sex-related differences, although still present, were considerably attenuated. Furthermore, the differences in La’ between males and females were larger in the 40–49 age group (0.34 vs 0.20 mmol l-1 s-1 for 50-m distance) than in the 70–79 age group (0.12 vs 0.14 mmol l-1 s-1 for 50-m distance). Different physiological factors, supported by the considered anthropometric measurements, are suggested to explain the results

Diagnosis and Treatment of Chronic Neuropathic and Mixed Pain in Children and Adolescents: Results of a Survey Study amongst Practitioners

Валідовані діагностичні засоби для діагностики хронічного невропатичного та змішаного болю у дітей відсутні. Терапевтичні варіанти часто походять від терапевтичних засобів для дорослих. Щоб дослідити міжнародну практику серед практикуючих лікарів з діагностики та лікування хронічного невропатичного болю у дітей та підлітків, ми провели опитування серед членів наукових товариств або груп, члени яких залучені до лікування дитячого болю. Опитування включало питання стосовно практиків та характеристик практики, оцінки та діагностики, лікування та прийому ліків. Ми проаналізували 117 повернутих анкет, з яких 41 (35%) була повністю заповнена, а 76 (65%) заповнені частково. Більшість респондентів базували діагноз невропатичного болю на фізичному обстеженні (68 (58,1%)), анамнезі пацієнтів (67 (57,3%)) та основному захворюванні (59 (50,4%)). Габапентин, амітриптилін та прегабалін були першим вибором засобів для лікування помірного невропатичного болю. Трамадол, ібупрофен, амітриптилін і парацетамол були першочерговими методами лікування помірного змішаного болю. Консенсусу щодо діагностичного процесу невропатичного болю у дітей та підлітків бракує. Медикаментозне лікування широко варіюється у разі помірного, сильного невропатичного та змішаного болю. Отже, діагностичні засоби та терапію необхідно узгодити та перевірити для використання у дітей.Утвержденные диагностические инструменты для диагностики хронической невропатической и смешанной боли у детей отсутствуют. Варианты лечения часто основываются на терапии для взрослых. Чтобы изучить международную практику среди практикующих врачей по диагностике и лечению хронической нейропатической боли у детей и подростков, мы провели исследование среди членов научных обществ или групп, члены которых принимают участие в лечении педиатрической боли. Опрос включал вопросы, касающиеся практикующих врачей и характеристик практики, оценки и диагноза, лечения и приема медикаментов. Мы проанализировали 117 возвращенных анкет, из которых 41 (35%) были заполнены полностью, а 76 (65%) - частично. Большинство респондентов ставили диагноз невропатической боли на основании медицинского осмотра (68 (58,1%)), истории болезни (67 (57,3%)) и основного заболевания (59 (50,4%)). Габапентин, амитриптилин и прегабалин были препаратами первого выбора при умеренной невропатической боли. Трамадол, ибупрофен, амитриптилин и парацетамол были препаратами первого выбора при умеренной смешанной боли. Единого мнения о диагностическом процессе невропатической боли у детей и подростков нет. Медикаментозное лечение умеренной, тяжелой невропатической и смешанной боли широко варьируется. Следовательно, диагностические инструменты и терапия должны быть согласованы и утверждены для использования у детей.Validated diagnostic tools to diagnose chronic neuropathic and mixed pain in children are missing. Therapeutic options are often derived from therapeutics for adults. To investigate the international practice amongst practitioners for the diagnosis and treatment of chronic, neuropathic pain in children and adolescents, we performed a survey study among members of learned societies or groups whose members are known to treat pediatric pain. The survey included questions concerning practitioners and practice characteristics, assessment and diagnosis, treatment and medication. We analyzed 117 returned questionnaires, of which 41 (35%) were fully completed and 76 (65%) were partially completed. Most respondents based the diagnosis of neuropathic pain on physical examination (68 (58.1%)), patient history (67 (57.3%)), and underlying disease (59 (50.4%)) combined. Gabapentin, amitriptyline, and pregabalin were the first-choice treatments for moderate neuropathic pain. Tramadol, ibuprofen, amitriptyline, and paracetamol were the first-choice treatments for moderate mixed pain. Consensus on the diagnostic process of neuropathic pain in children and adolescents is lacking. Drug treatment varies widely for moderate, severe neuropathic, and mixed pain. Hence, diagnostic tools and therapy need to be harmonized and validated for use in children

Non-inferiority double-blind randomised controlled trial comparing gabapentin versus tramadol for the treatment of chronic neuropathic or mixed pain in children and adolescents: the GABA-1 trial-a study protocol

Introduction Gabapentin is currently used ‘off-label’ in children and adolescents with chronic neuropathic pain, and reliable evidence of its effects and optimal dosing are lacking. Objectives The GABA-1 trial aims to compare the efficacy and safety of gabapentin liquid formulation relative to tramadol and to explore the pharmacokinetics of both drugs in the treatment of chronic, neuropathic or mixed pain in the paediatric population. Methods and analysis The trial is a multicentre, doubleblind, double-dummy, randomised, active-controlled, non-inferiority trial. Participants aged from 3 months to <18 years of age with moderate to severe (≥4/10 in ageappropriate pain scales) chronic neuropathic or mixed pain will be recruited in 14 clinical sites in eight European countries. A total of 94 subjects will be randomised to receive gabapentin and tramadol placebo or tramadol and gabapentin placebo throughout 16–19 weeks (including 3 weeks of titration [optimisation period], 12 weeks of treatment at a stable dose [maintenance period] and 1–4 weeks of tapering [discontinuation period]). The primary objective is to assess the efficacy of gabapentin relative t

The exposure of the hybrid detector of the Pierre Auger Observatory

The Pierre Auger Observatory is a detector for ultra-high energy cosmic rays. It consists of a surface array to measure secondary particles at ground level and a fluorescence detector to measure the development of air showers in the atmosphere above the array. The "hybrid" detection mode combines the information from the two subsystems. We describe the determination of the hybrid exposure for events observed by the fluorescence telescopes in coincidence with at least one water-Cherenkov detector of the surface array. A detailed knowledge of the time dependence of the detection operations is crucial for an accurate evaluation of the exposure. We discuss the relevance of monitoring data collected during operations, such as the status of the fluorescence detector, background light and atmospheric conditions, that are used in both simulation and reconstruction.Comment: Paper accepted by Astroparticle Physic