Clinical Trials In Pediatrics Research Articles

Nutraceuticals and Pain Disorders of the Gut-Brain Interaction in Infants and Children: A Narrative Review and Practical Insights.

Different nutraceuticals are often considered by parents of infants and children with abdominal pain and disorders of the gut-brain interaction. Herb extracts and natural compounds have long been used in traditional medicine, but clinical pediatric trials are very limited. This narrative review based on relevant studies identified through a search of the literature in Pubmed and Medline updated to October 2023 focused on the effect of nutraceuticals in infantile colic, functional abdominal pain, and irritable bowel syndrome in children and adolescents. Significant reductions in colic episodes and crying time were reported in two studies on fennel (seeds oil or tea), in three studies on different multiple herbal extracts (all including fennel), in one study on Mentha piperita, and in at least two double-blind randomized controlled studies on Lactobacillus reuteri DSM 17938 and Bifidobacterium lactis BB-12 (108 CFU/day for at least 21 days) in breast-fed infants. Compared to a placebo, in children with functional abdominal pain or irritable bowel syndrome, a significant reduction in pain was reported in two studies supplementing peppermint oil capsules or psyllium fibers, and in one study on corn fiber cookies, partial hydrolyzed guar gum, a specific multiple herbal extract (STW-5), or vitamin D supplementation. To date, there is moderate-certainty evidence with a weak grade of recommendation on Lactobacillus reuteri DSM 17938 (108 CFU/day) in reducing pain intensity in children with functional abdominal pain and for Lactobacillus rhamnosus GG (1-3 × 109 CFU twice daily) in reducing pain frequency and intensity in children with IBS. Further large and well-designed pediatric studies are needed to prove the efficacy and safety of different herbal extracts and prolonged use of studied products in infants and children with pain disorders of the gut-brain interaction.

Joint recommendations on cost calculation and estimation in paediatric clinical trials.

The conduct of clinical trials in paediatrics is essential to improve drug therapy in children. In Europe, paediatric clinical trials have been supported by the European Paediatric Regulation since 2007, but there is still a great need for high-quality clinical trials. The personnel and time required to conduct clinical trials in accordance with EU Regulations 536/2014 and 745/2017 is considerably higher compared to other studies, such as observational studies. It is important that this additional workload for the trial centre is fully compensated, also taking into account EU state aid rules. In paediatric trials, it is necessary to take into account the special requirements of paediatric and adolescent medicine when calculating the additional costs. Within the framework of the pan-European paediatric study network c4c/GermanNetPaeT, a working group dealt with specific aspects of cost calculation in order to support paediatric study centres in internal cost calculation as well as in the subsequent preparation of financing requirements for industrial sponsors or public funders. In several workshops the working group developed a cost calculation template with the content derived from the "Joint recommendations for a total services account as a factor in simplifying contracts" of the Deutsche Hochschulmedizin (DHM, German University Medicine), the Netzwerk der Koordinierungszentren für Klinische Studien (KKS Network, Network of Coordinating Centres for Clinical Trials) and the Verband Forschender Arzneimittelhersteller (vfa, German Association of Research-Based Pharmaceutical Companies). By estimating the specific time required for measures and investigations as part of a sample study, the background to the increased time required was discussed and a list with aspects to be considered for cost calculation was compiled together with the study centres. The paediatrics-specific aspects mentioned in detail are intended to increase understanding of the particular problem of higher costs for clinical trials involving children and adolescents and the need for correspondingly appropriate remuneration. This transparent and comprehensible presentation of the higher financial requirements for both the study centres and the financial supporters is intended to promote the high-quality conduct of clinical trials in paediatric study centres in the long term.

The development of the Belgian paediatric clinical trial network

ABSTRACT Paediatric clinical trials are critical to ensure that medications prescribed to children are safe and effective. However, evidence-based dosing and labelling of such medications remain limited, and most clinical trials in paediatrics fail. Factors for lack of trial completion include performance at site level (limited patient recruitment, limited site staff experience and lack of infrastructure), the sponsor team (limited paediatric specific expertise in design, uncertainties on robustness of biomarkers or outcome variables) as well as regulatory and administrative burdens. As a result of the growing demand for site support, the Belgian Paediatric Clinical Research Network (BPCRN) established in 2009 has been relaunched in 2018 to improve paediatric clinical trials, with the support of innovative-medicines-initiative 2 (IMI2) pan-European network conect4children (c4c) and the transatlantic network I-ACT for Children (US). This paper highlights the formation of the BPCRN and the practical insights it offers for advancing paediatric clinical trials through national networks. A national network can improve trial quality, safety and efficiency, provide clinical research expertise, identify suitable sites, and help with troubleshooting of common trial issues. The BPCRN’s centralized approach has advanced paediatric clinical trials by streamlining communication and standardizing trial conduct. Challenges and opportunities have arisen, including a relaunch in 2018, orphan medicine trials, and network sustainability. Collaboration between network activities, government support, site-level improvements, efficient communication, and interaction with industry are key to achieve lasting transformation in paediatric medicine research.

Pharmacokinetics and safety of a single dose of telavancin in pediatric subjects 2-17 years of age.

Antimicrobial resistance increases infection morbidity in both adults and children, necessitating the development of new therapeutic options. Telavancin, an antibiotic approved in the United States for certain bacterial infections in adults, has not been examined in pediatric patients. The objectives of this study were to evaluate the short-term safety and pharmacokinetics (PK) of a single intravenous infusion of telavancin in pediatric patients. Single-dose safety and PK of 10 mg/kg telavancin was investigated in pediatric subjects >12 months to ≤17 years of age with known or suspected bacterial infection. Plasma was collected up to 24-h post-infusion and analyzed for concentrations of telavancin and its metabolite for noncompartmental PK analysis. Safety was monitored by physical exams, vital signs, laboratory values, and adverse events following telavancin administration. Twenty-two subjects were enrolled: 14 subjects in Cohort 1 (12-17 years), 7 subjects in Cohort 2 (6-11 years), and 1 subject in Cohort 3 (2-5 years). A single dose of telavancin was well-tolerated in all pediatric age cohorts without clinically significant effects. All age groups exhibited increased clearance of telavancin and reduced exposure to telavancin compared to adults, with mean peak plasma concentrations of 58.3 µg/mL (Cohort 1), 60.1 µg/mL (Cohort 2), and 53.1 µg/mL (Cohort 3). A 10 mg/kg dose of telavancin was well tolerated in pediatric subjects. Telavancin exposure was lower in pediatric subjects compared to adult subjects. Further studies are needed to determine the dose required in phase 3 clinical trials in pediatrics.

Clinical trials in pediatrics-review of ethics and law

Children were acknowledged as ‘therapeutic or pharmaceutical orphans’ in 1960s, since then there has been a worldwide recognition of the need to conduct clinical trials in children, to improve their health. Prescribing in children is often based on extrapolation of trial results from adults, due to the lack of paediatric data. Children have different pharmacokinetic and pharmacodynamics responses as compared to adults. Hence extrapolating the adult safety and efficacy data and using it for prescribing in children can have disastrous effects. Relevant literature on clinical trials in paediatrics was gathered and scrutinized with emphasis on legal and ethical perspectives. This research is an exploratory attempt which surveys and summarizes previously published studies simultaneously trying to answer few research questions which addresses the current debates and scenario. Common problems encountered during pediatric clinical trials are unnecessary scrutiny of even minimal risk studies, difference in interpretation of research protocol in multicentre trials causing delay in trials, prolonged review process. The proposed changes to overcome the above mentioned drawbacks are standardized data security protections, enforcing universal ethical principles for conducting pediatric trials, sstandardizing adverse drug reaction reporting to regulatory bodies. There is a need to increase the number of clinicians actively involved in pediatric research. All the stake-holders such as regulators, parents, ethics committees, research institutions, investigators, sponsors, media, pharmaceutical companies and scientists have to collaborate to ensure that ethical pediatric research is promoted, equipping them with knowledge needed to provide optimal care to their patients.

French pediatricians’ views on industry-sponsored clinical trials: Toward stronger research on ethics?

IntroductionThere is a crucial need to perform clinical trials in pediatrics due to an increased prescription rate of unapproved drugs. Since pediatricians are the gatekeepers of clinical trials, the primary objective of the current study was to evaluate, for the first time in France, pediatricians’ views on performing clinical trials. The second objective was to identify the factors that influence their perceptions. Material and methodsIn 2017, pediatricians who were members of the French Pediatric Society completed an online survey comprising 27 questions. Fisher's exact test was performed to evaluate possible correlations between pediatrician characteristics (age, sex, parenthood, professional experience, status, type of practice, previous participation in clinical trials, ethics education) and personal views on clinical trials. A value of P≤0.001 was considered statistically significant. ResultsOverall, 207 pediatricians completed the questionnaire. Almost all participants (96.6%) were in favor of performing clinical trials. Pediatricians with teaching experience at university hospitals were more reluctant to propose children's participation in clinical trials for fear of increasing parental stress (P<0.001), or the occurrence of serious adverse reactions (P<0.001). Pediatricians with coordinator or investigator experience considered that one of the ethical drifts in pediatric clinical trials is the risk of child exploitation (P<0.001). ConclusionOur findings suggest a favorable position of pediatricians concerning clinical trials, despite numerous concerns. Another outcome is the need to create an educational system of research in ethics in France dedicated to pediatricians in order to guarantee good clinical practice in research.

Results of the First Pilot Randomized Controlled Trial of Fecal Microbiota Transplant In Pediatric Ulcerative Colitis: Lessons, Limitations, and Future Prospects

Results of the First Pilot Randomized Controlled Trial of Fecal Microbiota Transplant In Pediatric Ulcerative Colitis: Lessons, Limitations, and Future Prospects

Pediatric Stroke: Overview and Recent Updates.

Stroke can occur at any age or stage in life. Although it is commonly thought of as a disease amongst the elderly, it is important to highlight the fact that it also affects infants and children. In both populations, strokes have a high rate of morbidity and mortality. Arguably, it is more detrimental in the pediatric population given the occurrence at a younger age and therefore, a longer duration of disability, potentially over the entire lifespan. The high rate of morbidity and mortality in pediatrics is attributed to significant delays in diagnosis, as well as misdiagnosis. Acute stroke management is time dependent. Patients who receive acute treatment with either intravenous (IV) tissue plasminogen activator (tPA) or mechanical thrombectomy, have improved mortality and functional outcomes. Additionally, the earlier treatment is initiated, the higher the likelihood of preserving penumbra, restoring cerebral blood flow and potentially reversing symptoms, thereby limiting disability. Prompt identification is essential as it leads to improved patient care in such a narrow therapeutic window. It enhances the care received during hospitalization and reduces the risk of early stroke recurrence. Despite limited data and lack of large randomized clinical trials in pediatrics, both IV tPA and mechanical thrombectomy have been successfully used. Bridging the gap of acute stroke management in the pediatric population is an essential part of minimizing adverse outcomes. In this review, we discuss the epidemiology of pediatric stroke, the diverse etiologies, presentation as well as both acute and preventative management.

Early termination of clinical trials in paediatrics.

Early termination of clinical trials in paediatrics.

Pediatric Safety of Polysorbates in Drug Formulations.

Polysorbates 20 and 80 are the most frequently used excipients in biotherapeutics, the safety data for which have been well documented in adults. The polysorbate content in therapeutic formulations that are administered to children, however, has been less clearly regulated or defined with regard to safety. In pediatric patients, excessive amounts of polysorbate in biotherapeutics have been linked to hypersensitivity and other toxicity-related effects. To determine safe levels of polysorbates for young patients, we have developed the progressive pediatric safety factor (PPSF), an age- and weight-based tool that estimates the amount of parenterally administered polysorbates 20 and 80 in formulations that will avoid excipient-related adverse events. Compared with existing modalities for calculating maximum acceptable doses of excipients for initial clinical trials in pediatrics, the PPSF is far more conservative, thus constituting an added margin of safety for excipient exposure in the most sensitive subpopulations—i.e., neonates and infants. Further, the PPSF may be applied to any relevant excipient, aiding pharmaceutical developers and regulatory authorities in conservatively estimating the safety assessment of a biotherapeutic’s formulation, based on excipient levels.

So You Want to Give Stem Cells to Babies? Neonatologists and Parents’ Views to Optimize Clinical Trials

To identify barriers and enablers that may influence parents' and neonatologists' participation in clinical trials of mesenchymal stromal cells for bronchopulmonary dysplasia. This qualitative study involved one-on-one semistructured interviews with parents of extremely preterm infants (n=18) and neonatologists (n=16). Interview guides and directed content analysis were framed using the theoretical domains framework, a tool specifically developed for implementation research to identify influences on behavior. Key barriers for parents included their lack of knowledge about clinical trial processes in general, stem cells, and concerns about their risks and side effects. Importantly, parents preferred to be approached for recruitment directly by a neonatologist, either before delivery or 1 or 2weeks after birth. However, the majority of neonatologists felt that approaching parents was not part of their role. Neonatologists reported competing priorities, time commitment, costs, and lack of institutional support as significant barriers to their ability to recruit patients. By integrating stakeholders early into the development of a clinical trial of mesenchymal stromal cell therapy, we identified and can address important barriers to enrollment. Some identified barriers were unanticipated and could have compromised recruitment had they not been identified by this study. We suggest that this approach can be used more broadly for other early phase clinical trials in pediatrics.

Dosage Problems in Children: Well-Known Facts and Unresolved Issues

The problem of dosing drugs at an early age is conditioned by specific metabolism of medicinal products (MP) in the child's body. Currently, there are a few clinical trials on the study of physiological characteristics in different periods of childhood and systematised data. It is still relevant to understand the characteristic differences that affect the bioavailability, distribution and excretion of MP, especially in children over one month of life. The results of such studies are necessary in order to formulate the recommendations for use of MP in children taking into account their age and compensate for the lack of data from direct clinical trials in pediatrics. The possibility of using a dose calculation method regarding the fat content of the body in different periods of childhood and the chemical properties of the substance has been discussed.

Current clinical trials in paediatrics: Report of the ESPEN special interest group in paediatrics

At the 38th annual ESPEN congress in The Hague, the Netherlands, the Special Interest Group (SIG) in Paediatrics presented data about current research activities in the field of paediatric nutrition which are performed worldwide and translated this to future research perspectives. Extensive search of all registered observational and interventional clinical trials in the database ClinicalTrials.gov using the search terms: children nutrition, paediatrics nutrition and children feeding. A total of 717 studies were found; 173 were duplicates and 114 included adult participants and were therefore excluded. Hence, 430 remained for analysis, of which 69% were randomized controlled trials. The most investigated research topic was nutrition in specific diseases (n=98), followed by obesity (n=92), and studies including premature infants (n=48). The overall median estimated enrolment of children in the trials was 150 children [IQR 50-365]. There were 44 studies in which >1000 participants will be enrolled and six studies with >10,000 participants. Studies including >1000 participants were primarily performed in North America (39%), Africa (27%), and Europe (16%). This SIG report showed that 430 clinical nutrition trials in paediatrics are registered and current research focusses primarily on specific diseases and obesity. The SIG paediatrics encourages future research to invest in well-controlled interventional trials.

Clinical trial simulations in paediatric oncology: A feasibility study from the Innovative Therapies for Children with Cancer Consortium

IntroductionPaediatric dose-finding studies are challenging to perform due to ethical reasons, the limited number of available patients and restricted number of blood samples. In certain cases, the adult pharmacokinetic (PK) exposure can be used as target for dose finding in paediatrics. The aim of this study was to investigate the performance of a paediatric phase I dose-finding clinical trial in silico. MethodsUsing an adult pharmacokinetic model, clinical trial simulations were performed to determine the power of a proposed clinical trial design. Power was defined as the fraction of 1000 trials with an area under the plasma concentration–time curve at steady-state (AUC0-24,SS) within ±20% of the adult geometric mean AUC0-24,SS. Different scenarios were compared to optimise the design of the trial. To show the potential of this framework for similar compounds, the current simulation method was also evaluated with adult and paediatric data from literature on sunitinib. ResultsAt the starting dose of 300 mg/m2, the power of the trial design was 66.9%. Power did not improve by dose escalation to 350 mg/m2 (65.3%). Power increased to 78.9% with inclusion of 10 patients per trial. Paediatric sunitinib PK data were adequately predicted from adult data with a mean prediction error of 1.80%. ConclusionThe performance of PK-based clinical trials in paediatrics can be predicted and optimised through PK modelling and simulation. Application of this approach enables clinical trials in paediatrics to be performed as efficiently as possible while protecting the child from unnecessary harm.

Clinical Trials in Pediatrics and Neonatology: Reasons for Ups and Downs

научный биометрический журнал, который знакомит читателя с клиническими рекомендациями и особенностями применения лекарственных и вакцинных средств у детей, предоставляет исчерпывающую информацию о воздействии лекарственных средств на плод, о проводимых в

Immediate rescue designs in pediatric analgesic trials: a systematic review and meta-analysis.

Designing analgesic clinical trials in pediatrics requires a balance between scientific, ethical, and practical concerns. A previous consensus group recommended immediate rescue designs using opioid sparing as a surrogate measure of analgesic efficacy. The authors summarize the performance of rescue analgesic designs in pediatric trials of four commonly used classes of analgesics: opioids, nonsteroidal antiinflammatory drugs, acetaminophen, and local anesthetics. MEDLINE, Embase, CINAHL, The Cochrane Library, and Web of science were searched in April 2013. The 85 studies selected were randomized or controlled clinical trials using immediate rescue paradigms in postoperative pain settings. A random-effects meta-analysis was used to synthesize predefined outcomes using Hedges' g. Difference between the means of the treatment arms were also expressed as a percentage of the corresponding value in the placebo group (placebo-treatment/placebo). Distributions of pain scores in study and control groups and relationships between opioid sparing and pain scores were examined. For each of the four study drug classes, significant opioid sparing was demonstrated in a majority of studies by one or more of the following endpoints: (1) total dose (milligram per kilogram per hour), (2) percentage of children requiring rescue medication, and (3) time to first rescue medication (minutes). Pain scores averaged 2.4/10 in study groups, 3.4/10 in control groups. Opioid sparing is a feasible pragmatic endpoint for pediatric pain analgesic trials. This review serves to guide future research in pediatric analgesia trials, which could test whether some specific design features may improve assay sensitivity while minimizing the risk of unrelieved pain.

Clinical trials in pediatrics

“Children are not little adults.” Almost all aspects of children's health including clinical trials and drug development are poor cousins of adult health. Over the years, pediatricians worldwide caution against blind extrapolation of adult data to children as it may result in considerable harm [1,2]. Also, it is increasingly recognized that the roots of many chronic diseases in adulthood stem from childhood and tackling health issues in children lead to improved health in adults [3,4]. Furthermore, investment in early childhood has long-term benefits in adults not only in health but also in other aspects of life such as education and crime reduction [4,5]. Arguably, health at birth is the single most important predictor of health in adulthood as the inequality of an infant at birth has intergenerational effects [5]. The Carolina Abecedarian Project showed that early childhood programs that are of high quality result in substantial societal benefits (e.g., reduction of crime, increased earnings, better education) [4,5]. A recent publication from this project found that this benefit also translated into improved adult health outcomes [4]. In a randomized trial, Campbell and colleagues described that disadvantaged children who were randomized to the intervention group (early education, health screenings and nutrition program) had significantly lower rates of metabolic syndrome, obesity and hypertension, when aged in their mid-30s, compared with the control group [4]...

Abstract B58: The novel MDM2 inhibitor RG7388 is highly effective against neuroblastoma in vitro and in vivo

Abstract Introduction: Novel less toxic therapeutic approaches to neuroblastoma therapy are urgently needed to improve survival and reduce treatment related side effects. As neuroblastoma is nearly uniformly p53 wild-type, research efforts have focused on activating innate p53-mediated apoptotic mechanisms, specifically through the inhibition of MDM2, the primary inhibitor of p53. The compound RG7388 has proven effective against adult tumors and is under consideration for clinical trials in pediatrics. Here we demonstrate the efficacy of this new class of MDM2 inhibitors against p53 wild-type neuroblastoma in vitro and in vivo orthotopic models of neuroblastoma. Methods: The human neuroblastoma cell lines, NGP, SH-SY5Y, LAN5 and LAN5 si-p53 (p53 silenced by shRNA), were utilized for in vitro and in vivo studies. Using graded concentrations of RG7388 (0 nM - 1500 nM), cell viability was measured by MTS assay. Apoptosis with RG7388 (0 nM, 100 nM, 500 nM) was measured using a flow cytometric annexin assay. In vivo effect of RG7388 was assessed in an orthotopic mouse model of neuroblastoma, in which neuroblastoma cells were intrarenally implanted into 80 female NCr nude mice (NGP n=22, SH-SY5Y n=18, LAN5 n=20, LAN5 si-p53 n=20). The mice were randomly divided into a control group which received vehicle (hydroxypropylcellulose/Tween 80) and a treatment group which received RG7388. RG7388 was initiated three weeks post-implantation by intraperitoneal injection once daily for 14 days at a concentration of 25 mg/kg for mice implanted with NGP and SH-SY5Y, and 35 mg/kg for mice implanted with LAN5 and LAN5 si-p53. At five weeks post-implantation, all mice were sacrificed, xenograft tumors resected and weighed. Xenograft tumor specimens underwent immunohistochemistry for apoptosis. Results: Using MTS assay and annexin apoptosis assay to measure cell viability and apoptosis in several cell lines of neuroblastoma (NGP, SH-SY5Y, LAN5) treated with RG7388, we found robust decrease in cell proliferation and increase in apoptosis compared to vehicle control in all p53 wild-type cell lines. The p53 silenced cell line, LAN5 si-p53, was found to be resistant to RG7388 with no decrease in cell proliferation and no increase in apoptosis. In vivo, all mice tolerated RG7388 well without morbidity. RG7388 significantly inhibited tumor growth by 59% in NGP (p=0.003), 67% in SH-SY5Y (p=0.006), and 75% in LAN5 (p=0.0019) xenograft tumors. However, RG7388 had no inhibitory effect on LAN5 si-p53 xenograft tumors compared to vehicle treatment (p=0.57). Tumor apoptosis was analyzed by cleaved caspase-3 staining, which showed xenografts treated with RG7388 had significantly increased apoptotic cells per high power field in NGP xenografts (p&amp;lt;0.0001) and SH-SY5Y xenografts (p=0.0014). Conclusion: The MDM2 small molecule inhibitor RG7388 significantly inhibits p53 wild-type neuroblastoma tumor growth but has no effect on p53-silenced neuroblastoma xenografts in an orthotopic mouse model. Our studies suggest that RG7388 inhibits tumor growth by p53-mediated apoptosis. Ongoing studies include assessment of the effect of RG7388 on tumor angiogenesis and metastasis. In vitro studies are ongoing to verify the molecular mechanism of RG7388 and confirm increase in p53 levels as well as downstream p53 pathways. Further studies are also being performed in several other p53 mutant neuroblastoma cell lines to elucidate the role of p53 for RG7388 treatment. Citation Format: Anna Lakoma, Eveline Barbieri, Matthew C. McVay, Zaowen Chen, Charitra Adhikari, Jason M. Shohet, Eugene S. Kim. The novel MDM2 inhibitor RG7388 is highly effective against neuroblastoma in vitro and in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B58.

Conducting clinical trials in pediatrics

Conducting clinical trials in pediatric critical care patients are necessary both to determine the value of new treatment strategies and to improve clinical outcomes. However, there are significant challenges to clinicians, parents, and child subjects. There is a serious danger to children through exposure to unforeseen risk as a result of lack of pediatric trials if "trickle down" from adult treatments is permitted. The relatively small size of the pediatric critical care population and relatively low mortality rates limit the utility of mortality as a primary trial outcome in many trials. Innovative trial designs including incorporation of nonfatal outcome measures are increasingly being developed. Increasingly, effective research collaborations are developing either for specific clinical trials or to form the base from which clinical trials are commissioned and supervised. Involvement of children and parents in the development of clinical trials is recommended and valued both by ethical review boards and patient/parent support organizations.

Activity of Ethics Committees in Europe on issues related to clinical trials in paediatrics: Results of a survey

The rights and well-being of children involved in clinical research in Europe should be assured by the respect of ethical considerations and legal rules. Specific provisions are included in the Directive 2001/20/EC (CT-Dir) aimed at providing a homogeneous ethical and legal context to perform clinical trials in Europe. The TEDDY Network of Excellence carried out a “Survey on the ethical and legal frameworks existing in Europe for paediatric clinical trials” to examine the measures enforced by Member States to implement the CT-Dir and other relevant ethical norms. The results showed that many differences exist in the protection of children enrolled in clinical trials. Such differences are especially due to a non-coordinated implementation of the Directive’s Article 4 and a lack of public awareness on ethical issues in this field. The recently approved ‘Ethical considerations for clinical trials on medicinal products conducted with the paediatric population’ should speed up the implementation of an ‘ad hoc set of ethical rules’ and increase the level of minors’ protection. Nevertheless, in lack of ‘binding rules’, a coordination at European level is still needed. Public initiatives aiming at promoting in-depth debates have to be supported in order to encourage this process of coordination.