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Introduction: Regulatory decisions on paediatric investigation plans (PIPs) aim at making effective and safe medicines timely available for children with high unmet medical need. At the same time, scientific knowledge progresses continuously leading frequently to the identification of new molecular targets in the therapeutic area of oncology. This, together with further efforts to optimise next generation medicines, results in novel innovative products in development pipelines. In the context of global regulatory development requirements for these growing pipelines of innovative products (e.g. US RACE for children Act), it is an increasing challenge to complete development efforts in paediatric oncology, a therapeutic area of rare and life-threatening diseases with high unmet needs.Objective: Regulators recognise feasibility challenges of the regulatory obligations in this context. Here, we explain the EU regulatory decision making strategy applied to paediatric oncology, which aims fostering evidence generation to support developments based on needs and robust science. Because there is a plethora of products under development within given classes of or within cancer types, priorities need to be identified and updated as evidence evolves. This also includes identifying the need for third or fourth generation products to secure focused and accelerated drug development.Conclusion: An agreed PIP, as a plan, is a living document which can be modified in light of new evidence. For this to be successful, input from the various relevant stakeholders, i.e. pa-tients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meet-ings.(c) 2022 Elsevier Ltd. All rights reserved.

Antibiotics are among the most commonly prescribed drugs in children. Adherence to the treatment with these drugs is of the utmost importance to prevent the emergence of resistant bacteria, a global health threat. In children, medicine acceptability is likely to have a significant impact on compliance. Herein we used a multivariate approach, considering simultaneously the many aspects of acceptability to explore the drivers of oral antibiotic acceptability in children under twelve, especially in toddlers and in preschoolers. Based on 628 real-life observer reports of the intake of 133 distinct medicines, the acceptability reference framework highlighted the influence of many factors such as age and sex of patients, previous exposure to treatment, place of administration, administration device, flavor agent in excipients and active pharmaceutical ingredient. These findings from an international observational study emphasize the multidimensional nature of acceptability. Therefore, it is crucial to consider all these different aspects for assessing this multi-faceted concept and designing or prescribing a medicine in order to reach adequate acceptability in the target population.

Child trafficking is a form of modern slavery, a rapidly growing, mutating and multifaceted system of severe human exploitation, violence against children, child abuse and child rights violations. Modern slavery and human trafficking (MSHT) represents a major global public health concern with victims exposed to profound short-term and long-term physical, mental, psychological, developmental and even generational risks to health. Children with increased vulnerability to MSHT, victims (in active exploitation) and survivors (post-MSHT exploitation) are attending healthcare settings, presenting critical windows of opportunity for safeguarding and health intervention.Recognition of child modern slavery victims can be very challenging. Healthcare providers benefit from understanding the diversity of potential physical, mental, behavioural and developmental health presentations, and the complexity of children’s responses to threat, fear, manipulation, deception and abuse.Healthcare professionals are also encouraged to have influence, where possible, beyond the care of individual patients. Research, health insights, advocacy and promotion of MSHT survivor input enhances the collaborative development of evidence-based approaches to prevention, intervention and aftercare of affected children and families.

Accepted manuscript version, licensed CC BY-NC-ND 4.0. Published version available at https://doi.org/10.1136/ejhpharm-2018-001562. Objectives: The main objective was to investigate Y-site compatibility of intravenous drugs with one standard total parenteral nutrition (TPN) admixture for preterm infants. Since micro-precipitation was observed in the water phase after addition of trace elements, the concentration effect on micro-precipitation formation developed as a sub-goal. Methods: Seven drugs (ampicillin, ceftazidime, fluconazole, fosphenytoin, furosemide, metronidazole and paracetamol) were mixed in three mixing ratios with one preterm TPN admixture. Samples were investigated within 1 hour and again after 4 hours. Precipitation was studied in a lipid-free version called TPNaq by light obscuration, turbidimetry and visual examination. Emulsion stability data were assessed by light obscuration and laser diffraction. pH was measured to assess the theoretical risk of precipitation and emulsion destabilisation. The influence of different concentrations of trace elements on precipitation was investigated by visual examination, turbidimetry and light obscuration. Results: Ampicillin, ceftazidime, fosphenytoin and furosemide led to precipitation after mixing with TPNaq. In some samples of TPN and fluconazole, metronidazole and paracetamol, the emulsion droplet size was above the acceptance limit, although this might also be inherent to the TPN admixture. An unexpected formation of micro-precipitate correlating with increasing amounts of added trace elements might be caused by an interaction of cysteine and copper, and complicated the compatibility assessment with drugs. Conclusions: The micro-precipitate resulting from the addition of trace elements should be investigated further. This study did not provide sufficient evidence to recommend Y-site infusion of the tested drugs and the preterm admixture; however, it might offer some additional support to other compatibility data.

The acceptability of pediatric pharmaceutical products to patients and their caregivers can have a profound impact on the resulting therapeutic outcome. However, existing methodology and approaches used for acceptability assessments for pediatric products is fragmented, making robust and consistent product evaluations difficult. A pediatric formulation development workshop took place in Washington, DC in June 2016 through the University of Maryland's Center of Excellence in Regulatory Science and Innovation (M-CERSI). A session at the workshop was dedicated to acceptability assessments and focused on two major elements that affect the overall acceptability of oral medicines, namely swallowability and palatability. The session started with presentations to provide an overview of literature, background and current state on swallowability and palatability assessments. Five parallel breakout discussions followed the presentations on each element, focusing on three overarching themes, risk-based approaches, methodology and product factors. This article reports the key outcomes of the workshop related to swallowability and palatability assessments.

AIM This study provided an overview of manipulating oral medicines given to hospitalised children and evaluated this practice in two hospitals. It focused on the type of manipulation and the dosage forms that were manipulated. METHOD This was a cross-sectional, prospective study, carried out on the paediatric wards at two Norwegian hospitals for four weeks in 2013. A medicine was said to have been manipulated if it was not administered as described in the Norwegian summary of product characteristics. RESULTS This study showed that 17% of the 3070 administrations of oral medicines to the hospitalised children involved manipulation. Tablets, including modified release preparations, were the most frequently manipulated medicines. In approximately half of these cases, only a segment of the unit dose was administered. No manipulation of oral liquids was seen. The bioavailability of as much as 44% of the most frequent given substances may be sensitive to such manipulations due to limited aqueous solubility. Various routines for splitting and handling the unit doses were observed. CONCLUSION Manipulation of oral medication was regularly performed on paediatric wards. There is an urgent need for age-appropriate medicines, documented and standardised processes for manipulating medicines and staff training on the consequences of manipulation.

Objectives Infusion of precipitate or destabilized emulsion can be harmful. The purpose of this study was to obtain Y-site compatibility data on intravenous drugs and total parenteral nutrition (TPN) relevant for children. Methods Two three-in-one TPN admixtures (Olimel N5E and Numeta G16E) used for children of different age groups were tested with ten drugs (ampicillin, ceftazidime, clindamycin, dexamethasone, fluconazole, fosphenytoin, furosemide, metronidazole, ondansetron and paracetamol). Drug : TPN ratios were estimated from a wide range of age and weight classes, and the most extreme mixing ratios (drug > TPN, TPN > drug) in addition to 1 + 1 were chosen. Assessment of potential precipitation was performed by subvisual particle counting, visual examinations and measurements of turbidity and pH. Emulsion stability was investigated by estimation of percentage of droplets above 5 μm (PFAT5), mean droplet diameter and pH measurements. Complimentary theoretical evaluations were performed. Key findings Ampicillin, fosphenytoin and furosemide precipitated when mixed with TPN. The results for ceftazidime, clindamycin, dexamethasone, fluconazole, metronidazole, ondansetron and paracetamol suggest that they were compatible with either TPN in the tested concentrations. None of the drugs were found to destabilize the emulsions. Conclusion Three drugs showed clear signs of precipitation when mixed with TPN and these products should not be co-administered in the same infusion line.

ObjectivesThe aim of this study was to investigate the use of off-label (OL) and unlicensed (UL) medicines to hospitalised children in Norway, to add to the current knowledge on use of medicines in this vulnerable patient group.MethodsThe study was performed as a cross-sectional prospective study. Medication was classified as on- or off-label based on the comparison with the SmPC regarding age, indication, dosage, route of administration and handling of the product. UL products were classified as imported or pharmacy produced.Key findingsMore than 90% of children receiving medicines in our study were given OL or UL medicines. More patients received OL (83%) than UL (59%). Route of administration was the most frequently observed OL category. The vast majority of the OL prescriptions were for ‘off-patent’ products. One-third of products prescribed were UL.ConclusionsThe study confirms that medicines to children in hospital to a significant degree are being used outside or without authorisation, in spite of recent paediatric regulatory initiatives. More data are still needed on efficacy and safety of medicines used in children, data to be incorporated in the SmPC. In addition, suitable formulations are needed to ensure optimal dosing and adherence without risky manipulations.

Purpose: This study investigates the validity, reliability, and detection limit of a visual examination method utilizing the Tyndall effect to enhance visible detection of particles. The suitability of the method for compatibility testing of intravenous fluids in a hospital pharmacy context is discussed. Methods: A panel of 20 inspectors examined 20 samples, with and without particles, using two light sources (halogen lightbulb in a focused desk lamp and a red pocket laser pointer). The samples contained particles of different origin (precipitate, polystyrene standards), varying size, and concentrations. Light obscuration and turbidimetric measurements were used to obtain numeric references. The samples were divided into rejection probability zones, and the validity (sensitivity, specificity, and likelihood ratios) and reliability (inter-rater agreement coefficients Fleiss9 kappa and Gwet9s AC1) were estimated. Results: The sensitivity of the laser pointer for detecting microprecipitates was quite high; however, it also showed a high false rejection rate. The specificity was slightly higher for the focused desk lamp than the laser pointer. The likelihood ratios were not within the recommended limits of a useful test, indicating that the method could not securely confirm the presence/absence of particles in the samples. The inter-rater agreement coefficients indicated fair to moderate agreement between the inspectors. Conclusions: The validity and reliability were not satisfactory for either of the light sources. The visual detection limit seemed to be around 5 μm, although we propose that an exact detection limit is not that relevant for compatibility testing. Based on the current findings, the visual examination method cannot be recommended as the sole method for judging compatibility of parenteral nutrition and drugs, but rather in a program of several methods. In the hospital pharmacy, the method may be a resource, together with theoretical considerations, in situations where other methods are unavailable; however, use of in-line-filters is essential to protect the patient. LAY ABSTRACT: Many patients under intensive care are in need of several intravenous drugs simultaneously. These drugs cannot be given in the same infusion line unless compatibility has been documented. Incompatibilities can result in, for example, precipitation of particles. Injected particles can harm the patient and should be avoided. Visual screening of blends of drugs for possible incompatibility, using a focused light source to enhance visual detection based on the Tyndall effect, could be a quick and easy methodology to identify incompatibility. In the following study the objective was to investigate how reliable visual inspection, with the utilization of the Tyndall effect, is at detecting particles and precipitations in blends of intravenous drugs and parenteral nutrition mixtures. Twenty inspectors each examined 20 different samples with two different light sources. Some of the samples were without particles (clean), and some contained different types and degrees of particle contamination. The inspectors9 judgment of the samples was recorded and validity and reliability parameters were calculated to evaluate the method9s suitability. The conclusion was that because of false positive and negative findings the visual inspection method alone is not enough to securely document compatibility/incompatibility, but it is more suitable as support together with additional methods.

The Paediatric Regulation in the European Union sets up a framework governing mandatory requirements and incentives for industry in development of new medicinal products as well as a series of accompanying measures to facilitate approaches to gain access and improve exchange of relevant information on medicinal products in paediatric use. This chapter first presents an overview of this regulatory framework and the requirements that have to be met by industry. It describes the role of the Paediatric Committee (PDCO) at the European Medicines Agency (EMA) and the main points to consider in discussing Paediatric Investigation Plans (PIP). The second part focuses on the specific implications of this regulatory framework on the development of drug formulations for paediatric populations. Essential elements to ensure suitably adapted formulations are reviewed, focusing on dosing appropriateness, acceptability and safety for all relevant age groups.

Even though the regulatory authorities to some extent accept the extrapolation of efficacy data from adults to paediatric patients, it is often the case that differences in the disease process and the developmental stage of the children prevent the extrapolation of efficacy in these populations. Where efficacy studies are needed, the development, validation, and employment of different endpoints for specific age and developmental subgroups become necessary. Children are in continuous development and any measure to assess the efficacy of an intervention should take carefully into account how this development affects the endpoints, including the performance capacity of the child and differences in the condition and symptoms presented. Clinical endpoints that are used in the adult trials to evaluate treatment effect may not be suitable in paediatric studies. The development of surrogate endpoints for benefit and risk assessment in children is necessary. Collaboration between the academic researchers, pharmaceutical industry, and regulatory authorities is needed to meet the challenges in proper validation of biomarkers and surrogate endpoints in paediatric trials.

Background It is generally not recommended to give two drugs together or drugs in addition to total parenteral nutrition in parallel infusion unless compatibility has been documented. The possibility of performing simple compatibility testing in the hospital pharmacy has attracted attention, and visual examination using a focused light source (Tyndall beam) has been suggested as a simple tool for this purpose1. Purpose To investigate the validity and reliability of the Tyndall method using two different light sources, to determine the visual detection limit in terms of particle size and concentration and to evaluate the suitability of the method for simple compatibility testing in a hospital pharmacy setting. Materials and methods A panel of 20 inspectors examined 20 samples, with and without particles, using two different light sources. The samples contained particles of different origin, varying size and concentrations. Light obscuration measurements were used as reference. The samples were classed as accept, grey or reject and the validity (sensitivity, specificity and likelihood ratios (LR)) and reliability (Fleiss’Kappa and Gwets’AC1) of the classifications were calculated. Results Gross particles and massive precipitations were easily detected, but for smaller particles in low concentrations, the inspectors were more uncertain. The LR + ratios were high, indicating that if a sample is rejected, there is a high probability that the samples actually contain particles. The LR- ratios were not low enough, meaning that if a sample is accepted there is still a considerable chance that the sample contains particles. The Fleiss9 Kappa and AC1 indicated only fair to moderate agreement between the inspectors. Conclusions The validity and reliability were not satisfactory using either of the light sources. The visual detection limit seemed to be around 5 µm, but a more data is required. The visual examination method cannot be recommended as the only method for determining compatibility, and it is not suitable for simple compatibility testing at the hospital pharmacies. Acknowledgements Vigdis Staven is a PhD student of Hospital Pharmacy North, Norway, and Dept. of Pharmacy, University of Tromso, Norway, sponsored by Helse Nord RHF. We gratefully acknowledge the financial support from the Norwegian Medicines for Children Network, Bergen, Norway. Thank you to Frode Skjold, Dept. of Pharmacy, University of Tromso, for valuable discussions on the statistical issues, to Margaret Aarag Antonsen, Hospital Pharmacy North and the employees of the Hospital Pharmacy of Tromso, Norway, for discussions, help and practical support. Reference Veggeland, T. & Brandl, M. Evaluation of a Simple Method for Visual Detection of Microprecipitates in Blends of Parenteral Drug Solutions Using a Focused (Tyndall) Light Beam. International Journal of Pharmaceutical Compounding 2010;14:78-81. No conflict of interest.

Lipid peroxidation in human LDL (0.05 mg protein/mL) incubated with Cu(2+)-ions (5 microM) in vitro was dose-dependently inhibited by the flavonoid myrigalone B (MyB) and by ascorbic acid. MyB at 6 microM increased the oxidation lag time by 135 +/- 24 min (approximately 5-fold compared to controls) and reduced the maximum oxidation rate by 46 +/- 5%. Ascorbic acid, at 9 microM, increased the lag time by 179 +/- 29 min (6-fold compared to controls) but did not affect the maximum oxidation rate. The increase in lag time induced by MyB was enhanced in the presence of ascorbic acid. Their effects were additive, except when both were present at the highest concentration tested, when a significant potentiation, giving an increase in lag time of approximately 2 hr more than the sum of separate effects, occurred. Concentration-time curves for MyB in the absence and presence of ascorbic acid showed that the vitamin protected MyB against deterioration during incubation, and indicated that the net consumption of MyB in the oxidation process was reduced. No differences were observed when ordinary ascorbic acid and Ester-C, a commercial vitamin C product, were compared. In conclusion, MyB and ascorbic acid seem to interact in a way that further improves the antioxidant status of the LDL particle relative to each substance separately.

The mutual influences of wheat selenium (Se) and n-3 polyunsaturated fatty acids (n-3 PUFA) on plasma Se and indicators of increased oxidative stress were investigated in a randomized, double-blind study with 31 women (23.5 +/- 3.4 yr). Groups 1 and 2 ingested 5.4 g n-3 PUFA daily (as ethyl esters), whereas groups 3 and 4 received placebo capsules. Groups 2 and 3 received 3 slices of high-Se bread daily, providing 115 micrograms Se, in addition to the 77 +/- 26 micrograms Se in the diet. Groups 1 and 4 received placebo slices. Blood samples were drawn at baseline and at 3 and 6 wk. Serum Se concentrations increased in both groups given Se-enriched bread, but significantly less in subjects given n-3 PUFA (group 2). There were no changes in the plasma ratio alpha-tocopherol:mg cholesterol or plasma ascorbic acid levels. In group 1, plasma-conjugated dienes and thiobarbituric acid-reactive substances (TBARS) rose by 130% (p < 0.005) and 126% (p < 0.005), respectively. Two-way ANOVA showed significant interaction effects of Se and n-3 PUFA on changes in conjugated dienes (p = 0.03) and TBARS (p = 0.015), Se treatment apparently modifying the peroxidative effects of n-3 PUFA. In subjects receiving n-3 PUFA, changes in conjugated dienes and TBARS were negatively correlated with changes in serum Se. In summary, n-3 PUFA modified the effect of Se supplementation, whereas Se seemed to modify the peroxidative effects of n-3 PUFA.