European regulatory strategy for supporting childhood cancer therapy developments.

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. patients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meetings.

Exploring Acceptability Drivers of Oral Antibiotics in Children: Findings from an International Observational Study.

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.

Physical stability of an all-in-one parenteral nutrition admixture for preterm infants upon mixing with micronutrients and drugs.

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.

Does the EU's Paediatric Regulation work for new medicines for children in Denmark, Finland, Norway and Sweden? A cross-sectional study.

OBJECTIVE: The aim of this study was to assess the marketing status of the new paediatric medicinal products listed in the 10-year report as initially authorised between 2007 and 2016, reflecting the product availability in four Nordic countries. DESIGN: This is a cross-sectional study. SETTING: Analysis of the national medicine agency's databases in Denmark, Finland, Norway and Sweden. DATA SOURCE: New medicinal products with paediatric indications and new paediatric formulations listed in the Annex of European Medicines Agency's EU Paediatric Regulation 10-year report. DATA ANALYSIS: The products were classified according to national marketing status between January 2019 and March 2019, whether a product was authorised and whether the product was marketed. MAIN OUTCOME MEASURES: The percentages of the new medicinal products with paediatric indications and new paediatric formulations having a valid marketing authorisation and being marketed, both in terms of the sums of all countries and separately for each country. RESULTS: Across the four countries, 21%-32% (16/76-24/76) of the new medicinal products were not marketed. Of the new formulations relevant to children, 29%-50% (16/56-28/56) were not marketed, and a significant proportion of these products had never been marketed. CONCLUSIONS: This study reflects the reality of the implementation of the Paediatric Regulation. The results show that several new paediatric medicines and new formulations are not marketed. This affects the product availability. Similar data from other countries are needed to evaluate the overall European status to find remedies to current situation and increase the availability of the medicines for children.

Oral medicine acceptance in infants and toddlers: measurement properties of the caregiver-administered Children's acceptance tool (CareCAT).

BACKGROUND: Developing age-appropriate medications remains a challenge in particular for the population of infants and toddlers, as they are not able to reliably self-report if they would accept and consequently take an oral medicine. Therefore, it is common to use caregivers as proxies when assessing medicine acceptance. The outcome measures used in this research field differ and most importantly lack validation, implying a persisting gap in knowledge and controversy in the field. The newly developed Caregiver-administered Children's Acceptance Tool (CareCAT) is based on a 5-point nominal scale, with descriptors of medication acceptance behavior. This cross-sectional study assessed the measurement properties of the tool with regards to the user's understanding and its intra- and inter-rater reliability. METHODS: Participating caregivers were enrolled at a primary healthcare facility where their children (median age 6 months) had been prescribed oral antibiotics. Caregivers, trained observers and the tool developer observed and scored on the CareCAT tool what behavior children exhibited when receiving the medicine (n = 104). The video-records of this process served as replicate observations (n = 69). After using the tool caregivers were asked to explain their observations and the tool descriptors in their own words. The tool's reliability was assessed by percentage agreement and Cohen's unweighted kappa coefficients of agreement for nominal scales. RESULTS: The study found that caregivers using CareCAT had a satisfactory understanding of the tool's descriptors. Using its dichotomized scores the tool reliably was strong for acceptance behavior (agreement inter-rater 84-88%, kappa 0.66-0.76; intra-rater 87-89%, kappa 0.68-0.72) and completeness of medicine ingestion (agreement inter-rater 82-86%, kappa 0.59-0.67; intra-rater 85-93%, kappa 0.50-0.70). CONCLUSIONS: The CareCAT is a low-cost, easy-to-use and reliable instrument, which is relevant to assess acceptance behavior and completeness of medicine ingestion, both of which are of significant importance for developing age-appropriate medications in infants and toddlers.

Assessment of swallowability and palatability of oral dosage forms in children: Report from an M-CERSI pediatric formulation workshop.

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.

Off-label and unlicensed medicines to hospitalised children in Norway.

OBJECTIVES: The 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. METHODS: The 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 FINDINGS: More 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. CONCLUSIONS: The 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.

Physical compatibility of total parenteral nutrition and drugs in Y-site administration to children from neonates to adolescents.

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.

Manipulating tablets and capsules given to hospitalised children in Norway is common practice.

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.

Development and evaluation of a test program for Y-site compatibility testing of total parenteral nutrition and intravenous drugs.

BACKGROUND: There is no standardized procedure or consensus to which tests should be performed to judge compatibility/incompatibility of intravenous drugs. The purpose of this study was to establish and evaluate a test program of methods suitable for detection of physical incompatibility in Y-site administration of total parenteral nutrition (TPN) and drugs. METHODS: Eight frequently used methods (dynamic light scattering, laser diffraction, light obscuration, turbidimetry, zeta potential, light microscopy, pH-measurements and visual examination using Tyndall beams), were scrutinized to elucidate strengths and weaknesses for compatibility testing. The responses of the methods were tested with samples containing precipitation of calcium phosphate and with heat destabilized TPN emulsions. A selection of drugs (acyclovir, ampicillin, ondansetron and paracetamol) was mixed with 3-in-1 TPN admixtures (Olimel® N5E, Kabiven® and SmofKabiven®) to assess compatibility (i.e. potential precipitates and emulsion stability). The obtained compatibility data was interpreted according to theory and compared to existing compatibility literature to further check the validity of the methods. RESULTS: Light obscuration together with turbidimetry, visual inspection and pH-measurements were able to capture signs of precipitations. For the analysis of emulsion stability, light obscuration and estimation of percent droplets above 5 µm (PFAT5) seemed to be the most sensitive method; however laser diffraction and monitoring changes in pH might be a useful support. Samples should always be compared to unmixed controls to reveal changes induced by the mixing. General acceptance criteria are difficult to define, although some limits are suggested based on current experience. The experimental compatibility data was supported by scattered reports in literature, further confirming the suitability of the test program. However, conflicting data are common, which complicates the comparison to existing literature. CONCLUSIONS: Testing of these complex blends should be based on a combination of several methods and accompanied by theoretical considerations.

Utilization of the tyndall effect for enhanced visual detection of particles in compatibility testing of intravenous fluids: validity and reliability.

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 Fleiss' kappa and Gwet's 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 inspectors' judgment of the samples was recorded and validity and reliability parameters were calculated to evaluate the method's 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.

Pediatric formulation issues identified in Paediatric Investigation Plans.

Since the European Paediatric Regulation was introduced in 2007, companies developing new medicinal products or new indications/routes of administration/pharmaceutical forms are obliged to present age-appropriate formulations for the pediatric population within a Paediatric Investigation Plan (PIP) to the European Medicines Agency. Our review highlights a number of discrepancies between what is proposed by applicants and what is considered acceptable by regulators, taking a sample of PIP applications assessed by a specialized Formulation Working Group (FWG) of the Paediatric Committee in 2009. This Working Group assessed 43% of the total number of validated PIP applications during that year. Ninety-two percent of the formulations assessed raised at least one issue, mainly relating to excipients, appropriateness of the route of administration or pharmaceutical form, dosing accuracy and patient's acceptability. A stronger focus on all these aspects, considering the targeted age range, the severity of the disease and the treatment duration, could streamline the development process.

Efficacy assessment in paediatric studies.

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.