Fabrice Ruiz

Background/Objectives: Scabies is a disease that disproportionately affects young children. Oral ivermectin is a mainstay of scabies therapy, yet children ®), wherein CHILD-IVITAB was compared to a reference dataset. Results: The 40 mg tablets had a tensile strength of 1.87 ± 0.16 MPa, and met Ph. Eur. requirements for uniformity of mass and dosage units. CHILD-IVITAB tablets disintegrated in vitro in 18.3 ± 1.1 s and released >50% of the dose within 1 min in artificial saliva. Thirteen children were enrolled in the trial. The full dose was taken in 100% of the 26 evaluations, 73% of administrations elicited a neutral or positive reaction, and no dosage form alteration, food/drink co-administration, or extra device was required. The barycenter of all evaluations fell within the positive zone of the CAST^® framework. Conclusions: These results support CHILD-IVITAB as a child-friendly ivermectin formulation suitable for children 5 to <15 kg, a population currently excluded from ivermectin treatment and prevention programs.

L'acceptabilité des médicaments représente un enjeu majeur pour les populations pédiatriques et gériatriques, elle influence directement l'adhésion thérapeutique, l'efficacité et la sécurité des traitements. Les régulateurs tels que l'Agence Européenne des Médicaments (EMA), la Food and Drug Administration (FDA) et l'Organisation Mondiale de la Santé (OMS) soulignent l'importance qui doit être portée à l'acceptabilité des médicaments pour ces populations fragiles, tout au long du développement. La population pédiatrique, couvrant tous les enfants de moins de 18 ans, est très hétérogène en termes de capacités cognitives et physiques. Les recommandations de l'EMA ont imposé, depuis 2014, l'évaluation de l'acceptabilité au cours du développement clinique d'un médicament. Cependant, elles reconnaissaient dans le même temps, qu'il n'existait pas de méthode standardisée pour évaluer l'acceptabilité. Ces travaux, décrivent le développement d'un outil, d'évaluation standardisée de l'acceptabilité des médicaments pédiatriques, par une approche multidimensionnelle, intégrant les caractéristiques des patients (âge, sexe, environnement...) et celles du médicament (avalabilité, palatabilité, reconstitution...). Cet outil a reçu le soutien, en autre, de l'EMA, pour évaluer l'acceptabilité chez les enfants de moins de 12 ans. Cette méthode, a aussi été transposée aux populations de plus de 65 ans. Des études observationnelles, conduites au cours de ces travaux, en ambulatoire, en établissements de santé, mais aussi en laboratoire sur modèle animal, ont permis de montrer que des pistes d'améliorations existaient, pour proposer aux patients les plus fragiles, une spécialité plus adaptée à leur besoin. L'évaluation devant se dérouler tout au long de la chaine du médicament, de sa formulation jusqu'à sa prescription.

Background: The epidemiological, clinical and medico-economic burden of unexplained or refractory chronic cough (URCC) is poorly known. Objective: To describe sociodemographic characteristics, clinical impact, healthcare resource utilisation and associated costs in French patients with URCC. Methods: Populations of interest (chronic cough, URCC, controls) were identified from the general population-based Constances cohort (124 565 participants at the time of study inception) and invited to answer a specific ad hoc questionnaire on cough. Their healthcare resource utilisation data were extracted from the National Healthcare Database System. Results: Populations of interest were identified among participants for whom data and questionnaire responses were available (n=5277): URCC (n=116), non-URCC (n=1357) and no chronic cough (reference group; n=3804). The extrapolated frequencies of chronic cough and URCC in the Constances cohort were 3.8% and 0.22%, respectively. URCC was mainly associated with gastro-oesophageal reflux disease (31.0%) and asthma/COPD (18.3%). Depressive symptoms (Center for Epidemiological Studies Depression scale score ≥16) were significantly more frequent in patients with URCC than in controls (43.0% versus 24.0%, p=0.0036). Over the previous 12 months, the mean number of medical visits was higher in the URCC group than in controls (9.1 versus 6.0, p=0.0002). Treatment for underlying conditions of interest were also more frequent in the URCC group. Compared to controls, a 36% increase in medical visits and a four times increase in treatments of underlying conditions of interest were observed in the URCC group. Conclusions: URCC is associated with an important clinical impact and high healthcare resource utilisation and associated costs. The burden of URCC is significant and remains an unmet medical need.

Although drug acceptability can have a significant impact on patient adherence in pediatric therapy, data are limited, even for common therapeutic areas. We present the second part of an acceptability study conducted at the University Children’s Hospital Düsseldorf, Germany. The study investigated the acceptability of most commonly used antibiotics in a pediatric hospital setting. The researchers used the acceptability reference framework to score the acceptability of five antibiotics based on 150 real-life observer reports of medicine intake. Four antibiotics assessed in this study were formulated as preparations for injection (ampicillin, ampicillin/sulbactam, ceftriaxone, and gentamicin) and one as a powder for oral liquid suspension (co-amoxiclav). All the antibiotics formulated as preparations for injection were rated negatively due to high rates of negative reactions (80%), the use of restraint (51%), the use of extra devices (99%), and long preparation and administration times (100%). The antibiotic formulated as a powder was significantly more well accepted. The study concluded that there is a lack of appropriate formulations for antibiotics for use in children. These findings are important in improving knowledge on acceptability drivers and might help in formulating and prescribing better medicines for children. The study highlights the need for healthcare professionals to have knowledge about the acceptability of different products to select the best-adapted product for each patient.

It is well established that treatment regime compliance is linked to the acceptability of a pharmaceutical formulation, and hence also to therapeutic outcomes. To that end, acceptability must be assessed during the development of all pharmaceutical products and especially for those intended for paediatric patients. Although acceptability is a multifaceted concept, poor sensory characteristics often contribute to poor patient acceptability. In particular, poor taste is often cited as a major reason for many patients, especially children, to refuse to take their medicine. It is thus important to understand and, as far as possible, optimise the sensory characteristics and, in particular, the taste/flavour/mouthfeel of the formulation throughout the development of the product. Sensory analysis has been widely practiced, providing objective data concerning the sensory aspects of food and cosmetic products. In this paper, we present proposals concerning how the well-established principles of sensory analysis can best be applied to pharmaceutical product development, allowing objective, scientifically valid, sensory data to be obtained safely. We briefly discuss methodologies that may be helpful in reducing the number of samples that may need to be assessed by human volunteers. However, it is only possible to be sure whether or not the sensory characteristics of a pharmaceutical product are non-aversive to potential users by undertaking sensory assessments in human volunteers. Testing is also required during formulation assessment and to ensure that the sensory characteristics remain acceptable throughout the product shelf life. We provide a risk assessment procedure to aid developers to define where studies are low risk, the results of a survey of European regulators on their views concerning such studies, and detailed guidance concerning the types of sensory studies that can be undertaken at each phase of product development, along with guidance about the practicalities of performing such sensory studies. We hope that this guidance will also lead to the development of internationally agreed standards between industry and regulators concerning how these aspects should be measured and assessed throughout the development process and when writing and evaluating regulatory submissions. Finally, we hope that the guidance herein will help formulators as they seek to develop better medicines for all patients and, in particular, paediatric patients.

Although medicine acceptability is likely to have a significant impact on the patient’s adherence in pediatrics and therefore on therapy success, there is still little data even for common therapeutic areas. For analgesics/antipyretics, healthcare professionals face a wide variety of products and need knowledge to select the best adapted product for each patient. We investigated acceptability of those products most used at the University Children’s Hospital Düsseldorf, Germany. Based on 180 real-life observer reports of medicine intake, we used the acceptability reference framework to score acceptability of six distinct medicines. Both ibuprofen and paracetamol tablets, mainly used in adolescents, were positively accepted. This was not the case for the solution for injection of metamizole sodium. Regarding syrups, mainly used in children under 6 years of age, ibuprofen flavored with strawberry and provided with an oral syringe was positively accepted, while paracetamol flavored with orange and provided with a measuring cup was not. Suppository appeared to be an alternative to oral liquids in infants and toddlers with palatability and administration issues. Differences appeared to be driven by dosage forms and formulations. These findings improve knowledge on acceptability drivers and might help formulating and prescribing better medicines for children.

Soil-transmitted helminthiasis (STH) is among the most common of parasitic infections, affecting vulnerable populations in tropical/subtropical areas globally. In endemic countries, children, a high-risk population, require treatment and preventive interventions. Mebendazole, a WHO-recommended medicine, originally formulated as a tablet that was often crushed for administration to young children unable to swallow it, was reformulated as a chewable tablet. Acceptability is a key aspect for treatment effectiveness in pediatrics. Herein, we used a validated data-driven approach to investigate the acceptability of the 500-mg mebendazole chewable tablet in children aged 2 to 4 years in Peru. Observer-reported outcomes were collected for 182 medicine intakes. Acceptability was scored using the acceptability reference framework: a three-dimensional map juxtaposing “positively accepted” and “negatively accepted” profiles. Results found that the 500-mg mebendazole chewable tablet was classified as “positively accepted” in children aged 2 to 4 years. Acceptability increased with age and some acceptability issue remain for the younger children. Nevertheless, this formulation was considerably better accepted than the conventional tablets regardless of treatment in young children. This chewable formulation appears to be an appropriate alternative to the hard tablet of mebendazole for treatment of STH and preventive interventions in children aged 2 to 4 years.