Patient acceptability, safety and access : A balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations

© 2017 Elsevier B.V. All rights reserved.The selection and design of age-appropriate formulations intended for use in paediatric and geriatric patients are dependent on multiple factors affecting patient acceptability, safety and access. The development of an economic and effective product relies on a balanced consideration of the risks and benefits of these factors. This review provides a comprehensive and up-to-date analysis of oral dosage forms considering key aspects of formulation design including dosage considerations, ease of use, tolerability and safety, manufacturing complexity, stability, supply and cost. Patient acceptability has been examined utilising an evidence-based approach to evaluate regulatory guidance and literature. Safety considerations including excipients and potential risk of administration errors of the different dosage forms are also discussed, together with possible manufacturing and supply challenges. Age appropriate drug product design should consider and compare i) acceptability ii) safety and iii) access, although it is important to recognise that these factors must be balanced against each other, and in some situations a compromise may need to be reached when selecting an age-appropriate formulation.Peer reviewedFinal Accepted Versio

Responsive Sensory Evaluation to Develop Flexible Taste-Masked Paediatric Primaquine Tablets against Malaria for Low-Resource Settings

Primaquine is an important antimalarial drug for malaria transmission blocking and radical cure, but it is not currently available in child-friendly formulations in appropriate doses. Adult-strength tablets are often crushed and dissolved in water to obtain the required dose, which exposes the drug’s bitter taste. As part of the developing paediatric primaquine (DPP) project, this study adopted a responsive sensory pharmaceutics approach by integrating real-time formulation development and pre-clinical taste assessment to develop palatable, flavour-infused primaquine tablets. A design of experiment (DoE) approach was used to screen different taste-masking agents and excipient blends with trained, expert sensory assessors, with quinine hydrochloride as a model bitter tastant. The taste-masking efficacy of selected prototype formulation blends was validated with naïve assessors using the highest 15 mg primaquine dose. The mean bitterness intensity rating, measured on a discrete 11-point scale, was halved from 7.04 for the unflavoured control to 2.74–3.70 for the formulation blends. Sucralose had the biggest impact on bitterness suppression and improving palatability. Two different flavouring systems have been developed, and their acceptability in paediatric patients will be assessed as part of upcoming validation field clinical trials in Africa

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 crosssectional 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 videorecords 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

Methodologies for Assessing the Acceptability of Oral Formulations among children and older adults: A Systematic Review

This is an open access article distributed under the terms and conditions of the Creative Commons Attribution NonCommercial-NoDerivatives 4.0 International CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/Acceptability of medicinal products in children and older populations is pivotal in ensuring adherence and therapeutic outcomes. This review systematically identifies studies reporting on formulation aspects of oral medications that affect their acceptability in these patient groups. Particular emphasis is placed on the evaluation of the methodologies employed in the studies. Sixty-eight studies were included for analysis, with 51 (75%) in children and 17 (25%) in older populations. The studies evaluated a range of oral formulations; however, the methodologies used differ considerably in participants’ characteristics, study settings, tools, acceptability definitions and criteria. It is evident that there is a lack of standardisation in study design as well as the assessment methods used in assessing acceptability of medicines in children and older populations. This review presents a systematic analysis on methods employed for assessing acceptability of oral medicines in children and older adults, to provide insights and recommendations regarding the design of reliable instruments in future studies.Peer reviewe

Interventions for Improving Communication with Children and Adolescents about their Cancer

BACKGROUND: Communication with children and adolescents with cancer about their disease and treatment and the implications of these is an important aspect of good quality care. It is often poorly performed in practice. Various interventions have been developed that aim to enhance communication involving children or adolescents with cancer. OBJECTIVES: To assess the effects of interventions for improving communication with children and/or adolescents about their cancer, its treatment and their implications, updating the 2003 version of this review. SEARCH STRATEGY: In April 2006 we updated searches of the following sources: CENTRAL (The Cochrane Library, issue 1 2006); MEDLINE (Ovid), (2003 to March week 5 2006); EMBASE (Ovid) (2003 to 2006 week 13); PsycINFO (Ovid) (2003 to March week 5 2006); CINAHL (Ovid) (2003 to March week 5 2006); ERIC (CSA) (earliest to 2006); Sociological Abstracts (CSA) (earliest to 2006); Dissertation Abstracts: (2002 to 6 April 2006).In 2003 we conducted searches of CENTRAL; MEDLINE, EMBASE, PsycINFO, CINAHL, ERIC, Sociological Abstracts and Dissertation Abstracts.For the initial (2001) publication of this review we also searched the following databases: PsycLIT; Cancerlit; Sociofile; Health Management Information Consortium; ASSIA; LISA; PAIS; Information Science Abstracts; JICST; Pascal; Linguistics and Language Behavior Abstracts; Mental Health Abstracts; AMED; MANTIS.We also searched the bibliographies of studies assessed for inclusion, and contacted experts in the field. SELECTION CRITERIA: Randomised and non-randomised controlled trials, and before and after studies, evaluating the effects of interventions for improving communication with children and/or adolescents about their cancer, treatment and related issues. DATA COLLECTION AND ANALYSIS: Data relating to the interventions, populations and outcomes studied and the design and methodological quality of included studies were extracted by one review author and checked by another review author. We present a narrative summary of the results. MAIN RESULTS: One new study met the criteria for inclusion; in total we have included ten studies involving 438 participants. Studies were diverse in terms of the interventions evaluated, study designs used, types of people who participated and the outcomes measured.One study of a computer-assisted education programme reported improvements in knowledge and understanding about blood counts and cancer symptoms. One study of a CD-ROM about leukaemia reported an improvement in children's feelings of control over their health. One study of art therapy as support for children during painful procedures reported an increase in positive, collaborative behaviour. Two out of two studies of school reintegration programs reported improvements in some aspects of psychosocial wellbeing (one in anxiety and one in depression), social wellbeing (two in social competence and one in social support) and behavioural problems; and one reported improvements in physical competence. One newly-identified study of a multifaceted interactive intervention reported a reduction in distress (as measured by heart rate) related to radiation therapy.Two studies of group therapy, one of planned play and story telling, and one of a self-care coping intervention, found no significant effects on the psychological or clinical outcomes measured. AUTHORS' CONCLUSIONS: Interventions to enhance communication involving children and adolescents with cancer have not been widely or rigorously assessed. The weak evidence that exists suggests that some children and adolescents with cancer may derive some benefit from specific information-giving programs, from support before and during particular procedures, and from interventions that aim to facilitate their reintegration into school and social activities. More research is needed to investigate the effects of these and other related interventions

Potential of helper-dependent Adenoviral vectors in CRISPR-cas9-mediated lung gene therapy

Abstract Since CRISPR/Cas9 was harnessed to edit DNA, the field of gene therapy has witnessed great advances in gene editing. New avenues were created for the treatment of diseases such as Cystic Fibrosis (CF). CF is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Despite the success of gene editing with the CRISPR/Cas9 in vitro, challenges still exist when using CRISPR/Cas9 in vivo to cure CF lung disease. The delivery of CRISPR/Cas9 into lungs, as well as the difficulty to achieve the efficiency required for clinical efficacy, has brought forth new challenges. Viral and non-viral vectors have been shown to deliver DNA successfully in vivo, but the sustained expression of CFTR was not adequate. Before the introduction of Helper-Dependent Adenoviral vectors (HD-Ad), clinical trials of treating pulmonary genetic diseases with first-generation viral vectors have shown limited efficacy. With the advantages of larger capacity and lower immunogenicity of HD-Ad, together with the versatility of the CRISPR/Cas9 system, delivering CRISPR/Cas9 to the airway with HD-Ad for lung gene therapy shows great potential. In this review, we discuss the status of the application of CRISPR/Cas9 in CF gene therapy, the existing challenges in the field, as well as new hurdles introduced by the presence of CRISPR/Cas9 in the lungs. Through the analysis of these challenges, we present the potential of CRISPR/Cas9-mediated lung gene therapy using HD-Ad vectors with Cystic Fibrosis lung disease as a model of therapy

I Spy with My Little Eye: A Paediatric Visual Preferences Survey of 3D Printed Tablets

3D printing (3DP) in the pharmaceutical field is a disruptive technology that allows the preparation of personalised medicines at the point of dispensing. The paediatric population presents a variety of pharmaceutical formulation challenges such as dose flexibility, patient compliance, taste masking and the fear or difficulty to swallow tablets, all factors that could be overcome using the adaptable nature of 3DP. User acceptability studies of 3D printed formulations have been previously carried out in adults; however, feedback from children themselves is essential in establishing the quality target product profile towards the development of age-appropriate medicines. The aim of this study was to investigate the preference of children for different 3D printed tablets (Printlets™) as an important precursor to patient acceptability studies. Four different 3DP technologies; digital light processing (DLP), selective laser sintering (SLS), semi-solid extrusion (SSE) and fused deposition modeling (FDM) were used to prepare placebo printlets with similar physical attributes including size and shape. A single-site, two-part survey was completed with participants aged 4–11 years to determine their preference and opinions based on visual inspection of the printlets. A total of 368 participants completed an individual open questionnaire to visually select the best and worst printlet, and 310 participants completed further non-compulsory open questions to elaborate on their choices. Overall, the DLP printlets were the most visually appealing to the children (61.7%) followed by the SLS printlets (21.2%), and with both the FDM (5.4%) and SSE (11.7%) printlets receiving the lowest scores. However, after being informed that the SSE printlets were chewable, the majority of participants changed their selection and favoured this printlet, despite their original choice, in line with children’s preference towards chewable dosage forms. Participant age and sex displayed no significant differences in printlet selection. Printlet descriptions were grouped into four distinct categories; appearance, perceived taste, texture and familiarity, and were found to be equally important when creating a quality target product profile for paediatric 3D printed formulations. This study is the first to investigate children’s perceptions of printlets, and the findings aim to provide guidance for further development of paediatric-appropriate medicines using different 3DP technologies