Developing methodologies for the evaluation of Age-appropriate Formulations (AaFs) in Children

Abstract

Children deserve access to medicines that have been tailored to their individual needs and developed in an age-appropriate dosage form (or formulation). Unfortunately, pharmaceutical development has often neglected children in the past so there is a general lack of suitable, commercially available age-appropriate formulations (AaFs). Consequently, clinicians often have no choice but to treat children with available medicines as it would be considered unethical to withhold these treatments. Available options may have originally been ‘intended’ for use in adults or for different indications and so have not been fully evaluated for paediatric use, making their use off-label (OL) as they deviate from the manufacturer’s instructions. OL medicines may be unsuitable for children in terms of their strength, dosage form (DF) and/or excipients. Other medicines which do not have a marketing authorisation (MA) in the United Kingdom and are therefore said to be unlicensed (UL), may need to be sourced or manufactured, in order to fill this gap. An age-inappropriate formulation (AiF) is a medicine which needs to be manipulated at the point of administration (by parents/carers/users) to allow the ‘intended’ dose of the DF prescribed to be given and/or modified to allow administration to the patient, in an acceptable manner. Conversely, AaFs are licensed medicines used in accordance with the MA and accepted for use by the patient. Assessment of age-appropriateness can be very subjective. There is currently no standardised way of assessing the age-appropriateness of a medicine used/taken by a child. This thesis describes a series of studies conducted at either Alder Hey Children’s NHS Foundation Trust (AH) or Liverpool Women’s NHS Foundation Trust (LWH) with the aim of estimating the proportion of AaFs / AiFs being used by a cohort of paediatric and neonatal patients with a chronic illness. The data generated from this study helped to develop a new assessment tool, the AaF tool, to distinguish between AaFs and AiFs being administered to children. The AaF tool has undergone internal validity and reliability testing. Several methods were used to explore, evaluate and describe the impact of the lack of AiFs in children in order to inform on the scale of the problem: an investigation of the AH pharmacy dispensing records, the AaF study and development of the AaF tool and a qualitative study using semi-structured interviews with parents of children taking AiFs. Only 2.1% (705) of 32,927 items dispensed across a one year period at AH were deemed to be AiFs when pharmacy dispensing records were retrospectively reviewed and analysed using a basic AaF assessment. The assessment was based on setting a priori age-appropriate age threshold for each DF type. The total spend on AiFs represented only 0.4% of the £9 million AH annual budget spent on medicines for all patient linked items. In the AiF study, 2,199 medicine administration episodes given to 427 children (from AH and LWH site) were assessed using the new AaF assessment tool. Overall, 259/2,199 (11.8%) medicines were found to be AiFs. The prevalence of AiFs detected generally decreased as age increased at both sites. Parents want medicines that are readily available, in an easy-to-use format which taste “nice” and provide accurate dosing on administration. However, the physical act of modifying medicines in order to give them to children was not considered to be of great significance by most families. This work has identified some clinical areas to focus paediatric drug development. It has highlighted the challenges associated with available DFs when suitable paediatric formulations are not available on the market. It has also identified the continued need to develop new licenced medicines given the prevalence of ULOL medicine use in children. Modification of DFs at the point of administration to achieve the required dose or make them acceptable for children to take is common in paediatric practice. However the safety and risks in terms of dose accuracy and handling associated with this practice are often unknown.