Paediatric Medicines Research Unit

LEADS:

Dr Louise Bracken Louise.Bracken@alderhey.nhs.uk

Professor Matthew Peak matthew.peak@alderhey.nhs.uk

Dr Dan Hawcutt dan.hawcutt@alderhey.nhs.uk  

Professor Mark Turner mark.turner@liverpool.ac.uk

Professor Elisangela da Costa Lima eclima.ufrj@gmail.com

Many medicines prescribed for children are not authorised for use in this age group. Many common medicines have not been tested properly or at all in children; frequently medicines are administered to this age group based on how they work in adults and the doses used are often a best guess. This means that children are at a high risk of suffering serious and unexpected side effects (adverse drug reactions) from many medicines prescribed by doctors or available at the chemist.

The PMRU leads on original research in the following areas;

• Characterisation of Adverse Drug Reactions In Children (ADRIC)

This research characterised the causes, severity and preventability of adverse drug reactions (ADRs) for a range of medicines administered to children. The study explored the experiences of parents and children in whom ADRs were identified. It also aimed to find out what healthcare professionals think their role is in the context of preventing, managing and communicating with families about ADRs in children.

• Developing tools to assess ADRs in children and neonates

The PMRU team has developed and validated tools to assess the causality (Liverpool Causality Assessment Tool – LCAT) and avoidability (Liverpool Avoidability Assessment Tool – LAAT) in children.  LCAT and LAAT have been translated and culturally adapted into Brazilian Portuguese (https://www.researchsquare.com/article/rs-108151/v1) and are being used in multicentre studies and clinical trials in the UK and Brazil. The Adverse Drug Reaction in Neonates (ADRIN) study prospectively identified and collected data on suspected ADRs in neonates. The study aims to improve the understanding of the drugs, reactions, causality assessment (including comparisons of various severity tools), and severity of ADRs in this population.

• Improving adverse drug reaction (ADR) reporting

The majority of ADRs that occur are not reported to the national regulator (the Medicines and Healthcare Products Regulatory Authority – MHRA). Suspected ADRs in children and babies are particularly poorly reported. In collaboration with other hospitals in the region, Alder Hey is leading on studies aiming to increase the quality and quantity of ADR reports of medicines used in children, with the aim of improving patient safety.

There is particular focus on reports from families and from young people themselves. The study includes implementing the LCAT including use of the e-learning package, developed in the ADRIC programme.

Work is also ongoing to explore the rate and type of ADR reporting in neonates by comparing prospectively collected reports from an independent researcher with retrospective spontaneously reported Yellow Cards. This research is confirming that there are a number of differences between neonatal ADRs reported to the MHRA and those occurring commonly.

• Identification of novel drug safety signals in international pharmacovigilance systems

Working with colleagues in Brazil, the PMRU team has undertaken analyses of serious adverse drug reactions in children reported in the national Notivisa pharmacovigilance database for the Brazilian Surveillance Agency. A number of novel safety signals and drug-event pairs were identified by the team. The PMRU team continues to work with colleagues in Brazil in the healthcare and Surveillance Agency on strategies to improve spontaneous reporting of ADRs

LEADS:

Dr Jennifer Duncan Jennifer.Duncan@alderhey.nhs.uk

Professor Matthew Peak matthew.peak@alderhy.nhs.uk

Dr Mohamed Albed Alhnan alhnan@kcl.ac.uk

Dr Matt Roberts M.Roberts1@ljmu.ac.uk

Professor Bernie Carter bernie.carter@edgehill.ac.uk

This theme focuses on the consequences of age-inappropriate formulations, acceptability of existing and new formulations and development of novel formulations for children. The programme involves multiple academic and commercial collaborators and a strong involvement of children and families using methods of coproduction.

Adaptation of forumaltions

Some of the medicines given to children are designed for adults; this means that it may not be straightforward to prepare a dose for a child. Tablets, patches and capsules may give a dose that is too much for a child. If a tablet is too big for a child then the tablet must be split. Suppositories, or patches used on the skin are often cut to give the dose needed for the age or weight of the baby or child. Sometimes injections or liquid medicines for babies and small children are too strong and must be diluted down so that we can measure the right amount. All these processes are examples of adaptation (previously referred to as ‘manipulation’).

• Manipulation of Drugs in Children (MODRIC)

This programme identified when and why medicines for children need to be manipulated. Using the findings of this study, guidance for healthcare professionals was produced.

• Manipulation of Drugs in Children: MODRIC Guidelines

For further information about this programme, please see the publications listed below or contact Professor Tony Nunn: A.J.Nunn@liv.ac.uk

• Age-appropriate hydrocortisone formulations

There is no age appropriate licensed form of hydrocortisone for children and young people. The MODRIC programme revealed that hydrocortisone is one of the most frequently manipulated medicines in paediatric practice. Splitting of hydrocortisone tablets to derive an intended dose for use in children is highly imprecise, leading to under- or over-dosing. We have demonstrated that the dose and weight uniformity of halved and quartered hydrocortisone tablets is highly variable. We are developing novel, age-appropriate and flexible solid dosage forms of hydrocortisone through mini-tablets and 3D printing. These will undergo bioavailability studies in children in the NIHR Alder Hey Clinical Research Facility for Experimental Medicine.

For further information about this programme, please see the publication(s) listed below or contact: Professor Matthew Peak: matthew.peak@alderhey.nhs.uk

Assessment of acceptability of formulations

When developing and prescribing medicines for children it is important to consider how suitable the product (or formulation) is for them. One important factor is the acceptability of the medicine to the child who needs to take it. Acceptability includes how straightforward it is to prepare the dose, how easy it is to take and how it tastes.

• Creating acceptable tablets - a pilot study to assess the acceptability of solid dosage forms in children and young people (CAT study)

New research is emerging showing paediatric patients’ acceptability towards solid medicines, but knowledge in this area of research is still in its infancy. Tablets are the most cost effective formulation when considering medicines delivery and can be offered to paediatric patients as an alternative to the conventional oral liquid medicines.

This study investigates the swallowability and acceptability of different sized tablets in children. Secondary objectives include addressing key variables such as estimates of consent rates, recruitment rates, completeness of intervention administration and gaining estimates of the effect size of the primary outcome; the feasibility of swallowability and acceptability assessments in children – all which will determine the feasibility of a larger, definitive trial.

This work is conducted with combined expertise from clinical researchers (Alder Hey), university academics (University of Hertfordshire) and pharmaceutical industry partners (Co-Formulate Ltd).

For further information about this study, please contact Dr Louise Bracken: louise.bracken@alderhey.nhs.uk

Characterisation of age inappropriate forumlations

• Age inappropriate formulations

Children sometimes need to be administered medicines that are not specially designed for them. This research aims to find out when, why and how this happens. We will ask parents what they think about needing to use medicines not specially designed for children. We will also provide feedback to manufacturers who make medicines for children.

For further information about this study, please contact Dr Jennifer Duncan: jennifer.duncan@alderhey.nhs.uk

LEADS:

Ms Andrea Gill andrea.gill@alderhey.nhs.uk

Mrs Catrin Barker catrin.barker@alderhey.nhs.uk

Mr Octavio Aragon octavio.aragon@alderhey.nhs.uk

Medicines optimisation aims to help patients to make the most out of their medicines. The Royal Pharmaceutical Society outlines four principles of medicines optimisation. These relate to the patient’s experience of needed to use medicines, the use of evidence-based medicines, medicines safety and value for money from medicines.

Strategies to reduce medication errors and improve administration

• Evaluation of the introduction of a pharmacy-technician supported paediatric medicines administration system

In some children’s hospitals, in order to reduce the risk of medication error, medication preparation and administration is carried out by one registered nurse and checked by another. In a pilot study at Alder Hey we made a change to this. For some of the working day, one of the nurses involved in this process was replaced by a suitably trained pharmacy technician. We assessed the impact of this new way of working on medicines optimisation, healthcare staff, children and their families. This study was funded by the Health Education England Forerunner Fund and is a collaboration between Edge Hill University and Alder Hey Children’s NHS Foundation Trust.

For further information about this study, please contact Mrs Catrin Barker: catrin.barker@alderhey.nhs.uk

Medicine administration outside hospital

• PROMOTE study

(Procalcitonin Monitoring in Paediatric Outpatient Parenteral Antimicrobial Therapy)

The paediatric Outpatient Parenteral Antimicrobial Therapy (pOPAT) service supports the delivery of intravenous antibiotics in the patient’s home. This study investigates the usefulness of a blood test which can help doctors understand if the antibiotics are working properly to treat the infection. We also want to find out parents’ and children’s views on the experience of being monitored like this at home.

This study is funded by the North West Coast CLAHRC Delivering Personalised Health and Care Theme.

For further information about this study, please click here or contact Dr Louise Bracken: louise.bracken@alderhey.nhs.uk

• Medicines in schools

Using questionnaires, this research aimed to understand how medicines are managed at school and the perspectives of children, their parents, school staff and healthcare professionals in relation to this.

For further information about this study, please contact Dr Louise Bracken: louise.bracken@alderhey.nhs.uk

• Click here to see publications from 2018-2020

2017

Cooney L, Loke YK, Golder S, Kirkham J, Jorgensen A, Sinha I, Hawcutt D. Overview of systematic reviews of therapeutic ranges: methodologies and recommendations for practice. BMC Medical Research Methodology 2017 17 (1), 84

Cooney L, McBride A, Lilley A, Sinha I, Johnson TN, Hawcutt DB. Using pharmacokinetic modelling to improve prescribing practices of intravenous aminophylline in childhood asthma exacerbations. Pulmonary Pharmacology & Therapeutics 2017 43, 6-11

Bracken LE, Nunn AJ, Kirkham JJ, Peak M, Arnott J, Smyth RL, et al. (2017) Development of the Liverpool Adverse Drug Reaction Avoidability Assessment Tool. PLoS ONE 12(1): e0169393. doi:10.1371/journal.pone.0169393

Ainscough L P, Ford J L, Morecroft C W, Peak M, Turner M A, Nunn A J, Roberts M. Accuracy of Intravenous and Enteral Preparations Involving Small Volumes for Paediatric Use: A Review. European Journal of Hospital Pharmacy. 2017 Published Online First: 05-Jan-2017 doi:10.1136/ejhpharm-2016-001117

Richey RH, Hughes C, Craig JV, Shah UU, Ford JL, Barker CE, Peak M, Nunn AJ, Turner MA. A systematic review of the use of dosage form manipulation to obtain accurate doses to inform use of manipulation in paediatric practice. International Journal of Pharmaceutics. 2017; 518(1-2): 155-166. Final version published online: 04-Jan-2017. doi: 10.1016/j.ijpharm.2016.12.032

Thiesen S, Yin P, Jorgensen AL, Zhang E, Manzo V, McEvoy L, Barton C, Picton S, Bailey S, Brock P, Vyas H, Walker D, Makin G, Bandi S, Pizer B, Hawcutt DB*, Pirmohamed M* (*Joint senior author). TPMT, COMT and ACYP2 genetic variants in paediatric cancer patients with cisplatin-induced ototoxicity. Pharmacogenetics and Genomics 2017 27 (6), 213-222

2016

Cooney L, Sinha I*, Hawcutt D* (Joint senior Author). Aminophylline Dosage In Asthma Exacerbations in Children: A Systematic Review. PLOS One 2016 http://dx.doi.org/10.1371/journal.pone.0159965

Cooney L, Hawcutt D*, Sinha I* (*Joint senior author). The Evidence for Intravenous Theophylline Levels between 10-20mg/L in Children Suffering an Acute Exacerbation of Asthma: A Systematic Review. PLOS One 2016 11(4) e0153877 (http://dx.doi.org/10.1371/journal.pone.0153877)

Hawcutt DB, Russell NJ, Maqsood H, Kouranloo K, Gomberg S, Waitt C, Sharp A, Riordan A, Turner MA. Spontaneous Adverse Drug Reaction Reports for Neonates and Infants in the UK 2001-2010: Content and Utility analysis. British Journal of Clinical Pharmacology 82(6):1601-1612 Dec 2016

Rieder M, Hawcutt D. Design and Conduct of Early Phase Drug Studies in Children; Challenges and Opportunities. British Journal of Clinical Pharmacology 2016 DOI: 10.1111/bcp.13058

Hawcutt DB, Cooney L, Oni L, Pirmohamed M. Precision Dosing in Children. Expert Review of Precision Medicine and Drug Development 2016, 1(1), 69-78

Turner S, Francis B, Vijverberg S, Pino-Yanes M, Maitland-van der Zee AH, Basu K, Bignell L, Mukhopadhyay S, Tavendale R, Palmer C, Hawcutt D, Pirmohamed M, Burchard EG, Lipworth B on behalf of the Pharmacogemonics in Childhood Asthma consortium. Childhood asthma exacerbations and the Arg-16 beta2 receptor polymorphism: a meta-analysis stratified by treatment. Journal of Allergy and Clinical Immunology 2016 138 (1), 107-113 http://dx.doi.org/10.1016/j.jaci.2015.10.045

Da Costa Lima-Dellamora E & Peak M. Translational research and the contribution of clinical pharmacists to health services. Res Bram Farm Hosp Serv. (2016); 6:4-5

Orubu E S F, Okwelogu C, Opanuga O, Nunn T, Tuleu C (2016). Access to age-appropriate essential medicines: a retrospective survey of compounding of medicines for children in hospitals in Nigeria and implications for policy development. Health Policy and Planning; DOI: 10.1093/heapol/czw115
2015

Conroy, E. J., Kirkham, J. J., Bellis, J. R., Peak, M., Smyth, R. L., Williamson, P. R. and Pirmohamed, M. (2015), A pilot randomised controlled trial to assess the utility of an e-learning package that trains users in adverse drug reaction causality. International Journal of Pharmacy Practice, 23: 447–455. doi:10.1111/ijpp.12197

2014

Smyth R, Peak M, Turner M, Nunn A, Williamson P & Young B, e.a. 2014, "ADRIC: Adverse Drug Reactions In Children - a programme of research using mixed methods. ", Programme Grants Appl Res, vol. 2, no. (3).

2013

Thiesen S, Conroy EJ, Bellis JR, Bracken LE, Mannix HL, Bird KA, et al. Incidence, characteristics and risk factors of Adverse Drug Reactions (ADRs) in hospitalised children – a prospective observational cohort study of 6601 admissions. BMC Medicine. 2013;11(237):doi:10.1186/741-7015-11-237.

Richey RH, Shah UU, Peak M, Craig JV, Ford JL, Barker CE, et al. Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence. BMC Pediatrics. 2013;13:81.

2012

Richey RH, Craig JV, Shah UU, Ford JL, Barker CE, Peak M, et al. The manipulation of drugs to obtain the required dose: systematic review. Journal of Advanced Nursing. 2012; 68(9): 2013-12.

Arnott J, Hesselgreaves H, Nunn AJ, Peak M, Pirmohamed M, Smyth RL, et al. Enhancing Communication about Paediatric Medicines: Lessons from a Qualitative Study of Parents’ Experiences of Their Child’s Suspected Adverse Drug Reaction. PLoS One. 2012;7(10):e46022-e.

Gallagher R, Mason J, Bird K, Kirkham J, Peak M, Williamson P, et al. Adverse drug reactions causing admission to a paediatric hospital. PL0S ONE. 2012;7(12):e50127. doi:10.1371/journal.pone.0050127.

Nunn A, Richey R, Shah U, Barker C, Craig J, Peak M, et al. Estimating the requirement for manipulation of medicines to provide accurate doses for children. European Journal of Hospital Pharmacy: Science and Practice. 2012.