Directors of Centre:

Director: Professor Ian Wong

Deputy Director: Dr Catherine Tuleu

About the Group:

The Centre for Paediatric Pharmacy Research (CPPR), established in April 2002, is a fruitful collaboration between The School of Pharmacy, the Institute of Child Health and the Great Ormond Street Hospital for Children (GOSH)    

The mission of the Centre is to improve the health of children through interdisciplinary collaborative research which addresses questions central to medicines for children. In addition, the specialist resources of universities and hospitals nationwide are utilised collaboratively to provide a focus for the training of health care professionals in the optimum use of medicines for children.

The Centre hosts the Paediatric Psychopharmacology Clinical Research Group of the UK Mental Health Research Network (MHRN) and the Pharmacy and Pharmacology Clinical Study Group of the UK Medicines for Children Research Network (MCRN) Furthermore, the centre is the UK coordinating Centre of the FP6-funded Taskforce in Europe for Drug Development in the Young (TEDDY) . 

The Centre is also a member of the newly-formed European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) and MCRN London Local Research Network. The Centre also contributes to the MCRN formulation workstream and the European Paediatric Formulation Initiative. 

The ultimate goal of the CPPR is to improve the use of medicines in clinical settings, hence translational research and supporting medicines for licensing are important parts of our research and development portfolio. In 2006, the CPPR set up Therakind Ltd to develop paediatric medicines for “Paediatric Use Marketing Authorisation” 

The mission of the Centre:

• Improve the health of children through interdisciplinary collaborative research that addresses questions central to medicines for children.
• Understand the biological, genetic, developmental, environmental and social mechanisms underlying the effectiveness and safety of medicines for children.
• Develop new methodologies in advancing research of medicines for children.
• Increase research capacity through the provision of training in pharmaceutical science, clinical pharmacology and pharmacoepidemiology applied to children.
• Conduct translational research in order to bring medicines to the clinical use.  

Research Themes:

Paediatric Pharmacoepidemiology and Drug Safety 

Theme Leader: Professor Ian Wong 

Theme members: Dr Macey Murray, Dr Antje Neubert, Dr Paul Long, Dr Lynda Wilton, Dr Yingfen Hsia, Dr Joseph Standing, Professor Frank M C Besag, Dr Aung Soe and Mr Stephen Tomlin 

PhD students: Ms Noor Almandil, Ms Aisha Elturki, Ms Asia Nasser Ali Rashed, Ms Noha Iessa 

Clinical trials will always be an invaluable means of acquiring vital information about a drug; however these trials are not always practical due to technical, ethical and financial reasons.  Therefore pharmacoepidemiology has huge potential to provide important information in paediatric drug safety and efficacy.  The Centre has been conducting paediatric pharmacoepidemiological studies since it was established in 2002, and will continue to focus research in this area.

Examples of research project undertaken:

CHAPTER (Children and Adolescents Psychotropic medication Therapy Evaluation Research):

This project was funded by the former Coordinating Centre of National Capacity Development of the National Institute of Health Research. This project investigated psychotropic medication use in children and adolescents in general practices using the General Practice Research Database and IMS Databases. We conducted cohort studies in over 500,000 children to investigate the utilisation and safety of different psychotropic drugs. Several papers were published and results were presented to both MPs and MEPs in the UK and European Parliaments. CHAPTER also led to further funding of the CADDY project and the formation of the Mental Health Research Network Paediatric Psychopharmacology Clinical Research Group.

Relevant publications:

Hsia Y, Neubert A, Sturkenboom MC, Murray ML, Verhamme KM, Sen F, Giaquinto C, Ceci A, Wong IC; on behalf of the TEDDY Network of Excellence. Comparison of antiepileptic drug prescribing in children in three European countries. Epilepsia 2009 Oct 8. [Epub ahead of print]

McCarthy S, Cranswick N, Potts L, Taylor E, Wong IC. Mortality associated with attention-deficit hyperactivity disorder (ADHD) drug treatment: a retrospective cohort study of children, adolescents and young adults using the general practice research database. Drug Saf 2009;32(11):1089-96.

McCarthy S, Asherson P, Coghill D, Hollis C, Murray M, Potts L, Sayal K, de Soysa R, Taylor E, Williams T, Wong ICK. Trends in prescribing prevalence and cessation of ADHD drug treatment among adolescents and young adults in the U.K. British Journal of Psychiatry 2009;194(3):273-7.

Rani FA, Byrne PJ, Murray ML, Carter P, Wong IC. Paediatric Atypical Antipsychotic Monitoring Safety (PAMS) Study: Pilot Study in Children and Adolescents in Secondary- and Tertiary-Care Settings. Drug Saf 2009;32(4):325-33.

Ackers R, Besag FMC, Wade A, Murray ML, Wong ICK. Changing trends in antiepileptic drug prescribing in girls of child-bearing potential. Arch Dis Child  2009;94(6):443-7

Rani F, Murray M, Byrne P, Wong ICK. Epidemiologic features of antipsychotic prescribing to children and adolescents in primary care in the United Kingdom. Pediatrics 2008;121(5):1002-9.

Shah T, Tse A, Gill H, Wong I, Sutcliffe A, Gringras P, Appleton R, Tuleu C. Administration of melatonin mixed with soft food and liquids for children with neurodevelopmental difficulties. Dev Med Child Neurol 2008;50(11):845-9.

Ackers R, Murray ML, Besag FMC, Wong ICK. Prioritising Children’s medicines for research: A pharmacoepidemiological study on antiepileptic drugs. British Journal of Clinical Pharmacology 2007;63(6):689-97.

Murray ML, Thompson M, Santosh P, Wong ICK. Effects of the Committee on Safety of Medicines advice on antidepressants prescribing to children and adolescents in the UK. Drug Safety 2005;28(12):1151-7.

Wong ICK, Besag FMC, Santosh P, Murray ML. Use of selective serotonin reuptake inhibitors in children and adolescents. Drug Safety 2004;27(13):991-1000.

Murray ML, de Vries CS, Wong ICK. A drug utilisation study of antidepressants in children and adolescents using the General Practice Research Database. Archives of Disease in Childhood 2004;89:1098-102.

Wong ICK, Murray ML, Novak-Camilleri D, Stephens P. Increased prescribing trends of paediatric psychotropic medications. Archives of Disease in Childhood 2004;89:1131-2. 

COSMIC: Co-operative of Safety of Medicines in Children:

The project was funded by Patient Safety Research Programme of the Department of Health in England. This was a collaborative project between the Centre, the Royal College of Paediatrics and Child Health, the Neonatal and Paediatric Pharmacists Group, the British National Formulary and the University of Nottingham. We conducted a scoping study to analyse interventions used to reduce errors in calculation of paediatric drug doses. As the Centre was commissioned by the National Service Framework for Children to conduct a literature review on improving medications use in children, we completed a systematic literature review in paediatric medication dosing errors and the results of the review was published in Drug Safety. The data were used by an expert group at the National Patients Safety Agency to develop strategies in medication error reduction; Prof Wong has been invited to join the group as well as being invited by The World Health Organisation to be an expert advisor on their Paediatric Medication Safety documents.

Relevant publications:

Ghaleb M, Barber N, Franklin B, Wong ICK. The incidence and nature of prescribing and medication administration errors in paediatric inpatients Arch Dis Child  (In press 2010).  

Franklin BD, Birch S, Savage I, Wong I, Woloshynowych M, Jacklin A, Barber N. Methodological variability in detecting prescribing errors and consequences for the evaluation of interventions.  Pharmacoepidemiol Drug Saf 2009;18(11):992-9.

Wong IC, Wong LY, Cranswick NE. Minimising medication errors in children. Arch Dis Child 2009;94(2):161-4.

Jani YH, Ghaleb MA, Marks SD, Cope J, Barber N, Wong ICK. Electronic prescribing reduced prescribing errors in a pediatric renal outpatient clinic. Journal of Pediatrics 2008;152(2):214-8.

Conroy S, North C, Fox T, Haines L, Planner C, Wong ICK, Sammons H. Educational interventions to reduce prescribing errors. Archives of Disease in Childhood 2008;93:313-315.

Stebbing C, Wong ICK, Kausha R, Jaffe A. The Role of Communication in Paediatric Medication Safety. Archives of Disease in Childhood 2007;92(5):440-5.

Conroy S, Yeung V, Sweis D, Collier J, Haines L, Wong ICK. Systematic literature review of interventions to reduce dosing errors in children. Drug Safety 2007;30(12):1111-25.

Ghaleb MA, Dean Franklin B, Barber N, Khaki Z, Yeung Y, Wong ICK. A Systematic Review of Medication Errors in Pediatric Patients. Annals of Pharmacotherapy 2006 40(10):1766-76.

Sanghera N, Chan PY, Khaki ZF, Planner C, Lee KKC, Wong ICK. Systematic literature review of interventions of hospital pharmacists in improving drug therapy in children. Drug Safety 2006;29(11):1031-47.

Wong ICK, Basra N, Yeung V, Cope J. Supply problems of unlicensed and off-label medicines after discharge. Archives of Disease in Childhood 2006;91(8):686-8.

Ghaleb MA, Wong ICK. Medication Errors in Children. Archives of Disease in Childhood Education and Practice. 2006; 91: ep20 doi:10.1136/adc.2005.073379

Ghaleb MA, Barber N, Franklin BD, Wong ICK. What constitutes a prescribing error in paediatrics – a delphi study. Quality and Safety in Health Care 2005;14(5):352-7.

Wong ICK, Ghaleb M, Dean Franklin B, Barber N. Incidence and nature of dosing errors in paediatric medications – A systematic review. Drug Safety 2004;27(9):661-70. 

APAC: (Appropriate Prescribing of Antibiotics in Children): 

This project is funded by the European Commission via TEDDY (Task-force European Drug Development for the Young). The UK General Practice Research Database is being used to conduct a case-control study to determine whether the observed increase in mastoiditis is a casual association with the fall in antibiotic prescribing for otitis media. Professor Wong has been invited to join the former Specialist Advisory Committee on Antimicrobial Resistance (SACAR) Paediatric Sub-group to provide his research expertise and data to the Committee.

Relevant publications: 

Saxena S, Thompson P, Birger R, Bottle A, Spyridis N, Wong I, Johnson AP, Gilbert R, Sharland M, on behalf of Improving Children’s Antibiotic Prescribing Group (iCAP). Rising skin infections in primary care and increasing hospital admissions for Staphylococcus aureus complications in children in England. Emerging Infectious Diseases (In press 2010) 

Thompson PL, Gilbert RE, Long PF, Saxena S, Sharland M, Wong ICK. Effect of antibiotics for otitis media on mastoiditis in children:  a retrospective cohort study using the UK General Practice Research Database. Pediatrics 2009;123(2):424-30. 

Thompson PL, Spyridis N, Sharland M, Gilbert RE, Saxena S, Long PF, Johnson A,  Faulding S, Wong ICK. Changes in clinical indications for community antibiotic prescribing for children in the UK from 1996-2006: will the new NICE prescribing guidance on upper respiratory tract infections be ignored? Arch Dis Child 2009;94(5):337-40. 

Thompson PL, Gilbert RE, Long PF, Saxena S, Sharland M, Wong IC. Has UK guidance affected general practitioner antibiotic prescribing for otitis media in children? J Public Health (Oxf). 2008;30(4):479-86. 

DISKCO (Diclofenac Safety and Pharmacokinetics in Children for post-Operative pain):

This project was funded by Rosemont Pharmaceuticals and investigated the safety of diclofenac (a pain-killer) in children after surgery.  We worked closely with the sponsor and the Medicines & Healthcare products Regulatory Agency (MHRA); and the data was intended for licensing purposes. The pharmacokinetics of a new formulation of diclofenac was also studied in collaboration with Professor Atholl Johnston (Analytical Unit, St George’s Medical School). DISKCO can be described as a model study for future “Paediatric Use Marketing Authorisation”. Therakind, a spin-out company of the SOP, GOSH and UCL, is currently using the same model to obtain paediatric marketing authorisation of intranasal diamorphine and buccal midzolam. 

Relevant publications: 

Standing JF, Howard RF, Johnson A, Savage I, Wong ICK. Population pharmacokinetics of oral diclofenac for acute pain in children. British Journal of Clinical Pharmacology 2008;66(6):846-53 

Standing JF, Ooi K, Keady S, Howard RF, Savage I, Wong IC. Prospective observational study of adverse drug reactions to diclofenac in children.  Br J Clin Pharmacol 2009;68(2):243-51. 

Standing JF, Savage I, Pritchard D, Waddington M. Diclofenac for acute pain in children. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD005538. 

Paediatric Pharmaceutics and Drug Delivery 

Theme Leader: Dr Catherine Tuleu

Team members: Dr Mine Orlu Gul, Ms Chung Man Wan, Usha Langam, Smita Salunke (EuPFI Scientific manager)

PhD students: Maria Carvhalo, Alexandra Bowles 

As stated in the EMA Reflection Paper on the Formulations of Choice for Children (2005), an ideal for paediatric patients of all ages should allow both safe and accurate dose administration. The EU paediatric regulation (2007) enforces paediatric investigation plans which include measures to adapt the way the medicine is presented (formulation) to make its use more acceptable in children. Our research outcomes in this field ties very much into this and translates into a pro-active involvement as academic mediator in between the children and their carers, the prescribers, the industry and the regulators. Our mission is clear and concrete: safer and better formulations for children The team is focusing on the prioritized areas in the field: 

• Taste Masking and Taste Testing,
• Age Appropriateness of Formulations and Administration Devices or Aids,
• The Use of Unlicensed Medicines with emphasis on Extemporaneous Preparations
• Safety of Excipients issues.

 

Examples of research projects undertaken

Extemporaneous preparations 

TOPPER (Tacrolimus Oral Paediatric Preparation Evaluation Research) was funded by Fujisawa. Birmingham Children’s Hospital observed higher rejection rates in liver transplant children after using extemporaneous-prepared tacrolimus formulation. This project investigated the physical, chemical and microbiological properties of the extemporaneous products in order to identify the possible causes of higher rejection rates. The study found that the commercially available product had not been produced with a standardised method which may be a possible cause of problems. The results led to standardisation of the commercial products. 

The team has been involved in many other related projects (Captopril, Omeprazole, lidocaine-adrenaline epidural, melatonin, sildenafil, Hydrocortisone etc). 

Cyclodextrins in paediatric drug delivery systems:

This project was funded by the Engineering and Physical Science Research Council and Astra Zeneca. Cyclodextrins are a group of non-toxic excipents which can be used to increase the solubility of different drugs. Furthermore, it can be used to “conceal” the drug molecules in the solution in order to improve the often unacceptable bitter taste of medicines. This project investigated the feasibility of using the cyclodextrins in paediatric drug formulation with the help an electronic tongue and tastes panels to assess the taste of the formulations. The project showed that cyclodextrins are likely to be used in future paediatric drug formulation.

In fact projects looking at the formulation and evaluation of cyclodextrin-based fast dissolving oral films for paediatric patients are on going.

Cysteamine delivery system for corneal application

This project is funded by the Cystinosis Research Network. Cystinosis is a hereditary disorder, the body accumulates the amino acid cystine within cells. Excess cystine forms crystals that can build up and damage cells. These crystals negatively affect many systems in the body, especially the kidneys and eyes. Cysteamine eye drops have been used to delay the damage caused by the formation of cystine crystal in the cornea. However, the traditional eye drop requires application every 2 to 3 hours; therefore compliance/adherence is poor especially in children. This project will result in a modified release eye treatment followed by a clinical trial on the new formulation. If the study is successful, the new formulation is likely to replace the current formulation.

Multiparticulates for Paediatric Dosing 

These projects were/are partly funded by the Biotechnology and Biological Sciences Research Council and GSK.

Minitablets are very small tablets, even smaller than the artificial sweetener tablets. They can potentially be swallowed by very young children. They are far more stable than liquid preparations; therefore offering more advantages in terms of formulation and patient acceptance. This project investigated the challenges of manufacturing minitablets and also the practicality of giving it to very young children. Our recommendation to use minitablest to the World Health Organisation for example for HIV drugs was cited in their latest document on essential medicines for children and they are looking into it. 

Another project on the development of a Multiparticulate-based Formulation Platform for Delivering Modified Release Capability as an Oral Liquid Dosage Form is on going. 

Relevant publications:

Thomson SA, Tuleu C, Wong ICK, Keady S, Pitt KG, Sutcliffe AG. The Mini-tablet: A new modality of delivering medicines to pre-school children? Pediatrics 2009;123(2):e235-8. 

Hempenstall J, Tuleu C. Meeting commentary--formulating better medicines for children. Int J Pharm 2009;379(1):143-5. 

Tomlin S, Cokerill H, Costello I, Griffith R, Hicks R, Sutcliffe A, Tuleu C, Wong ICK, Wright D. Making medicines safer for children— guidance on the use of unlicensed medicines in paediatric patients. Guidelines handbook. March 2009. pp 9. 

Shah T, Tse A, Gill H, Wong I, Sutcliffe A, Gringras P, Appleton R, Tuleu C. Administration of melatonin mixed with soft food and liquids for children with neurodevelopmental difficulties. Dev Med Child Neurol 2008;50(11):845-9. 

Cram A, Breitkreutz J, Desset-Brèthes S, Nunn T, Tuleu C. Challenges of developing palatable oral paediatric formulations. European Paediatric Formulation Initiative (EuPFI). Int J Pharm 2009;365(1-2):1-3. 

Davies EH, Tuleu C. Medicines for children: a matter of taste. J Pediatr 2008;153(5):599-604, 604.e1-2. 

Carvalho M, Tuleu C, Taylor KMG. Current compounding practice in Europe. Int J Pharm Compound 2008;12(2): 8-13. 

Tuleu C, Allam J, Gill H, Yentis SM. Short term stability of pH-adjusted lidocaine-adrenaline epidural solution used for emergency caesarean section. Int J Obstet Anesth 2008;17(2):118-22. 

Tuleu C, Arenas-Lopez S, Robinson C, McCarthy D, Paget RI, Tibby S, Taylor KM. 'Poppy seeds' in stomach aspirates: is oral omeprazole extemporaneous dispersion bioavailable?  Eur J Pediatr 2008;167(7):823-5.

Ghulam A, Keen K, Tuleu K, Wong ICK, Long PF. Poor preservation efficacy versus quality and safety of pediatric extemporaneous liquids. The Annals of Pharmacotherapy 2007;41(5):857-60. 

Han J, Wong I, Long P, Beeton A, Tuleu C. Physical and microbial stability of extemporaneous tacrolimus suspensions. Journal of Clinical Pharmacy and Therapeutics 2006;31(2):167-72. 

Yeung V, Wong ICK. When do children convert from liquid antiretroviral to solid formulations? Pharmacy World and Science 2005;27(5);399-402. 

Han J, Beeton A, Long P, Karimova A., Robertson C, Cross N, Smith L, O’Callaghan M, Goldman A, Brown K, Tuleu C. Plasticizer di(2-ethylhexyl)phthalate (DEHP) release in wet-primed extracorporeal membrane oxygenation (ECMO) circuits. Int J Pharm 2005;294:157-159. 

Karimova A, Smith L, Robertson A, Cross N, Han J. Beeton A, Tuleu C, Long PF, Cope J, O’Callaghan M, Goldman AP, Brown K. Storage of pre-assembled clear primed ECMO circuit may improve access to rapid deployment of mechanical support during CPR. Crit Care Med 2005;33(7):1572-1576. 

Standing JF, Khaki ZF, Wong ICK. Poor formulation information in published paediatric drug trials. Pediatrics 2005;116(4):e559-62.

Standing JF, Tuleu C. Paediatric formulations--getting to the heart of the problem. Int J Pharm 2005;300(1-2):56-66.