Paediatric Medicines in Europe: The Paediatric Regulation—Is It Time for Reform?

Objectives: In this paper, we investigated the effects of the European Paediatric Regulation (EC) N° 1901/2006 with respect to satisfying the paediatric therapeutic needs, assessed in terms of the increased number of paediatric medicinal products, new therapeutic indications in specific high-need conditions (neonates, oncology, rare disease, etc.) and increased number of paediatric clinical studies supporting the marketing authorisation.Methods: We analysed the paediatric medicinal products approved by the European Medicines Agency in the period January 2007-December 2019, by collecting the following data: year of approval, active substance, legal basis for the marketing authorisation, type of medicinal product (i.e., chemical, biological, or ATMP), orphan drug status, paediatric indication, Anatomical Therapeutic Chemical code (first-level), number and type of paediatric studies. Data were compared with similar data collected in the period 1996–2006.Results: In the period January 1996–December 2019, in a total of 1,190 medicinal products and 843 active substances, 34 and 38%, respectively, were paediatric. In the two periods, before and after the Paediatric Regulation implementation, the paediatric/total medicinal products ratio was constant while the paediatric/total active substances ratio decreased. Moreover, excluding generics and biosimilars, a total of 106 and 175 paediatric medicines were granted a new paediatric indication, dosage or age group in the two periods; out of 175, 128 paediatric medicines had an approved Paediatric Investigational Plan. The remaining 47 were approved without an approved Paediatric Investigational Plan, following the provisions of Directive 2001/83/EC and repurposing an off-patent drug. The analysis of the clinical studies revealed that drugs with a Paediatric Investigational Plan were supported by 3.5 studies/drug while drugs without a Paediatric Investigational Plan were supported by only 1.6 studies/drug.Discussion: This report confirms that the expectations of the European Paediatric Regulation (EC) N° 1901/2006 have been mainly satisfied. However, the reasons for the limited development of paediatric medicines in Europe, should be further discussed, taking advantage of recent initiatives in the regulatory field, such as the Action Plan on Paediatrics, and the open consultation on EU Pharmaceutical Strategy.

Cardiovascular Paediatric Medicines Development: Have Paediatric Investigation Plans Lost Heart?

This work aimed to establish whether paediatric needs in cardiovascular diseases have been met by paediatric investigation plans (PIPs) produced since the development of the European Union Paediatric Regulation in 2007. The European Medicines Agency repository was searched for patterns in the development of paediatric medicines in general. Next, positive PIPs related to cardiovascular diseases were scrutinized for outcomes and compared to specific paediatric cardiovascular needs. In total, 1866 PIPs were identified with 12% corresponding to decisions taken for cardiovascular medicines. However, despite this therapeutic area having the greatest number of overall PIPs, only 14% of established needs in paediatric cardiovascular diseases were addressed by PIPs with positive decisions. Further, 71.9% of PIPs with decisions in cardiovascular disease corresponded to full waivers, so the product would not be studied in paediatrics. Despite the progress found in overall numbers of PIPs published, cardiovascular products are still commonly used off-label in paediatrics. Particularly, there is a need to develop products to treat heart failure and hypertension, two areas with clear unmet clinical needs in paediatrics. A case study on valsartan showed that industry, regulators, health technology assessment bodies, and prescribers should work together to reduce off-label use of paediatric cardiovascular diseases (CVD).

P23 Accelerating and de-risking the production of paediatric oral formulations

Background & AimAs part of the EU paediatric regulation, the paediatric use marketing authorisation (PUMA) was introduced, with an aim to stimulate research in existing compounds that are off-patent and/or to help transform known off-label use into authorised use.1 However, success has been limited, with only a few products gaining a PUMA, such as Sialanar 320 micrograms/mL glycopyrronium (equivalent to 400 micrograms/mL glycopyrronium bromide). A distinct challenge to overcome in this area is the development of more ‘age appropriate formulations’, particularly with an excipient composition and load that is suitable for paediatric patients. This project aims to establish an excipient screening platform, supplemented with analytical characterisation of materials, which will act as a decision making tool to accelerate and de-risk the production of age appropriate paediatric medicines.MethodTo develop this excipient screening platform, a list of drugs that require an age appropriate formulation was produced using the ‘needs for paediatric medicines’ documents provided by the European medicines agency (EMA),2whilst common problematic excipients in paediatrics were identified using an EMA reflection paper.3 Literature and prescribing data were also reviewed to ensure drugs selected would benefit from an age appropriate formulation. Differential scanning calorimetry (DSC) to determine compatibility of selected drugs with widely used excipients was carried out using a TA DSCQ200 instrument (TA Instruments, New Castle, DE) with TA Instruments Universal Analysis 2000 software. Data was collected under nitrogen atmosphere (50 mL min−1) using pierced flat-bottomed TZero aluminium pans (sample mass about 2 mg) and heating rate of 10 °C min−1 in the range from 50 to 400°C. For samples containing both the drug and an excipient, 1 mg of each was measured out and gently mixed with a spatula for one minute.ResultsThe most common class of drugs identified as requiring age appropriate formulations were related to cardiovascular disorders and neurology, whilst the majority of drugs identified also exhibit poor aqueous solubilities. Some identified problematic excipients include ethanol, sodium benzoate and sorbitol; however, these excipients may still be used in paediatric formulations, as long as they are below certain concentrations (for example, ethanol concentration should not exceed 0.5% w/v for under 6 years old). Two drugs identified through the initial screening, carvedilol and nifedipine, were analysed by DSC, alone and then alongside starch from corn and starch 1500; the resulting DSC curves showed no changes in peak size, position (peak onset temperatures for nifedipine and carvedilol were observed at 173.2°C and 117.3°C, respectively) and shape, as well as no additional peaks, therefore suggesting compatibility between the tested samples.ConclusionThis first phase of the development of an excipient screening platform will continue to scan several different excipients with selected active pharmaceutical ingredients (APIs) in order to create compatibility profiles. The excipient screening platform generated will accelerate and de-risk the production of age appropriate formulations, as it would allow screening for potential incompatibilities and acceptability, alongside informing formulation of appropriate oral paediatric dosage forms.ReferencesEuropean Commission. State of Paediatric Medicines in the EU. 10 years of the EU Paediatric Regulation. COM (2017) 626. Available at: https://ec.europa.eu/health/sites/health/files/files/paediatrics/docs/2017_childrensmedicines_report_en.pdfNeeds for paediatric medicines - European Medicines Agency [Internet]. 2019 [cited 28 June 2019]. Available from: https://www.ema.europa.eu/en/human-regulatory/research-development/paediatric-medicines/needs-paediatric-medicinesReflection paper: formulations of choice for the paediatric population [Internet]. European Medicines Agency. 2019 [cited 28 June 2019]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-formulations-choice-paediatric-population_en.pdf

P59 Assessing medicines for safe use in paediatrics

AimThis service review aimed to reassess and upgrade the ‘New Products Assessment Form’ and to develop an assessment tool in line with European regulations governing paediatric medicines. Many medicinal products routinely used to treat the paediatric population have not been studied or authorised for paediatric use, which means there is widespread unlicensed and ‘off-label’ use of medicines. Medicines deemed safe in adult formulations may not be appropriate for paediatric patients. Medicines must therefore be carefully selected based on agreed criteria including, but not limited to: licensing, excipients, administration, labelling, similarity to other products, safety and handling.MethodA literature review was conducted. Guidance, information, and advice was sought from other healthcare institutions, and European guidelines and directives informing current practise around excipients in paediatric medicines. Pharmacy colleagues were consulted during the development of the tool, and an accessible assessment tool was completed for use in a tertiary paediatric hospital.1–4ResultsThis is the first comprehensive ‘New Products Assessment Form’ in the hospital which complies with the European Medicines Agency (EMA) directives governing excipients in paediatric medicines. The document highlights clearly potential issues and risks associated with product excipients, licensing status, warning label guidance and allows for recording of rationale for the selection of medicines. The ‘New Products Assessment Form’ is intended to highlight potential issues associated with excipients and their associated acceptable daily intake (ADI), but it will also highlight other risks associated with medicines used in paediatrics e.g. inadequate labelling, translation requirements for foreign products, sound-alike/look-alike products, safety and handling, and others.ConclusionThis revised assessment tool has been approved for use in the hospital pharmacy. It will be made available in hospital and community pharmacies on request. Use of the tool should be monitored and audited.ReferencesAnnex to the European Commission guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’ (SANTE-2017-11668). https://www.ema.europa.eu/en/documents/scientific-guideline/annex-european-commission-guideline-excipients-labelling-package-leaflet-medicinal-products-human_en.pdf. NPPG Neonatal and Paediatric Pharmacists Group Newsletter No 61 Autumn 2016. Excipients in medicines for children. http://nppg.org.uk/wp-content/uploads/2017/04/NPPG-61.pdfQuestions and Answers on Ethanol in the context of the revision of the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’ (CPMP/463/00) https://www.ema.europa.eu/en/documents/scientific-guideline/questions-answers-ethanol-context-revision-guideline-excipients-label-package-leaflet-medicinal_en.pdfEMA. Guideline on pharmaceutical development of medicines for paediatric use.https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmaceutical-development-medicines-paediatric-use_en.pdf

P46 Dose-banding limits for commonly prescribed medications for children in the UK

AimCurrently, majority of prescribed medication doses are calculated according to a child’s body weight without considering the available drug products for administration or the therapeutic range of the drug. This can lead to lack of consistency in dosing and drug administration errors, which affects many children of all ages treated with medicines.1 There are no established standards for dose-banding in national or international healthcare systems. This project aimed to establish dose-banding limits for paediatric medicines, to be used for prescribing and administering accurate, safe, and effective drug doses.MethodA list of the most common oral prescribed medications was established from the medication dispensing database of four hospitals in the UK. Then the evidence for safe and effective dose ranges for each drug on the list was identified from paediatric reference books, Summary of Product Characteristics (SPC) and published literature. After using these data to develop dose bands based on body weight, we used a Delphi process to achieve healthcare professionals’ consensus about the suggested dose bands for each drug on the list.ResultsA total of 45 drugs for 45 specific indications were included. Four categories of dose-banding limits were established; drugs with 2-weight bands; 3-weight bands; 4-weight bands and 5-weight bands. Overall, for 53.3% (24/45) of the included drug, all their suggested dose-banding limits reached consensus after two rounds of Delphi. For 92% (22/24) of them, consensus was achieved on all their suggested bands in the first round. Only for 2 drugs the agreement was achieved after the second round. For the drugs included in 2-weight band and 5-weight band categories, all their suggested dose-banding limits received total consensus after round 1 of the Delphi process. For 9 drugs included in the 4-weight bands category, the agreement was achieved only on either one or two of their suggested dose bands. For 12 drugs, no agreement was reached on any of their suggested bands.ConclusionThe study results provide healthcare professionals with a set of recommended dose-banding limits for commonly prescribed drugs in the UK. These recommended limits could establish the basis for change in clinical practice to improve health care provided for children.AcknowledgementThis work is part of a larger project funded by the Neonatal and Paediatric Pharmacists Group.ReferenceRashed AN, Tomlin S, Arenas-Lópes S, et al. Evaluation of the practice of dose-rounding in paediatrics. Int J Pharm Pract 2019 May 29. doi:10.1111/ijpp.12549. [Epub ahead of print]

P27 Impact of having a paediatric medicines management pharmacy technician in a district general hospital

AimPatients are more likely to experience a ‘medicines-related safety incident’ when medicines reconciliation happens more than 24 hours after admission to an acute setting,1 according to the National Institute for Health and Care Excellence (NICE). The study aimed to assess the impact on medicine reconciliations following the introduction of a dedicated Paediatric Medicines Management Pharmacy Technician to the paediatric wards at a District General Hospital (DGH).MethodsData has been routinely collected by the pharmacy department over of a number of years showing the time of medicines reconciliations compared with the time of hospital admission. This data shows the number of medicine reconciliations that were completed within 24 hours of hospital admission and the number that were not completed within 24 hours. The data is routinely collected on the Thursday of the first full week of every month. All patients that were admitted to the paediatric wards were included in this data. The service is only funded Monday to Friday through the Child Health Department of the DGH. This data excludes neonates admitted to the Neonatal Intensive Care Unit. Data was collected from 83 paediatric patients in March/April/May 2017 and 78 paediatric patients in March/April/May 2019.ResultsData collected for the paediatric patients over March/April/May 2017 showed that around 21.7% of all paediatric patients admitted to the wards had a completed medicines reconciliation within 24 hours. The data collected over the same period in 2019 showed that 85% paediatric patients admitted to the wards had a completed medicines reconciliation within 24 hours.ConclusionThis study was useful in demonstrating the effectiveness of introducing a dedicated Paediatric Medicine Management Pharmacy Technician to the paediatric wards in a DGH. It showed that the proportion of medicine reconciliations within 24 hours prior to the change was very low, but after the change it was very high with nearly all patients having a completed medicines reconciliation within 24 hours. Prior to the introduction of a dedicated Paediatric Medicines Management Pharmacy Technician, the paediatric wards at this DGH were not meeting the standards set by NICE regarding medicines reconciliations within 24 hours of being admitted to an acute setting. After the introduction the paediatric wards were meeting these standards. By meeting NICE guideline QS120 Medicines Optimisation, the DGH has reduced the likelihood of medicines-related safety incidents. With the introduction of a dedicated Paediatric Medicines Management Pharmacy Technician there have been many other benefits. These include counselling to parents/children on the use of their medicines; checking of patients’ own medicines to see if they are still fit for purpose; advice to parents about unlicensed medicines and why they are used; where to obtain further supplies when new medicines have been started; and assisting parents and GP surgeries with any supply issues.ReferenceNational Institute for Health and Care Excellence. Medicines Optimisation (internet). (London):NICE; March 2016.(Quality Standard [QS120]). Available from www.nice.org.uk/guidance/qs120//chapter/Quality-statement-4-Medicines-reconciliation-in-acute-settings