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

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P59 Assessing medicines for safe use in paediatrics

Archives of Disease in Childhood ◽

10.1136/archdischild-2020-nppg.67 ◽

2020 ◽

Vol 105 (9) ◽

pp. e37.1-e37

Author(s):

Mary Worrall ◽

Anne Fitzpatrick

Keyword(s):

European Commission ◽

Assessment Tool ◽

New Products ◽

Daily Intake ◽

European Medicines Agency ◽

List Type ◽

Medicinal Products ◽

Pharmaceutical Development ◽

Human Use ◽

Paediatric Medicines

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

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Enabling Development of Paediatric Medicines in Europe: 10 Years of the EU Paediatric Regulation

Pediatric Drugs ◽

10.1007/s40272-017-0261-1 ◽

2017 ◽

Vol 19 (6) ◽

pp. 505-513 ◽

Cited By ~ 29

Author(s):

Paolo A. Tomasi ◽

Gunter F. Egger ◽

Chrissi Pallidis ◽

Agnes Saint-Raymond

Keyword(s):

Paediatric Regulation ◽

The Eu ◽

Paediatric Medicines

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P18 Provocation of paediatric hearts – a safe and smart solution

Archives of Disease in Childhood ◽

10.1136/archdischild-2020-nppg.27 ◽

2020 ◽

Vol 105 (9) ◽

pp. e15.1-e15

Author(s):

Moninne Howlett ◽

Anne Fitzpatrick ◽

Terence Prendiville

Keyword(s):

High Risk ◽

Brugada Syndrome ◽

Guideline Development ◽

Cost Savings ◽

Diagnostic Procedures ◽

Paediatric Population ◽

List Type ◽

Paediatric Hospital ◽

Smart Pump ◽

The Eu

AimsProvocation challenges are used to diagnose certain inherited life-threatening cardiac conditions; treatment can prevent malignant arrhythmias and sudden death. Provocation medications are administered to unmask pathognomic conduction characteristics on real-time electrocardiography. Pre-prepared rescue medications are administered should a ventricular arrhythmia be unintentionally provoked. These high-risk medications, in line with safety agency recommendations, should be delivered using smart-pump technology.1 They are also often unlicensed and expensive.2 We investigated the utilisation of smart-pumps and development of a guideline to optimise medicines management and safety of these procedures in an Irish tertiary paediatric hospital.MethodsPublished literature and current practices, including those in other paediatric and adult hospitals in Ireland and the UK, were reviewed to ascertain appropriate dosing and administration in the paediatric population.3 4 Multi-disciplinary input from nursing, cardiology, pharmacy and biomedical engineering was sought in guideline development.ResultsEvidence for such challenges in paediatrics is sparse. Suitable dosing was agreed and an indication-specific smart-pump drug library created. The ‘PCA Therapy’ module was employed to deliver repeated weight-based doses of the provocation medication (Ajmaline) in a controlled and timely manner; the rescue medication (Isoprenaline) was programmed as a continuous infusion. An auxillary calculator was developed in Microsoft Excel® to direct staff on preparation of both infusion solutions and bolus doses of medications to be manually administered (Magnesium and Isoprenaline). In 2017, relevant staff were trained, and the ‘Ajmaline Challenge’ guideline was approved and implemented in the Cardiac Catherisation Laboratory (CCL) and Cardiac Day Unit. Estimated cost savings of €19,400 were realised between January 2017 - October 2018 due to reduced wastage of unused medications. Further savings are likely due to decreased utilisation of the CCL.ConclusionMulti-disciplinary collaboration and health technology can improve the safety and cost-effectiveness of high-risk cardiac diagnostic procedures in the paediatric setting. Similar processes for other provocation challenges are under development.ReferencesInstitute for Safe Medication Practices, ISMP. 2018–2019 Targeted Medication Safety Best Practices for Hospitals 2018 [Available from: https://www.ismp.org/sites/default/files/attachments/2017-12/TMSBP-for-Hospitalsv2.pdf [Accessed: June 2019]European Commission. State of Paediatric Medicines in the EU - 10 years of the EU Paediatric Regulation 2017 [Available from: https://ec.europa.eu/health/sites/health/files/files/paediatrics/docs/2017_childrensmedicines_report_en.pdf [Accessed: June 2019]McMillan MR, Day TG, Bartsota M, et al. Feasibility and outcomes of ajmaline provocation testing for Brugada syndrome in children in a specialist paediatric inherited cardiovascular diseases centre. Open Heart 2014;1:e000023.Rolf S, Bruns HJ, Wichter T, et al. The ajmaline challenge in Brugada syndrome: diagnostic impact, safety, and recommended protocol. Eur Heart J. 2003;24:1104–12.

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Development of an Age-Appropriate Mini Orally Disintegrating Carvedilol Tablet with Paediatric Biopharmaceutical Considerations

Pharmaceutics ◽

10.3390/pharmaceutics13060831 ◽

2021 ◽

Vol 13 (6) ◽

pp. 831

Author(s):

Dilawar Khan ◽

Daniel Kirby ◽

Simon Bryson ◽

Maryam Shah ◽

Afzal Rahman Mohammed

Keyword(s):

Paediatric Population ◽

European Medicines Agency ◽

Gi Tract ◽

Anatomy And Physiology ◽

Conventional Tablet ◽

Adequate Dose ◽

Fasted State ◽

Swallowing Difficulties ◽

Age Appropriate ◽

And Performance

Owing to considerable differences observed in anatomy and physiology between paediatric subsets, it has been well established that children respond to drugs differently compared to adults. Furthermore, from a formulation perspective, there is a distinct challenge to develop a dosage form that is capable of safely, accurately, and reliably delivering the dose across the whole paediatric population. Orally disintegrating mini-tablets (ODMT) have widely been considered as an age-appropriate formulation option that possess the ability for adequate dose flexibility, avoids swallowing difficulties, and exhibits superior stability due to its solid state. Within this study, two strengths (0.5 mg and 2 mg) of carvedilol ODMT formulations were developed using an excipient composition and load that is appropriate for paediatric use. The formulations demonstrated adequate mechanical strength (>20 N) and fast disintegration times (<30 s). Dissolution profiles observed were robust and comparable to the marketed conventional tablet formulation across various parts of the gastrointestinal (GI) tract in both the fed and fasted state, signifying appropriate efficacy, quality, and performance. As such, the formulations developed in this study show potential to address the need of an ‘age-appropriate’ formulation of carvedilol, as highlighted by the European Medicines Agency (EMA) Inventory of the Needs for Paediatric Medicine.

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The Biosimilar Landscape: An Overview of Regulatory Approvals by the EMA and FDA

Pharmaceutics ◽

10.3390/pharmaceutics13010048 ◽

2020 ◽

Vol 13 (1) ◽

pp. 48

Author(s):

Ioana Gherghescu ◽

M. Begoña Delgado-Charro

Keyword(s):

Drug Administration ◽

Action Plan ◽

European Medicines Agency ◽

Patient Access ◽

Clinical Evaluations ◽

The Past ◽

The Us ◽

Improve Patient ◽

The Eu

Biosimilar medicines expand the biotherapeutic market and improve patient access. This work looked into the landscape of the European and US biosimilar products, their regulatory authorization, market availability, and clinical evaluation undergone prior to the regulatory approval. European Medicines Agency (EMEA, currently EMA) and Food and Drug Administration (FDA) repositories were searched to identify all biosimilar medicines approved before December 2019. Adalimumab biosimilars, and particularly their clinical evaluations, were used as a case study. In the past 13 years, the EMA has received 65 marketing authorization applications for biosimilar medicines with 55 approved biosimilars available in the EU market. Since the first biosimilar approval in 2015, the FDA has granted 26 approvals for biosimilars with only 11 being currently on the US market. Five adalimumab biosimilars have been approved in the EU and commercialized as eight different medicines through duplicate marketing authorizations. Whilst three of these are FDA-approved, the first adalimumab biosimilar will not be marketed in the US until 2023 due to Humira’s exclusivity period. The EU biosimilar market has developed faster than its US counterpart, as the latter is probably challenged by a series of patents and exclusivity periods protecting the bio-originator medicines, an issue addressed by the US’s latest ‘Biosimilar Action Plan’.

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Enhanced Economic Governance in the EU: Alternative to a Political Union?

International Journal of Management and Economics ◽

10.2478/ijme-2014-0001 ◽

2014 ◽

Vol 37 (1) ◽

pp. 10-35 ◽

Cited By ~ 1

Author(s):

Elżbieta Kawecka-Wyrzykowska

Keyword(s):

Debt Crisis ◽

Point Of View ◽

List Type ◽

Economic Governance ◽

Political Union ◽

Political Will ◽

Member States ◽

Eu Member States ◽

Realistic Approach ◽

The Eu

Abstract In reaction to the sharp deterioration of fiscal positions and a sovereign debt crisis in the majority of EU member states, EU leaders have been strengthening the EU economic governance framework, in particular for the eurozone member states. This has been reflected mainly through a reinforcement of the Stability and Growth Pact (SGP) within the so-called six-pack and through the recent adoption of the Treaty on Stability, Coordination and Governance in the Economic and Monetary Union (TSCG). The objective of this paper is to present the main decisions taken to address intensifying problems in the EU and assess them from the point of view of stability of the eurozone. The paper argues that the recent adoption of the six-pack and of the TSCG has created a legal basis for more effective governance structure that is much stronger than previously, and closer fscal coordination among EU member states in order to ensure public fnance sustainability. The practical results will depend, however, on the political willingness of countries to accept the new rules and rigorous enforcement of those rules. Most of the new solutions continue the previous approach: stricter preventive and punishing rules, and their more rigorous application. TSCG has adopted a new element: parallel to EU rules, there should be enhanced national rules (possibly in the form of constitutional commitments) and national institutions responsible for fscal discipline. This approach implies that international rules are not strong enough for sovereign countries, which agree to be subject to democratically elected national authorities but do not want to follow decisions by “outside” institutions. In addition, reverse voting in the Council encourages for more pragmatic, economically justifed use of the modifed SGP. In view of a lack of political will to move forward into a political union, this seems the only realistic approach to ensure fscal stabilization and keep the eurozone alive in the short and medium run. Two main research methods have been applied: (a)Statistical analysis of data on changes of the public fnances in the EU member states (budgetary defcit and public debt), (b)comparative analysis of successive EU documents on strengthening economic governance and identifcation of strong and weak aspects of the new documents from the point of view of stability of the eurozone. The main conclusion is that in a situation of a lack of political will to move forward into a political union, the only realistic approach to ensure fscal stabilization and keep the eurozone alive in the short and medium term seems to be to enforce rigorously the recently adopted new commitments aiming at better fscal control of euro area members.

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Biosimilars in the French and Polish System: Chosen Aspects of Reimbursement and Access

Comparative Economic Research ◽

10.18778/1508-2008.23.15 ◽

2020 ◽

Vol 23 (2) ◽

pp. 103-115

Author(s):

Olga Barszczewska ◽

Ralph Chami ◽

Anna Piechota

Keyword(s):

Public Expenditure ◽

Drug Expenditure ◽

European Medicines Agency ◽

Treatment Results ◽

Policy Goal ◽

Ministry Of Health ◽

Biological Drugs ◽

Reimbursement List ◽

Considerable Experience ◽

The Eu

The EU approved the first biosimilar drug in 2006. By 2017, the EU had authorized the highest number of biosimilars worldwide, acquiring considerable experience in their use and safety. In May 2019, the European Medicines Agency (EMA) search engine showed 54 authorized biosimilars. Biosimilars reduce public expenditure; however, the discussion about their potential disadvantages is still ongoing. Each country adopts different regulations on the interchangeability, switching, and substitution of a reference medicine by its biosimilar, since the EMA does not regulate this issue. Additionally, each nation has a unique reimbursement system, which results in significant differences in patients’ access to biosimilars. The importance of securing a higher availability of these cheaper versions of biological drugs is well-recognized. The better the access to these biosimilars is, the lower the overall drug expenditure and need for rationing would be, and therefore the better treatment results. The aim of this paper is to compare selected aspects of reimbursement and access to the EMA authorized biosimilar medicines in two countries – France and Poland. The stated drug policy goal of both countries is to significantly improve biosimilar implementation in the coming years. The research is based on an analysis of four main sources: the EMA biosimilars database, the Polish reimbursement list published by the Polish Ministry of Health, and two French reimbursement databases published by the French Ministry of Health. An additional literature review was conducted. The expected results concentrate on differences in the number of reimbursed biosimilars, the average time between EMA authorization and country reimbursement decision date, and the availability of biosimilars registered outside of the centralized (EMA) procedure. These findings could identify areas of improvement and help with discussions on how to optimize the reach of biosimilars, as well as improve French-Polish collaboration on this matter.

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Differences between the European and Eurasian Good Pharmacovigilance Practices

Safety and Risk of Pharmacotherapy ◽

10.30895/2312-7821-2021-9-2-75-84 ◽

2021 ◽

Vol 9 (2) ◽

pp. 75-84

Author(s):

A. V. Matveev ◽

A. E. Krasheninnikov ◽

E. A. Matveeva ◽

B. K. Romanov

Keyword(s):

Marketing Authorisation ◽

European Medicines Agency ◽

The European Union ◽

Current Version ◽

Eurasian Economic Union ◽

Expert Analysis ◽

The Russian Federation ◽

Economic Union ◽

Systems Effectiveness ◽

The Eu

Good pharmacovigilance practices (GVP) of the Eurasian Economic Union (EAEU) were prepared based on the GVP of the European Medicines Agency that have been in force in the European Union (EU) since 2012. The EAEU GVP have been in force in the Russian Federation and the other EAEU member states since 2016. It is important to identify potential diﬀerences between the current regulations in order to harmonise requirements for the pharmacovigilance systems in the EU and EAEU. The aim of the study was to analyse and compare GVP requirements in the EU and EAEU. The analysis helped to identify diﬀerences in the structure and contents of GVP sections, the deﬁnitions of terms (EU GVP deﬁnitions are more detailed and supported by examples, subsections, and references to other documents). Moreover, supplements and annexes to the EU GVP contain ﬁgures, templates, examples, algorithms, and tables, which are missing in the EAEU GVP. Expert analysis of these diﬀerences as applied to assessment of the pharmacovigilance systems’ eﬀectiveness, and practical activities of marketing authorisation holders, medicine developers, and regulatory authorities, demonstrated that the two GVPs are suﬃciently harmonised and have very few diﬀerences. However, the number of diﬀerences between the documents increases, as changes are made to the EU GVP. A more comprehensive harmonisation of the EAEU GVP with the current version of the EU GVP will make it possible to develop and use uniform pharmacovigilance documents in the EU and EAEU, and will facilitate the introduction of EAEU medicines into the global pharmaceutical market.

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An analysis of characteristics of post-authorisation studies registered on the ENCePP EU PAS Register

F1000Research ◽

10.12688/f1000research.12198.1 ◽

2017 ◽

Vol 6 ◽

pp. 1447 ◽

Cited By ~ 5

Author(s):

Robert Carroll ◽

Sreeram V. Ramagopalan ◽

Javier Cid-Ruzafa ◽

Dimitra Lambrelli ◽

Laura McDonald

Keyword(s):

Risk Assessment ◽

Chart Review ◽

Drug Utilisation ◽

Data Capture ◽

Primary Data ◽

European Medicines Agency ◽

Therapeutic Area ◽

The European Union ◽

Study Designs ◽

The Eu

Background: The objective of this study was to investigate the study design characteristics of Post-Authorisation Studies (PAS) requested by the European Medicines Agency which were recorded on the European Union (EU) PAS Register held by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Methods: We undertook a cross-sectional descriptive analysis of all studies registered on the EU PAS Register as of 18th October 2016. Results: We identified a total of 314 studies on the EU PAS Register, including 81 (26%) finalised, 160 (51%) ongoing and 73 (23%) planned. Of those studies identified, 205 (65%) included risk assessment in their scope, 133 (42%) included drug utilisation and 94 (30%) included effectiveness evaluation. Just over half of the studies (175; 56%) used primary data capture, 135 (43%) used secondary data and 4 (1%) used a hybrid design combining both approaches. Risk assessment and effectiveness studies were more likely to use primary data capture (60% and 85% respectively as compared to 39% and 14% respectively for secondary). The converse was true for drug utilisation studies where 59% were secondary vs. 39% for primary. For type 2 diabetes mellitus, database studies were more commonly used (80% vs 3% chart review, 3% hybrid and 13% primary data capture study designs) whereas for studies in oncology, primary data capture were more likely to be used (85% vs 4% chart review, and 11% database study designs). Conclusions: Results of this analysis show that study objectives and therapeutic area influence PAS design in terms of type of data capture used.

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