State of paediatric medicines in the European Union

State of Paediatric Medicines in the EU

At the end of October, the European Commission presented a report to the European Parliament and the Council on the progress made in children’s medicines since the entry into force of the Paediatric Regulation. The report highlights the positive advances in paediatric medicine development which, thanks to the Paediatric Regulation, has become an integral part of the overall development of medicines in the European Union (EU).

Since 2007, the Paediatric Regulation aims at encouraging and enabling high-quality research into the development of medicines for children, ensuring over time that most medicines used by children are specifically authorised for such use with age-appropriate forms and formulations and increasing the availability of high-quality information about medicines used by children. By setting up a system of obligations, rewards and incentives, the Regulation tries to encourage manufacturers to research and develop medicines for children’s specific therapeutic needs.

The report on the State of Paediatric Medicines in the EU showed an increase of research into paediatric medicines and that the Regulation works best in areas where the needs of adult and paediatric patients overlap. In relation to the paediatric investigation plans (PIPs)—development plans aimed at ensuring that the necessary data are obtained through studies in children to support the authorisation of a medicine for children—it was noted that the number of agreed PIPs surpassed 1000 in 2017. PIPs were mostly completed in relation to immunology/rheumatology (14%), infectious diseases (14%), cardiovascular diseases and vaccines (each 10%), while oncology (7%) was found on the lower end of the agreed paediatric investigation plans.

Despite a lot of positive developments, the report also acknowledged that the concept of a paediatric use marketing authorisation (PUMA), which aims at stimulating research in existing compounds that are off-patent and/or helping transform known off-label use into authorised use, has failed to deliver. To date, only three PUMAs have been granted. This number clearly lies below the expected levels.

Before proposing any amendments to the Paediatric Regulation, the European Commission intends to closer investigate the combined effects of the Orphan Regulation and the Paediatric Regulation through a joint evaluation. Results of this reflection will be presented by 2019 to allow the next European Commission to take informed decision about possible policy options. This report is consequently an intermediate step in the debate on a joint vision about the future parameters for paediatric and orphan medicines.

News from the European Medicines Agency (EMA)

During the last General Affairs Council meeting that took place on 20 November 2017, the EU27 ministers selected Amsterdam (the Netherlands) as the new seat of the EMA. A relocation of the agency is necessary in the context of Brexit as the agency is currently hosted in London (UK). EMA has now 16 months to prepare its move, before it starts taking up its operation on 30 March 2019 at the latest.

Besides its relocation, EMA has been working on a number of other initiatives including the review of flupirtine-containing and HES-containing medicines as well as the launch of a new EudraVigilance system.

Review of flupirtine-containing medicines started

The review of flupirtine-containing medicines for pain relief was requested by the German medicines authority, the Federal Institute for Drugs and Medical Devices. It follows a previous EMA review in 2013 that introduced measures to restrict the use of these medicines because of reports of serious liver problems associated with their use.

As part of the measures from the earlier review, flupirtine use was limited to no more than 2 weeks in patients who could not use other pain treatments and tests of liver function were introduced before and during treatment. EMA also requested studies to show whether these restrictions were effective in reducing the risks. Results from some studies have now become available and suggest that although the number of treated patients has gone down, the medicine is still being used outside the restrictions introduced in 2013. Furthermore, cases of serious liver damage associated with this medicine have continued to be reported.

EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has therefore begun a further review to determine how the latest available data affect the balance of benefits and risks for these medicines and to decide whether additional regulatory action should be taken. While the review is ongoing, patients who have any concerns about their medication should speak to their doctor or pharmacist.

Review of hydroxyethyl starch (HES)-containing medicines

Medicines containing HES are used for the management of hypovolaemia (low blood volume) caused by acute (sudden) blood loss, where treatment with alternative infusion solutions known as ‘crystalloids’ alone is not considered to be sufficient. HES medicines are given by infusion (drip) into a vein and are used as blood volume expanders to prevent shock following acute bleeding.

The PRAC has started to review the results of studies, and all other available data, and their impact on the benefit–risk balance of HES-containing medicines for infusion and issue a recommendation on whether their marketing authorisations should be maintained, varied, suspended or withdrawn across the EU. Input from stakeholders, such as healthcare professionals, patients’ organisations and the general public, that is relevant to this procedure will also be considered by PRAC.

New EudraVigilance system is live

For better safety monitoring of patients across Europe, EMA has launched a new and improved version of EudraVigilance, the European information system of suspected adverse reactions to medicines that are authorised or being studied in clinical trials in the European Economic Area (EEA). The new system makes it easier for marketing authorisation holders and sponsors of clinical trials to report suspected adverse reactions and allows for better analysis of this information for the benefit of patient safety in Europe.

In comparison with the previous version, the new EudraVigilance offers simplified reporting of individual case safety reports, enhanced interoperability, better searchability, more efficient data analysis as well as increased system capacity to support large volumes of users and reports. Moreover, it aims at strengthening the collaboration with the WHO as EMA will make the reports of individual cases of suspected adverse reactions within the EEA directly available to the WHO Uppsala Monitoring Centre.

The reporting of adverse reactions by patients and healthcare professionals to national competent authorities based on local spontaneous reporting systems will remain unchanged. There will also be no changes to the reporting of suspected unexpected serious adverse reactions during clinical trials until the application of the new Clinical Trial Regulation. Public access to data held in EudraVigilance will be provided through the adrreports.eu portal, which includes new features for data retrieval and representation.

The Agency will continue to support national competent authorities, marketing authorisation holders and sponsors of clinical trials in the EEA through targeted e-learning and face-to-face trainings, webinars and information days.

State of Health in the EU

Last week, the European Commission published its 2017 companion report on the State of Health in the EU alongside the 28 country health profiles that assess the strengths and challenges of health systems in relation to the individual context and specificities of each EU country. Overall, the report highlights the need to rethink our health systems in order to ensure that they remain fit-for-purpose and provide patient-centred care.

The State of Health in the EU is a 2-year initiative undertaken by the European Commission that provides policy makers, interest groups and health practitioners with factual, comparative data and insights into health and health systems in EU countries. The cycle is developed in cooperation with the Organisation for Economic Co-operation and Development (OECD) and the European Observatory on Health Systems and Policies.

The first part of the companion report proposes five ways to make healthcare effective, accessible and resilient. These suggestions include:

• Health promotion and disease prevention to pave the way for a more effective and efficient health system.

• Strong primary care to guide patients through the health system and that helps to avoid wasteful spending.

• Integrated care that tackles a labyrinth of scattered health services to the benefit of the patient.

• Proactive workforce planning and forecasting to make health systems resilient to future evolutions.

• Patient-centred health data for policy and practice.

The second part of the report focuses on the key findings of the 28 country health profiles by summarising the overall findings for each EU Member State.

The EU’s biennial companion report aims together with the 28 country health profiles at supplementing the picture drawn by Health at a Glance: Europe prepared by OECD. Following the presentation of the companion report to Health Ministries of all EU countries, national authorities can further discuss the above reports with the experts of the OECD and the European Observatory on Health Systems and Policies. The voluntary exchanges, which marks the end of the 2-year cycle of the State of Health initiative, will be able to take place from the beginning of 2018 and help ministries to better understand the main challenges and develop the appropriate policy responses.

Action plan on Science in Society related issues in Epidemics and Total pandemics (ASSET) Stakeholder Portal online

The ASSET, a European project that aims at improving the preparedness to the threat posed by pandemics (and epidemics) of infectious diseases has opened a Stakeholder Portal. By fostering better cooperation between science and civil society and by improving communication channels, the ASSET project seeks to develop an integrated, transdisciplinary strategy, which will take place at different stages of the research cycle, combining local, regional and national levels.

The project has identified Responsible Research and Innovation as well as public engagement as two increasingly important concepts in public health. To better align both the process and its outcomes with the values, needs and expectations of society, open debates are required and the active participation of civil society in research and practical public health projects. Consequently, the ASSET project has decided to build a Stakeholder Portal where participants can discuss on these themes and report (if appropriate) their experiences.

The Stakeholder Portal exists in two versions: as a LinkedIn group and as a Facebook group, for a larger visibility. Participants that wish to join the LinkedIn group, the ‘Stakeholder Portal – ASSET Project’ need to set up a LinkedIn account and request access to the group. Similarly, also for the participation in the Facebook group—the ‘Stakeholder Portal – ASSET Project’—a Facebook account is necessary. Anyone can view the discussion threads on Facebook. However, in order to start a new discussion or comment on an existing one, membership to the group is required.

Antimicrobial resistance (AMR): EU scientific opinion on outcome indicators

The European Centre for Disease Prevention and Control (ECDC), the European Food Safety Authority and the EMA have jointly established a list of harmonised outcome indicators to assist EU Member States in assessing their progress in reducing the use of antimicrobials and AMR in both humans and food-producing animals.

The report contains a set of primary and secondary indicators relating to antimicrobial consumption (AMC) as well as to AMR in both humans and food-producing animals. Monitoring of AMC is crucial for the prevention of AMR, since it was identified as the main AMR driver. The primary indicators broadly reflect the situation of AMC and AMR, while the secondary indicators were designed to provide information on more specific issues. These are also considered of importance for public health, but have a more restricted scope, or encompass areas that are not fully covered by the primary indicators. The indicators proposed for the different sectors should provide an overall indication of the situation regarding AMC and AMR at national level and should support Member States in assessing their progress and the effectiveness of the measures implemented to reduce AMC and the occurrence of AMR in both humans and food-producing animals.

The primary indicator for AMC in humans is the total consumption of antimicrobials, limited to antibacterials for systemic use, expressed as defined daily doses per 1000 inhabitants and per day. This indicator is used both by the hospital and the community sector. Two secondary indicators were identified, with the first being the ratio of consumption of broad-spectrum penicillins, cephalosporins, macrolides (except erythromycin) and fluoroquinolones to the consumption of narrow-spectrum penicillins, cephalosporins and erythromycin, in the community. The second secondary indicator is the proportion of total hospital AMC of glycopeptides, third-generation and fourth-generation cephalosporins, monobactams, carbapenems, fluoroquinolones, polymyxins, piperacillin and enzyme inhibitor, linezolid, tedizolid and daptomycin (defined daily doses per 1000 inhabitants and per day). It is an indicator of consumption of broad-spectrum antimicrobials used in healthcare settings.

For AMR in humans, the proposed primary indicator consists of the proportion of meticillin-resistant Staphylococcus aureus and third-generation cephalosporin-resistant Escherichia coli, expressed as two individual numbers. Both pathogens are of major public health importance. The proportion of Klebsiella pneumoniae with combined resistance to aminoglycosides, fluoroquinolones and third-generation cephalosporins is the first secondary indicator. It was chosen to reflect AMR in the hospital sector. The second secondary indicator is the proportion of penicillin-resistant and macrolide-resistant Streptococcus pneumoniae, given as two individual numbers. This indicator covers an important cause of community-acquired infections. The third secondary indicator is the proportion of carbapenem-resistant K. pneumoniae, which is an emerging threat.

European Directorate for the Quality of Medicines & HealthCare (EDQM): final report of the Pharmaceutical Care Quality Indicators Project published

The EDQM recently published its final report of the Pharmaceutical Care Quality Indicators Project. The report presents the results of a multinational validation study aimed at validating four basic sets of indicators to assess the quality of pharmaceutical care in Europe. It also contains the data collection forms that were developed and used in the above validation study.

Pharmaceutical care puts first the patient’s quality of life through the provision of safe and efficient healthcare while respecting the needs of healthcare professionals and society in general. The results of the specific study undertaken by EDQM should support competent authorities and stakeholders involved in the medication process in assessing the impact of pharmaceutical care and promoting the efficient and safe use of medicines.

EDQM worked since 2008 on the Pharmaceutical Care Quality Indicators Project. The four basic sets of indicators that were used for the assessment focused on the following pharmaceutical care areas:

• Adherence to nationally agreed clinical practice guidelines.

• Monitoring of therapeutic plans and medication safety by pharmacists through data linking and exchange of information about therapy and patient’s medical condition in anticoagulant and antibiotic therapy.

• Structured patient–pharmacist consultations (chronic therapy, polypharmacy and polymorbidity) via ‘My CheckList’.

• Pharmaceutical care: special needs in certain regions.

The results indicated that the development, testing and validation of quality indicators across the 12 European countries that participated in the project are complex. However, despite the differences between healthcare systems in Europe, the indicators under evaluation were considered to provide a pragmatic approach to encourage the implementation of the pharmaceutical care philosophy and working methods. Furthermore, the report highlighted that the indicators could help assure the quality of different key areas of the pharmaceutical care process.

For the delivery of pharmaceutical care and the use of the proposed indicators in daily practice, it was remarked that certain capabilities need to be in place in a healthcare system. These include for instance the availability of electronic health records, advanced education and training initiatives for healthcare professionals and improved interprofessional collaboration.

ECDC: toolkit for professionals in hospital and other healthcare settings

In preparation of the 10th anniversary of the European Antibiotic Awareness Day (EAAD), the ECDC redesigned its EAAD website and launched a new toolkit for hospital professionals. The EAAD, which takes place every year on 18 November, will focus on healthcare professionals and their efforts to keep antibiotics working.

The new EAAD website is a more dynamic and easy-to-access hub for resources to raise awareness about prudent use of antibiotics and about antibiotic resistance. It features a full set of informative resources aimed at the general public and at healthcare professionals, including fact sheets, videos and infographics. A set of communication tools that can be used to raise awareness about prudent use of antibiotics is available for free, together with a guidance document on how to develop a social media campaign on the topic. Stories of patients who battled infections by antibiotic-resistant bacteria and an overview of awareness campaigns on prudent antibiotic use and antibiotic resistance developed throughout Europe are also on display.

To further guide professionals in hospitals and other healthcare settings, the ECDC also released a new toolkit that contains materials to help these professionals influence the use of antibiotics in their work environment. It includes fact sheets, infographics, posters and leaflets that can be adapted. The toolkit addresses healthcare professionals such as prescribers, nurses and also hospital pharmacists by highlighting a series of actions that should be taken to prevent the spread of resistant bacteria as well as the misuse of antibiotics.

Hospital pharmacists are encouraged by ECDC to keep antibiotics working through:

• Participating in antibiotic stewardship teams, as a key member of the team.

• Collaborating with the infectious disease specialist and the clinical microbiologist to implement the antibiotic stewardship programme.

• Improving the quality of antibiotic prescribing (eg, checking for drug interactions, optimising dosage and route of administration and preventing adverse events).

• Consulting with hospital prescribers and providing them with feedback to ensure the quality of antibiotic prescribing.

• Implementing interventions on formulary restrictions, such as preapproval and postauthorisation requirements, and assessing compliance with these restrictions.

• Analysing data on antibiotic use and costs for the purpose of surveillance and benchmarking.

• Supporting evidence-based hospital antibiotic guidelines for common infections and for surgical prophylaxis.

• Managing your hospital’s antimicrobial formulary (ie, list of drugs available for prescribers).

By covering a number of professionals working at hospitals and other healthcare settings, the new toolkit aims at creating a sense of individual responsibility in tackling antibiotic resistance and at empowering professionals to take action.

To mark the 10th anniversary of the EAAD, ECDC has also launched a social media call-to-action initiative called #KeepAntibioticsWorking. This initiative prompts all EAAD stakeholders, professionals and members of the general public to share a message on social media to explain what they are doing to ensure antibiotics remain effective. On 15 November, the new toolkit was launched officially during the world antibiotic awareness week. EAHP participated in the launch event.

EMA/Directorate-General for Health and Food Safety (DG SANTE): action plan to foster development of advanced therapy medicinal products (ATMPs)

The EMA and the European Commission’s DG SANTE have adopted a joint action plan to foster the development of ATMPs.

ATPMs are medical products for human use based on genes or cells that offer potentially groundbreaking opportunities for the treatment of injury and disease, particularly in cases of severe, untreatable or chronic diseases that do not respond adequately to conventional treatments. They can be categorised into four main groups: gene therapy medicinal products, somatic cell therapy medicinal products, tissue engineered medicines and combined ATMPs.

These products are governed by Regulation 1394/2007 on advanced therapy medicinal products that mandates that a marketing authorisation must be obtained prior to the marketing of ATMPs. The evaluation of these products is led by the Committee for Advanced Therapies, a specialised committee within EMA. The Regulation also empowers Member States to permit the use of advanced therapies that have not been authorised by the Commission under certain conditions (so-called ‘hospital exemption’). The joint new action plan does not foresee changes to this regulatory framework, instead it identifies initiatives designed to optimise the regulatory environment. These include a European Commission guideline on good manufacturing practice for ATMPs, the initiation of dialogue with national competent authorities, new EMA scientific guidelines on ATMPs as well as awareness raising.