Earlier this month, the Heads of Medicines Agencies (HMA)/European Medicines Agency (EMA) task force on the availability of medicines for human and veterinary use released two guidance documents that seek to improve reporting and communication around medicines shortages. Both the ‘Guidance on detection and notification of shortages of medicinal products for Marketing Authorisation Holders in the Union’ and the ‘Good practice guidance for communication to the public on medicines’ availability issues’ lay the foundations for an improved and harmonised EU approach in reporting of and communication on medicines’ shortages and availability issues, a key public health priority for the EU network.
The ‘Guidance on detection and notification of shortages of medicinal products for Marketing Authorisation Holders in the Union’ seeks to facilitate the detection and early notification of medicines shortages. The document contains a template for shortage notification which should be used by companies when communicating to national competent authorities. Both the guidance and the template will be tested during a pilot phase starting at the end of 2019.
The ‘Good practice guidance for communication to the public on medicines’ availability issues’ has been issued for the use by EU national competent authorities and EMA. It contains principles and examples of good practices for communication that should be adhered to when sharing information about medicines shortages with the public, patients and healthcare professionals. The guideline highlights the need for timely, accurate and up-to-date information on availability issues to ensure continuity of care.
The HMA/EMA task force was set up in 2016 to look at availability issues, including medicines that are authorised but not marketed, as well as at supply chain disruptions, in order to improve continuity of supply of human and veterinary medicines across Europe.
WHO updates essential medicines list
The WHO has updated its global guidance on medicines and diagnostic tests to address health challenges, prioritise highly effective therapeutics, and improve affordable access. The revisions focuses on cancer and other global health challenges. With the addition of 28 medicines for adults and 23 for children as well as the specification of new uses for 26 already-listed products, the Model List of Essential Medicines now contains 460 products deemed essential for addressing key public health needs.
In the revised essential medicines list, WHO included 12 additional medicines for five cancer therapies which are regarded as the best in terms of survival rates to treat melanoma, lung, prostate, multiple myeloma and leukemias cancers. Moreover, the advice on antibiotic use was strengthened by incorporating the AWARE approach which clusters antibiotics in the categories ‘access’, ‘watch’ and ‘reserve’ (for more information see EAHP’s EU Monitor of 9 July 2019). This classifications helps to identify which antibiotics to use for the most common and serious infections to achieve better treatment outcomes and reduce the risk of antimicrobial resistance. Other updates to the medicines list include for example new oral anticoagulants, biologics and their respective biosimilars for chronic inflammatory conditions as well as heat-stable carbetocin for the prevention of postpartum haemorrhage.
In addition to the List of Essential Medicines also the List of Essential (in vitro) Diagnostics was updated. It now contains 46 general tests that can be used for routine patient care as well as for the detection and diagnosis of a wide array of disease conditions, and 69 tests intended for the detection, diagnosis and monitoring of specific diseases.
Clinical trials – Commission, EMA and HMA call on sponsors to publish results in EU database
The European Commission, the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) issued a joint letter addressed to all sponsors of clinical trials conducted in the European Union. With this letter the three institutions are reminding sponsors of their obligation to make summaries of results of concluded trials publicly available in the EU Clinical Trials Database. In particular the need for transparency and public access to clinical trial results are highlighted.
Transparency is an important element since it enhances scientific knowledge, and helps to advance clinical research and support more efficient medicine development programmes. To further increase the information contained in the EU Clinical Trials Database, EMA started in 2018 to identify trials with missing results. On a monthly basis the agency is reaching out to the sponsors of those trials in order to ensure compliance with the transparency rules.
WHO launches ‘AWaRe campaign’
The WHO has launched its ‘AWaRe’ campaign which promotes the use of a tool to help governments contain rising resistance and make antibiotic use safer and more effective. The acronym of the tool – ‘AWaRe’ – stands for access, watch and reserve. It classifies antibiotics into three groups and was developed by the WHO Essential Medicines List.
On the one hand, ‘AWaRe’ seeks to limit the use of drugs associated with the highest risk of resistance, while at the other hand it tries to increase the use of antibiotics in countries where supply and availability is low. Antibiotics included in the ‘access’ category should be used for the most common and serious infections. They should be made available at all times in an affordable and quality-assured manner. The ones in the ‘watch’ category should be used sparingly for specific and limited indications. The use of the last category – ‘reserve’ – is restricted. Antibiotics included therein are a last resort and should only be given when all other antibiotics have failed.
By grouping antibiotics into these three categories, the campaign aims to increase the proportion of global consumption of antibiotics in the ‘access’ group to at least 60%, and to reduce use of the antibiotics most at risk of resistance from the ‘watch’ and ‘reserve’ groups. Focusing on using antibiotics included in the first category lowers the risk of resistance because they are ‘narrow-spectrum’ antibiotics.
Medical devices – Factsheet for Healthcare Professionals and Health Institutions
The European Commission published a factsheet for healthcare professionals and health institutions dealing with the new Medical Device Regulations. The document – which has also been translated into the official languages of the EU – touches on the difference between the old regime and the new Medical Devices Regulation(2017/745/EU) as well as the new In Vitro Diagnostic Medical Devices Regulation(2017/746/EU). The implementation of both Regulations will progress gradually starting in May 2020 for medical devices and in May 2022 for in-vitro diagnostic devices.
The new Regulations aim at strengthening the regulatory regime for devices by
Widening and clarifying the scope of the legislation, including for example, aesthetic implants and medical software;
Ensuring a closer supervision of the notified bodies by the national authority;
Offering more responsibility and authority to the assessment bodies, including regular checks on manufacturers and thorough testing;
Clarifying the rights and obligations of the parties involved in the supply chain, covering also internet sales and diagnostic services;
Ensuring transparency to patients and healthcare professionals through a database (EUDAMED) containing comprehensive information about the devices available on the EU Market;
Introducing a Unique Device Identification system (UDI system) to ensure post-marketing surveillance and traceability;
Implementing stricter requirements for clinical evidence;
Adapting the safety and performance requirements to new health technologies; and,
Enhancing coordination between national surveillance authorities and aligning to international guidelines to facilitate trade.
The factsheet covers aspects of these changes that are relevant for healthcare professionals, such as for example clinical investigations, obligations and regulatory requirements of economic operators, CE marking, traceability, the EUDAMED database and reprocessing of single-use medical devices. In addition, the document contains some frequently asked questions.
Finnish Council presidency plans to tackle occupational health and safety
On the first of July Finland took over the rotating Council presidency from Romania. Ahead of this change, Finland published its programme for the next 6 months which touches on the economic well-being in Europe and fostering growth. Finland aims at achieving its goals through an increase of skilled workers in the EU, in particular by establishing more routes for legal migration, improving labour mobility and increasing women’s participation in the workforce.
The programme focuses on four key priorities which include strengthening of common values and the rule of law, making the EU more competitive and socially inclusive, strengthening the EU’s position as a global leader in climate action and protecting the security of citizens comprehensively. Health is covered in the second point, in particular the promotion of occupational health and safety within the competences of the EU and the digitalisation of the sector.
Electronic cross-border health services move to the next phase
In the EU Monitor of 17th April 2019, EAHP reported on the growth of the ePrescription network. The electronic cross-border health service initiative of the European Commission aims at facilitating the exchange of patient summaries and ePrescriptions. By 2021, these services should be gradually implemented by 22 EU countries, namely Austria, Belgium, Croatia, Cyprus, Czechia, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Luxembourg, Malta, the Netherlands, Poland, Portugal, Slovenia, Spain and Sweden.
The implementation of these services is supported by the new eHealth Digital Service Infrastructure (eHDSI). The eHDSI is the initial deployment and operation of services for cross-border health data exchange. It is financed by the Member States and the European Union. The infrastructure has been rolled-out in four countries. These are currently offering the following exchanges:
Finland: ePrescriptions of outgoing travellers
Estonia: ePrescriptions of incoming travellers
Luxembourg: Patient Summaries of incoming travellers
Czech Republic: Patient Summaries of outgoing travellers
Croatia: ePrescriptions of incoming travellers
Further action needed to drive forward implementation of the EU Cross-border healthcare Directive
In early June, the European Court of Auditors released a report touching on the implementation of the EU Cross-border Healthcare Directive, including the monitoring and the support provided by the European Commission. Overall, the court concluded that the European Commission had underestimated the complexity of the project since only two Member States are currently exchanging health data, several years after the entry into force of the Directive.
In its report the Court of Auditors analysed how the European Commission assisted with the implementation of the Directive, how the activities of the European Reference Networks (ERNs) are progressing and how electronic health infrastructures are developing. Given a number of shortcomings, the report issued by the Court of Auditors asks for
the provision of further support for the national contact points to enhance information sharing on patients’ rights to cross-border healthcare;
improved preparation for cross-border exchanges of health data; as well as,
additional support for and management of ERNs.
The EU Cross-border Healthcare Directive was adopted in 2011 and implemented by Member States in 2013 with the aim to strengthen patients’ rights to access safe and high-quality healthcare across national borders within the EU. In addition, the Directive seeks to establish national contact points, closer cooperation between Member States on eHealth and ERNs to facilitate the access of rare disease patients to healthcare.
Health recommendations proposed by the Commission
In relation to its European Semester spring package, the European Commission released health recommendations for Member States earlier this month. In particular expenditures relating to the ageing population have been addressed in the European Commission’s proposal. 16 Members States, including Austria, Bulgaria, Cyprus, Czechia, Finland, Greece, Hungary, Ireland, Latvia, Lithuania, Malta, Poland, Portugal, Romania, Slovenia and Slovakia have been asked to continue their national investments in order to improve effectiveness, increase accessibility and strengthen the resilience of their healthcare systems.
Recommendations touch on a wide range of topics, including but not limited to the shortage of healthcare workers, out of pocket payments, accessibility and the overall sustainability of the healthcare system. The country-specific propositions of the European Commission will now be discussed in the Council. Member States will have until early July to vote on the final adoption of the recommendations. Following their approval, their implementation will be monitored.
Updates from the European Medicines Agency
Between May and July the European Medicines Agency (EMA) released a number of updates. These include information on bacterial lysate medicines for respiratory conditions to be used only for prevention of recurrent infections, updates on the withdrawal of the marketing authorisations for fenspiride medicines, restrictions in use of Xeljanz as well as the effectiveness of medicines containing methocarbamol and paracetamol. Moreover, the Pharmacovigilance Risk Assessment Committee (PRAC) also published new measures to avoid dosing errors with methotrexate as well as information on a review of meningioma risk with cyproterone medicines.
PRAC recommends new measures to avoid dosing errors with methotrexate
EMA’s safety committee – the PRAC – is recommending new measures to avoid dosing errors that have led to some patients incorrectly taking methotrexate-containing medicines daily instead of weekly.
The new measures include restricting who can prescribe these medicines, making warnings on the packaging more prominent and providing educational materials for patients and healthcare professionals. In addition, to help patients follow the once-weekly dosing, methotrexate tablets for weekly use will be provided in blister packs and not in bottles (or tubes).
Review of meningioma risk with cyproterone medicines
EMA has started a review of medicines containing cyproterone, which are used for treating a range of conditions, including excessive hair growth, prostate cancer and acne, as well as in hormone replacement therapy.
The review will look into the risk of meningioma, a rare, usually non-malignant tumour of the membranes covering the brain and spinal cord. The risk of meningioma with cyproterone daily doses of 10 mg or more has been known since 2008 and information was included in the prescribing information for these medicines along with a warning that cyproterone should not be used in people who have or have had a meningioma tumour. However, there was no information at the time on the magnitude of the risk and how the risk could change with different doses.
A recent study in France has now suggested that the risk of meningioma, although still very low, may be greater in those taking high doses of cyproterone for a long period. The study also showed that after patients had stopped cyproterone treatment for at least 1 year, the risk of developing these tumours was much reduced but remained slightly higher than usual. EMA's safety committee will now examine the available evidence and make recommendations as to whether the marketing authorisations for cyproterone-containing medicines should be amended across the EU.
Bacterial lysate medicines for respiratory conditions to be used only for prevention of recurrent infections
EMA is recommending that bacterial lysate medicines authorised for respiratory conditions should only be used for the prevention of recurrent respiratory infections, with the exception of pneumonia. This follows a review that concluded that there are no robust data showing that these medicines are effective at treating existing respiratory infections, or for the prevention of pneumonia, therefore they should not be used for these purposes.
In the review, EMA’s human medicines committee (CHMP) considered the results of clinical studies, data on side effects reported with these medicines, and advice from an expert group on infectious diseases. Although data are limited, the review found some evidence of effectiveness of these medicines in the prevention of recurrent respiratory tract infections and the safety profile is in line with what is expected for this type of product. The CHMP therefore recommended that use of the medicines for prevention can continue, but the companies must provide further data on safety and effectiveness from new clinical studies by 2026.
Withdrawal of marketing authorisations for fenspiride medicines
EMA’s safety committee (PRAC) has recommended that the marketing authorisations for fenspiride medicines be revoked, so the medicines can no longer be marketed in the EU. This follows a review that has confirmed that these cough medicines could cause heart rhythm problems. The PRAC considered all the available evidence in its review. This included cases of QT prolongation and torsades de pointes (abnormalities of the heart’s electrical activity that may lead to heart rhythm disturbances) in patients using these medicines, results of laboratory studies, data from published literature and stakeholder input.
Heart rhythm problems can be serious and occur suddenly, and it is not feasible to identify in advance the patients who may be at risk of these problems with fenspiride. In contrast, fenspiride medicines are used to treat non-serious cough. Therefore, the PRAC considered that these medicines should no longer be marketed.
The PRAC recommendation will now be sent to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) to make a decision about its implementation. The CMDh is a body representing EU Member States as well as Iceland, Liechtenstein and Norway.
On 16 May 2019, EMA’s safety committee (PRAC) recommended that the marketing authorisations for fenspiride medicines be revoked, so the medicines can no longer be marketed in the EU. This follows a review that confirmed that these cough medicines could cause heart rhythm problems. The PRAC considered all the available evidence in its review. This included cases of QT prolongation and torsades de pointes (abnormalities of the heart’s electrical activity that may lead to heart rhythm disturbances) in patients using these medicines, results of laboratory studies, data from published literature and stakeholder input.
Heart rhythm problems can be serious and occur suddenly, and it is not feasible to identify in advance the patients who may be at risk of these problems with fenspiride. In contrast, fenspiride medicines are used to treat non-serious cough. Therefore, the PRAC considered that these medicines should no longer be marketed. The PRAC recommendation was adopted by the CMDh by consensus and will be implemented directly at national level.
Restrictions in use of Xeljanz while EMA reviews risk of blood clots in lungs
EMA’s safety committee (PRAC) is recommending that doctors must not prescribe the 10 mg twice daily dose of Xeljanz (tofacitinib) in patients who are at high risk of blood clots in the lungs. These include patients who have heart failure, cancer, inherited blood clotting disorders or a history of blood clots, as well as patients who take combined hormonal contraceptives, are receiving hormone replacement therapy or are undergoing major surgery. In addition, doctors should consider other factors that may increase the risk of blood clots in the lungs including age, obesity, smoking or immobilisation. Xeljanz is currently authorised for the treatment of rheumatoid arthritis, psoriatic arthritis and severe ulcerative colitis.
The PRAC’s recommendation follows results from an ongoing study in patients with rheumatoid arthritis. This study showed an increased risk of blood clots in the lungs and death when the 10 mg twice daily dose was used, which is double the recommended dose for rheumatoid arthritis.
The new advice means that, since 10 mg is the only recommended starting dose for ulcerative colitis, patients with this condition who are at high risk of blood clots must not be started on Xeljanz. Patients at high risk currently taking this dose for any condition must be switched to alternative treatments. Patients should not stop or change their dose of Xeljanz without talking to their doctor. They should seek medical attention immediately if they experience symptoms such as difficulty breathing, pain in the chest or upper back and coughing up blood, which could indicate the presence of a blood clot in the lungs.
The new recommendations are temporary and follow previous PRAC advice not to exceed the recommended 5 mg twice daily dose when treating rheumatoid arthritis. The PRAC will now carry out a review of all available evidence, and updated guidance will be provided to patients and healthcare professionals once the review is concluded.
EMA begins review of the effectiveness of medicines containing methocarbamol and paracetamol
EMA has started a review of the effectiveness of medicines containing a combination of methocarbamol and paracetamol for the treatment of painful muscle spasms. The review is being carried out at the request of the German medicines agency, BfArM, which has been asked to evaluate a marketing application for a generic medicine based on Robaxisal compuesto, a medicine authorised in Spain for painful muscle spasms associated with various short-term muscle disorders, such as low back pain.
Robaxisal compuesto, which has been authorised for many years, contains methocarbamol, a medicine that reduces muscle spasm and paracetamol, which is a painkiller. However, more recent evidence suggests that these two substances, in the doses in which they are combined in the medicine, might not be effective in the conditions such as low back pain for which it is currently used. Therefore the German agency has asked EMA to review the effectiveness of the combination.
For more information please visit EMA’s website at https://www.ema.europa.eu.
Footnotes
Competing interests: None declared.
Provenance and peer review: Commissioned; internally peer reviewed.