Rapid developments in technology have resulted in the generation of vast volumes of data, creating new evidence, which has the potential to add significantly to the way benefit-risk of medicinal products is assessed over their entire life cycle. While creating huge opportunities, it is recognised that there are also significant challenges in the use of these data. The HMA/EMA Joint Task Force on Big Data was launched in March of this year as an initial response to these challenges.
As part of its work, the Task Force launches an e-survey addressed to pharmaceutical companies to inform the development of a Big Data Strategy for the European Medicines Regulatory Network. The survey seeks to understand the current experience, key challenges, applicability and added value of Big Data in the context of the life cycle of a product.
The e-survey can be found here
The questionnaire is open until 20 October 2017. A summary report will be made publically available as an output of the Task Force. For queries on the survey, please write to email@example.com.
Veterinary stakeholders meeting: Lumpy skin disease
A Stakeholder focus group meeting on availability of Lumpy Skin Disease (LSD) vaccines attended by all National Competent Authorities was held in London on January 31, 2017.
There was an unequivocal preference by all stakeholders, notably National Competent Authorities, farmers and consumers, to have access to vaccines manufactured and tested to EU standards to guarantee the quality, safety and efficacy of products used on the territories. The objectives of the meeting were to assess the situation with regard to the currently available vaccines, and to identify steps that could facilitate the authorisation of LSD vaccines to EU standards.
Causes of Lumpy skin disease
Lumpy skin disease is caused by a Capripoxvirus affecting cattle, but showing specific characteristics when compared to Sheepoxvirus and Goatpoxvirus. The mechanism for virus transmission is still unclear, but mosquitoes and flies seem to play an important role as mechanical vectors. The disease was first identified in Zambia in 1929, and moved subsequently to the southern part of Africa, then spread north through Africa before reaching Israel in 1989. It is now endemic in Turkey and it reached Greece in 2015 and Bulgaria in 2016. These two member states started vaccination under Article 8 of Directive 2001/82/EC with non-EU authorized vaccines, in 2015 and 2016 respectively. Although not yet infected, Croatia started also vaccination because it is neighboring the infected areas.
Lumpy skin disease signs range from inapparent to severe disease, including fever, discharge from the eyes and nose, nodular, necrotic skin lesions, edema of the limbs, and swollen lymph nodes. Morbidity can be very high (up to 45%) but mortality is moderate (up to 10%). LSD is of economic importance, due to weight loss, drop in milk production, less frequently abortion and death.
There are currently no approved vaccines available in the EU for prevention of LSD despite incursion of disease into some MSs since 2015. Under emergency procedures, live homologous attenuated vaccines sourced from third regions had been used in MSs to control outbreaks of the disease under the emergency provision of Article 8 of EU Directive 2001/82/EC, based on published data indicating that vaccination can have a significant impact in reducing LSD virus spread and thereby reduce the extent of culling and improve the situation for animal health and welfare.
Preventive measures to avoid Lumpy skin disease
In this context, the feedbacks after vaccination indicated that, although the preventive measures have been effective to limit spreading of the disease, the side effects should not be underestimated: amongst the most serious ones, it appears that the currently available vaccines can cause increased morbidity and mortality of cattle and significant reduction in milk production. It was also highlighted that the clinical diagnosis of LSD is often difficult to achieve, amongst others because the appropriate diagnostic tools are not available.
With regard to the development of vaccines compliant with the EU standard levels, the focus group meeting highlighted major issues from a scientific point of view. As the basic knowledge on the virus and the disease is still incomplete, the development of vaccines is quite challenging; in particular, the morbidity and the mortality rates being low, the number of animals to be included in efficacy trials must be high to hope seeing any benefit from vaccination, and to establish onset and duration of immunity; and finally, even if the reduction in clinical signs might be beneficial for vaccinated animals, another important point would be to prevent spreading of the disease, or at least strongly limiting it. All these aspects have a deep impact on the choice of the vaccine strain and the vaccine formulation.
It was also recognised that more effective collaboration between EU competent authorities and stakeholders is paramount. The French Agency for Veterinary Medicines underlined that EU regulators and animal health risk managers need to understand product development challenges, manufacturing issues (particularly GMP requirements and capacity constraints) and supply time-lines to meet customer expectations. To facilitate the development of vaccines to EU standards, a shared approach for the risks would encourage manufacturers to invest in the development of products for which the potential market was uncertain and unpredictable.
Following the outcome of the UK European Union membership referendum in June 2016 the HMA will have to prepare for the UK leaving the EU. The British regulatory authorities (both MHRA and VMD) expressed and demonstrated that they are committed to the work in the EU medicines regulatory network as long as it remains unclear which changes will be implemented. However, the United Kingdom has invoked Article 50, thereby effectuating Brexit, on 29 March 2019.
The European Union has set terms for the negotiation during a Brexit-summit on 29 April 2017. The decision of the UK to leave the EU and the negotiations in the Council lead to uncertainties within the European Medicinal Regulatory Network. To ensure business continuity in case the UK cannot continue to carry out European regulatory procedures, changes in the assignment of MRP/DCP and Centralised Procedures could be implemented in the future.
The HMA and the consequences of the UK leaving the EU
During the HMA meeting on 11 and 12 May 2017 in Valetta during the Maltese EU Presidency all heads agreed to:
1. In cooperation with the EMA continuously supervise HMA and EMA actions in order to avoid any duplications of work.
2. Focus primarily on continuity of DCP/MRP procedures and reply on the EMA with regards to the centralised procedures.
3. Closely cooperate with CMDh, CMDv, Clinical Trial Facilitation Group and all other HMA working groups to ensure the best preperation for the UK leaving the EU. In doing so, to use the analysis and proposals presented in the draft CMD White Papers on Brexit and to invite other HMA groups if relevant to present a similar analysis.
The HMA agreed to set up a Brexit Preparedness working group that will keep oversight of all consequences of Brexit for the workload of the EU medicines regulatory network (the Network) within a preventive manner.
The heads reiterates the wish to have the UK as a close partner in the future and continue the collaboration with the MHRA and VMD.
Worksharing in the Active Substance Master File (ASMF) Assessment
In 2011, the HMA endorsed an idea to use worksharing in the assessment of the Active Substance Master File (ASMF) for multiple procedures. The idea was to save resources and increase consistency in procedures, as the same ASMF was used in different applications for marketing authorisation and was likely to be assessed repeatedly by different assessors. During previous 6 years, the Working Group On Active Substance Master File Procedures has invested a lot of work in the preparation and execution of a worksharing pilot (e.g. updates of existing guidelines, updated assessment report templates, development of ASMF AR database in CTS, development of an EU numbering system, training material for agencies and industry).
As the pilot was successfully finalised, the Heads agreed during the HMA Meeting held in Malta on 23 February 2017 that the ASMF worksharing procedure is a standard procedure to be used. The worksharing procedure is a voluntary option for the industry. In addition, CMDh has been asked to prepare a draft paper with proposals in the direction of an independent assessment of an ASMF as a self-standing procedure and including postmarketing aspects in the further development of an ASMF.
1000th Procedure HMA Voluntary Harmonisation Procedure (VHP) for clinical trials
The European Voluntary Harmonisation Procedure for clinical trials (VHP) was first established in March 2009. Now, the 1000th application for the evaluation of a clinical trial has been received by several European countries. The VHP procedure fosters simultaneous initiation of the authorisation procedure for clinical trials in more than one European member state by submitting a single application.
Developing new medicinal products is a long and complex process. After a pre-clinical phase of development and manufacture in conformity with GMP (“Good Manufacturing Practice”), new medicines must be evaluated in clinical trials, which asses the efficacy and safety of the product.
Every country within the European Economic Area, in which such a clinical trial is to be conducted, requires a national authorisation. While a separate procedure of validation, assessment, request for information, and approval/rejection was required for each country, the Voluntary Harmonisation Procedure has for several years been a tool for the initiation of an authorisation procedure across several countries selected by the applicant for conducting the clinical trial working together in the assessment.
The procedure was developed by the 'Clinical Trials Facilitation Group' (CTFG), a working group of the HMA ('Heads of Medicines Agencies'). For eight years, the Paul-Ehrlich-Institute (PEI) successfully coordinated this Network effort of national competent authorities.
The VHP reduced the period required for authorities to authorize a multinational trial to 60 days in all EU countries involved. Meanwhile, around 20 % of all applications for clinical trials to be conducted in more than one European country are submitted using the VHP.
Professor Klaus Cichutek, head of the HMA Management Group and president of the PEI said: “The HMA is proud that the Voluntary Harmonisation procedure has in the meantime been so well accepted by applicants world-wide, simplifying and reducing the period required for the authorisation of such multinational studies importantly, the VHP served as a model for the procedure to become applicable with the new regulation on clinical trial in future for the authorisation of multinational European clinical trials in Europe."
Compassionate use program
The EU regulatory framework makes it possible for non-authorized medicines to be made available under certain circumstances. This is achieved through a compassionate use program.
According to article 83 of Regulation (EC) No 726/2004, medicinal products without a Marketing Authorisation ‘may be made available for compassionate reasons to a group of patients with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who can not be treated satisfactorily by an authorized medicinal product.’
Compassionate use programs falls under national jurisdiction and, in most Member States under the remit of National Competent Authorities (NCA). Article 83 of Regulation (EC) No 726/2004, states that the Committee for Medicinal Products for Human Use (CHMP) has an advisory role at the request of a Member State. The individual NCA decide whether or not to approve the use of medicinal products without a market authorization.
The NCA in the Member State decides if such a program fulfils an unmet medical need according to their clinical practices and available alternatives. Some Member States have a long tradition on early access programs, including compassionate use, and others have different provisions in their national legislation.
Most of the compassionate use program notifications are submitted directly to the NCA within the different Member States.
NCAs that publish guidance on their compassionate use programs within their Member States | List | pdf
This list includes other early access schemes under article 5.
Colistin Resistance: The current human, food and animal situation
The use of colistin in animals and people in Europe varies greatly from country-to-country. It is used as an antibiotic of last resort in human medicine, with particular heavy use in cystic fibrosis patients in the community. Colistin is the antimicrobial with the 5th highest sales for use in lifestock in the EU[i]. The pattern of use in livestock amongst MSs is not indicative of uniform adoption of EMA’s Committee for Veterinary Medicinal Products (CVMP) best practice advice.
The European Commission requested in April 2013 a scientific advice from the EMA on the impact of the use of antibiotics in animals on public health and animal health and measures to manage the possible risk to humans. This was in accordance with the Commission "Action plan against the rising threats from AMR" adopted in November 2011.
The EMA advice of 2013 provided recommendations for colistin use in animals within the EU and indicated that they should be reviewed if there is a substantial increase of colistin resistance in animal bacteria and other new relevant information for public health.
To date resistance in bacteria to colistin had only been demonstrated in association with chromosomal mutations. A recent scientific publication[ii]indicated that in bacteria (Enterobacteriaceae) from pigs, retail raw meat (pork and chicken) and human patients in China a gene (mcr-1) has been found which enables horizontal (plasmid-mediated) transfer of resistance to colistin (polymyxins) between bacteria. This gene has now been found also in bacteria in Europe[iii],[iv],[v],[vi]. Since then, bacteria harbouring this transmissible colistin resistance have been reported from nearly all continents, and found also in ground beef, calves, chickens and turkeys. It has been found in archived material in the EU from as far back as 2005.
Based on this new evidence the European Commission requested in December 2015[vii] EMA to update its advice on colistin by 30.06.2016 at the latest. To undertake this work, EMA’s CVMP requested to reconvene the Antimicrobial Advice Ad Hoc Expert Group (AMEG), who prepared the 2013 advice.[viii]
[i] Fifth ESVAC report. Sales of veterinary antimicrobial agents in 26 EU/EEA countries in 2013. www.ema.europa.eu/docs/en_GB/document_library/Report/2015/10/WC500195687.pdf
[ii] Liu Y-Y, Wang Y, Walsh TR, et al. Emergence of plasmid-mediated Colistin resistance mechanism MCR-1 in animals and human beings in China: amicrobiological and molecular biological study. Lancet Infect Dis 2015 (Published online November 18, 2015: dx.doi.org/10.1016/S1473- 3099(15^00424-7').
[iv] Quesada, A. et al. Detection of plasmid mediated colistin resistance (MCR-1) in Escherichia coli and Salmonella enterica isolated from poultry and swine in Spain. Research in Veterinary science 2016; 105 pp 134-135
[v] Hasman, H. et al. Detection of mcr-1 encoding plasmid-mediated colistin-resistant Escherichia coli isolates from human bloodstream infection and imported chicken meat, Denmark 2015. Euro Surveill. 2015; 20(49)
[vi] Perrin-Guyomard, A. et al. Prevalence of mcr-1 in commensal Escherichia coli from French livestock, 2007 to 2014. Euro Surveill. 2016;21(6)
[viii] Antimicrobial Advice ad hoc expert group (AMEG) Updating the advice on the use in animals of colistin - Mandate and rules of procedure. EMA/24480/2016
Multi Annual Work Plan adopted by HMA
After finalisation of the joint HMA/EMA strategy to 2020, the HMA developed a Multi Annual Work Plan (MAWP) to bring the joint overarching strategy into operation on the HMA level with the involvement of all National Competent Authorities. The MAWP has been developed by a HMA taskforce and was debated extensively in break-out sessions during the 2015 HMA plenary meetings in Luxemburg and Dubrovnik. The MAWP has been adopted on 17 February 2016 during the 83rd HMA meeting in Amsterdam.
Eleven topics were agreed as priority areas, namely:
- Antimicrobial resistance
- Availability of good quality appropriately authorised medicines
- Competence development programme through the EU Network Training Centre
- Developing an efficient, effective and collaborative approach on inspections to address sustainability
- Innovation and access to new medicines
- International collaboration
- Optimisation of the regulatory operations
- Responding to public and animal health emergencies
- Strengthen surveillance
- Implementation of the Telematics strategy
- Support for better use of medicine
Article 57 database – Variations – regulatory information
On 17 December the EMA MB considered that the Article 57 database is functional for the purpose of notifications of changes in QPPV and PSMFL information. From 1 February 2016 Marketing Authorisation Holders no-longer need to notify EMA (for centrally authorised products) and National Competent Authorities (for nationally authorised products) of changes to the QPPV or PSMF data by submitting a type IAIN variation.
Following the EMA MB decision the Commission has published the information on their webpage.
Article 57 database – Variations – regulatory information
EU Medicines Agencies Network Strategy to 2020 adopted
The Network Strategy to 2020 by the HMA and EMA was adopted at EMA’s Management Board’s meeting on 17 December 2015.
Workshop report on requirements for the authorisation of vaccines
The European Medicines Agency (EMA) has published the outcome of a joint HMA/EMA/industry workshop which explored how to ensure the availability of veterinary vaccines in the European Union.
How to improve the availability of veterinary vaccines in Europe
Transatlantic Trade and Investment Partnership (TTIP)
TTIP is a trade agreement to be negotiated between the European Union and the United States. The HMA Management Group send a letter to the European Commission with the request to give National Competent Authorities the possibility based on their expertise to provided their input on the chapter of PHARMACEUTICALS within TTIP.
HMA MG Letter 6 May 2015 | pdf
HMA statement on the review of veterinary medicinal product legislation
The HMA provides a consensus statement on the review of the European veterinary medicinal product legislation.
Letter from Klaus Cichutek, Chairman of the HMA MG
Letter signed 10/04/15
HMA EMA common network strategy paper 2020
Making a difference to human and animal health
European Medicines Agency and Heads of Medicines Agencies consult on common network strategy to 2020 | pdf
The European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) have released the ‘EU Medicines Agencies Network Strategy to 2020’, a draft common strategy to 2020 for the European medicines agencies network, for a three-month public consultation. Stakeholders are invited to send their comments before 30 June 2015.
The document under consultation outlines for the first time joint key priorities for the network and a high level strategy to achieve these.
The need to further strengthen the collaboration between the members of the network and work together towards achieving agreed goals has become more urgent recently. Europe faces the global threat represented by antimicrobial resistance to human and animal health, and needs to be prepared for emerging epidemics, as reminded by the outbreak of Ebola in West Africa in March 2014. At the same time the healthcare needs of patients in Europe are changing. Advancements in science and medicine mean that new and more complex medicines are being developed, which may bring opportunities for personalised medicines and more treatments for rare diseases. Patients also require timely access to new, beneficial and safe medicines. The globalisation of the pharmaceutical industry means that greater collaboration with regulators beyond the European Union is essential to assure the supply of safe, effective and good quality medicines for humans and animals.
The joint strategy for the European medicines agencies network is based on a coordinated approach and a strengthened collaboration within the network over the next five years, to address the challenges and make the most of the opportunities to benefit human and animal health.
The network is unique in the global regulatory environment. It includes all national medicines regulatory authorities for both human and veterinary medicines from Member States of the European Union (EU) and the European Economic Area (EEA), united in the Heads of Medicines Agencies (HMA), and the European Medicines Agency (EMA). By working closely together, the network can draw on the resources and expertise available across the EU, avoid duplication and share workloads.
The draft strategy focuses on areas where collaboration within the network can make a real difference to human and animal health in the European Union over the next five years. It builds on the EMA roadmap to 2015 and the HMA strategy document 2011-15.
The draft network strategy is arranged under four key themes focussing on:
· human health
· animal health and human health in relation to veterinary medicines
· optimising the operation of the network
· the global regulatory environment
Separate multi-annual work programmes/implementation plans for EMA, HMA, and coordination groups for mutual recognition and decentralised procedures, human and veterinary (CMDh and CMDv) will be developed in order to give detailed information on the work of each component of the network, and will also describe how the strategy will be taken forward.
All stakeholders are invited to send comments on the draft network strategic vision using this template to EUnetworkstrategy@ema.europa.eu no later than 30 June 2015.
Contact the HMA Permanent Secretariat
Press Release | pdf
Network strategy | pdf
Template for comments | Word
Klaus Cichutek is the new chair of the HMA Management Group
On 19th March 2014, the HMA Management Group appointed from among its members a new chairman, Klaus Cichutek. The HMA MG consists of 5 permanent and two alternating members, the latter are heads of national competent agencies of the current and incoming EU presidencies (Greece and Italy). Klaus Cichutek is the head of the Paul Ehrlich Institute, the Federal Institute for Vaccines and Biomedicines in Germany.
Croatia - A new Member of the HMA
Croatia has finished accession negotiations and on 9 December 2011 signed the Treaty of Accession to become the 28th member of the EU. The ratification process was concluded on 21 June 2013 and entry into force and accession of Croatia took place on 1 July 2013.
Thus the HMA has a new member , the Head of the Croatian Agency for Medicinal Products and Medicinal Devices (HALMED), Viola Macolic Sarinic. Welcome!
More information about HALMED
21 December 2012: HMA raise concerns about discussion on progress on health claims on botanticals used in foods
The HMA express grave concerns regarding possible scenarios which are introduced in "Discussion paper on health claims on botanicals used in foods" published by the European Commission (EC). The outcome of this discussion may have a major impact on the future of the traditional herbal medicines regulatory regime, therefore every change of the current system should be evaluated very carefully to avoid any threats to public health safety. Read more
10 December 2012: HMA concerns regarding the adoption of the new Falsified Medicines Directive
The implementation of the Directive 2011/62/EU as regards the prevention of entry into the legal supply chain on falsified medicines is to strengthen existing quality control and health protection measures for medicines and to introduce new measures aimed at preventing falsified medicines and their components from entering the legal supply chain in the European Union. It should be noted that the Falsified Medicines Directive was not transferred into Directive 2001/82 for veterinary medicinal products. Read more