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The drug shortage situation - EIPG's point of view


by Maurizio Battistini The shortage of medicines has been a major concern in the countries of the European Union, and elsewhere, for more than 10 years, so much so that the Economic Community has devoted a great deal of effort Read more

EP’s draft position on Unitary SPC and SPC Regulation revision


by Giuliana Miglierini The Committee for Legal Affairs (JURI) of the European Parliament released the draft amendments to the Commission’s proposals aimed to establish a Unitary Supplementary Protection Certificate (SPC) (links to the document and to the procedure) and to Read more

Reactions to the proposed ban of PFAS


by Giuliana Miglierini A proposal to ban around 10,000 per- and polyfluoroalkyl substances (PFAS) was submitted in January 2023 to the European Chemicals Agency (ECHA) by authorities of Germany, Denmark, the Netherlands, Norway, and Sweden. The proposal was published on Read more

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EMA’s reflection paper on AI in the pharmaceutical lifecycle

September 22, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The rapidly evolving role of artificial intelligence (AI) and its possible application in the pharmaceutical field led the European Medicines Agency (EMA) to publish a draft Reflection paper on the use of AI along the entire lifecycle of both human and veterinary medicines.

The Reflection paper summarises the current view on the possible use of AI and machine leaning (ML) technologies and is open to public consultation until 31 December 2023. Comments, together with the outcomes of the joint HMA/EMA workshop to be held on 20-21 November 2023, will support its finalisation, as well as the possible development of new guidance. The initiative aims to identify the aspects of AI/ML use that would fall within the remit of EMA or of the single National Competent Authorities (NCAs) in charge of the dossiers’ assessment.

The document is part of the effort to improve the European Medicines Regulatory Network’s capability in data-driven regulation set forth by the joint HMA-EMA Big Data Steering Group (BDSG), and it has been developed in coordination with EMA’s CHMP and CVMP committees.

“The use of artificial intelligence is rapidly developing in society and as regulators we see more and more applications in the field of medicines. AI brings exciting opportunities to generate new insights and improve processes. To embrace them fully, we will need to be prepared for the regulatory challenges presented by this quickly evolving ecosystem” said Jesper Kjær, Director of the Data Analytics Centre at the Danish Medicines Agency and co-chair of the BDSG.

“With this paper, we are opening a dialogue with developers, academics, and other regulators, to discuss ways forward, ensuring that the full potential of these innovations can be realised for the benefit of patients’ and animal health” added Peter Arlett, EMA’s Head of Data Analytics and Methods, co-chair of the BDSG.

The main contents of the Reflection paper

The Reflection paper addresses the use of AI/ML with a dedicated chapter for each one of the steps, part of the overall lifecycle of a medicinal product. The interactions with regulators are then explored, as well as the different technical aspects to be taken into consideration. The final chapters discuss the governance of AI/ML applications, the integrity, and ethical aspects to be considered and how to address data protection.

The increasing use of AI technologies is based on the wide availability of big amounts of data produced and captured in electronic format on a routine basis. This data can be analysed by machine learning algorithms to inform the training of other systems able to analyse data and take actions with some degree of autonomy in order to achieve specific goals. These latter systems are the truly intended AI algorithms, those use is under discussion also in the field of regulatory decision making.

The Reflection paper recalls how the diffusion of these new technologies carries with it also some new risks, due to the “exceptionally great numbers of trainable parameters arranged in non-transparent model architectures”. Measures should thus be taken to ensure the safety of patients and the integrity of data, as well as to avoid the integration of bias into AI/ML applications.

The contents of the Reflection paper may also refer to combinations between a medicinal pro-duct and AI/ML-including medical device, as in such occurrence EMA is involved in the assessment of the characteristics of the device.

In general terms, existing guidelines, best practices, and recommendations relative to model in-formed drug development and biostatistics also apply to AI/ML; the adjacent methodology guidelines which may be relevant to this instance are listed in the document. The Reflection paper warns readers about the differences between the human and veterinary regulatory domains, suggesting that another reflection document specific for veterinary may be developed in future.

A risk-based approach

The usual risk-based approach typical of pharmaceutical development should be used to identify risks throughout the entire AI/ML tool lifecycle, including regulatory impact. According to the Reflection paper, the level of risk may depend also on the context of use and the degree of influence the AI technology exerts.

Developers should always seek early regulatory interaction and scientific advice, especially in cases where the AI/ML system may impact on the benefit-risk ratio of the medicinal product un-der development. To this instance, the EMA Innovation Task Force (ITF) is responsible for pro-viding early interaction on experimental technology, while scientific advice and qualification of novel methodologies in medicines development is provided by the Scientific Advice Working Parties (SAWP) of the CHMP for human medicines and of the CVMP for the veterinary ones.

As for all other steps of pharmaceutical lifecycle, the final responsibility for the suitability and use made of AI/ML algorithms, as well as their compliance to ethical, technical, scientific, and regulatory standards (GxP standards) and to current EMA scientific guidelines falls under the Marketing Authorisation Holders (MAHs) or applicants.

According to the Reflection paper, risks referred to in the discovery step may be limited, but they may impact the final evidence presented for regulatory review, thus principles for non-clinical development should be followed. This second step may include, for example, AI/ML modelling approaches according to the 3R principles. Regulators would expect to receive Standard Operating Procedures (SOPs) for AI/ML applications in preclinical studies; advisory documents on Application of GLP Principles to Computerised Systems and GLP Data Integrity should be also considered where appropriate. A pre-specified analysis plan would be needed for preclinical data potentially relevant for the assessment of the benefit-risk balance.

In the field of clinical trials, ICH E6 and VICH GL9 on human and veterinary GCPs should also be applied to the use of AI/ML. In particular, regulators expect the full model architecture and description of the data processing pipeline would be made fully available for comprehensive assessment should a model be generated for clinical trial purposes, as they would be considered parts of the clinical trial data or trial protocol dossier.

From precision medicine to pharmacovigilance

Particular considerations may be needed for applications of AI/ML in precision medicine, to individualise treatment according to the patient’s characteristics. AI/ML application supporting indication or posology decisions should be referenced in the Summary of product characteristics and their assessment falls under medicines regulation, representing a high-risk use both from the patient and regulatory perspectives. Close human supervision is also expected for AI applications used to draft or translate product information documents.

Many are the possible applications of AI/ML in the manufacturing of medicinal products, where they should follow the usual quality risk management principles (ICH Q8, Q9 and Q10) to guarantee safety, quality, and data integrity. New recommendations are also expected from EMA.

In the post-authorisation phase, AI/ML tools can effectively support efficacy and safety studies and post-marketing surveillance studies for veterinary medicines, as well as pharmacovigilance activities. Good pharmacovigilance practices should always be respected, and the used model should be validated, monitored and documented under the responsibility of the MAH. For conditional marketing authorisations, AI/ML applications should be discussed within a regulatory procedure unless details are agreed already at time of authorisation.


EMA’s new Quality Innovation Expert Group (QIG)

December 16, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

Innovative approaches to the development manufacturing and quality control of medicines are becoming the new paradigm to be faced both from an industrial and regulatory perspective. Not only innovative technologies for delivery, such as mRNA vaccines, many novel materials as well as new types of interconnected devices, wearables and digital health approaches need a particular attention to ensure the European regulatory network will be able to intercept and address gaps in the current framework. An increased predictability for developers is the final target objective.

EMA’s answer to this need passed through the establishment, in September 2022, of the new Quality Innovation Expert Group (QIG). The Group will act also as a preferential location for exchange and interaction between regulators and other stakeholders, at the European and global level. QIG is part of the Quality Domain of EMA’s working party structure; all its activities will be aligned to EMA’s Regulatory science strategy to 2025.

QIG’s composition

The eight members of the Quality Innovation Expert Group have a background in chemical, biological quality assessment and Good Manufacturing Practice (GMP) inspections. They have been nominated from the list of European experts and adopted by the CHMP and CVMP. Other ad hoc experts may be recruited were needed.

The Chair of the new group is Marcel Hoefnagel (he will also become a member of the Domain Governance); other members include Giampiero Lorenti, Leticia Martinez-Peyrat, Christina Meissner, Silke Schül, Barbara Stubbe, René Thürmer, and Marcos Timon. Further members may be appointed in future, based upon workload considerations.

The members’ selection process aims to include in the QIG two experts for each of the following areas: quality assessment for chemical medicinal products, quality assessment for biological medicinal products and ATMPs, GMDP inspections. Membership will be reviewed every three years; the chair’s appointment may be renewed only once.

The current schedule described within QIG’s provisional mandate indicates a maximum of six meetings per year (one of which face-to-face), planned to fit with Biologics Working Party (BWP), Quality Working Party (QWP) and/or GDMP Inspectors Working Group (IWG) meetings. Ad hoc meetings can also be organised as required. QIG’s work plan shall also include topics and frequency of the “Listen and Learn” platforms, while interactions with the stakeholders should be accommodated as needed, as well as meeting with other international regulators.

The technical, scientific and administrative support to the QIG will be provided by the EMA Secretariat.

QIG’s provisional mandate

The provisional mandate and rules of procedure of the Quality Innovation Expert Group was published in November 2022. The complete 2023 work plan is also expected to be published.

The main goal of the new QIG is to facilitate the translation into practice of innovative pharmaceutical manufacturing approaches, with respect to all the different range of medicinal products (i.e. chemical, biological and/or biotechnological substances, advanced therapy medicinal products).

To achieve this very ambitious task, the QIG shall be involved in many different activities, starting from the identification of innovative manufacturing approaches for pharmaceuticals and of the regulatory challenges associated with them. To this instance, possible tools to be used include horizontal scanning of emerging technologies, followed by proposals of regulatory measures to address them in the form of developing position papers, Q&A documents, etc.

Translation of innovative technologies into regulatory submissions or manufacturing and control facilities may be supported through actions at the level of scientific advice, marketing authorisation applications, related post-authorisation lifecycle changes and routine manufacturing and control operations. This objective shall be supported by the interaction with other EMA’s structures, such as the BWP and QWP Working Parties, and IWG Working Group.

Harmonisation at the European level of the approach to be used by regulators for the quality assessment of submissions and GMP inspections also falls under QIG’s mandate to operate. Attention should be paid to the advancement of regulatory sciences, by mean of a research driven agenda aimed to increase the effectiveness and awareness of the European Union as a centre for innovation, and shared between the European regulatory network and the academia.

QIG’s representatives are expected to participate to various international regulatory fora (e.g. ICH, ICMRA, PICs, IPRP) to inform about the European position and to facilitate cross-regional convergence on open issues. Existing channels and confidentiality agreements may also be used to facilitate the dialogue between the Group and other international regulatory partners on product- specific or technology-specific topics. Outcomes from QIG’s activities will be reported to the Quality Domain Governance, EMA Committees and Working Parties as needed.

The main initial tasks

The provisional mandate lists the points to be addressed by QIG’s experts as the first tasks for new new-born group. Acting as an entry point for developers to discuss new approaches along the entire life cycle of innovative medicinal products is a main one, to be declined by QIG on technology only. Continuity with other dialogue pathways already put in place by EMA should be pursued through the participation of a QIG member to the primary assessment as part of the (Co)-Rapporteur team or alternatively, as CHMP peer reviewer.

Emerging technologies that might impact regulatory decision making in the medium to long term represent another QIG’s priority; their assessment may be performed also with engagement of ad hoc experts and academia.

QIG members may support the Quality Domain Governance with recommendations on the quality and GMP requirements of medicinal products (e.g. data requirements and expected regulatory impact of analytical technologies, control strategy approaches, devices, drug delivery systems, materials, manufacturing technologies and novel facility designs for active substances and finished products – including continuous manufacturing and decentralised manufacturing-, digitalisation). The implications for the regulatory and supervisory system of the implementation of innovative quality and manufacturing technologies may also be addressed.

The QIG group may contribute to the preparation, review and/or update of quality position papers and guidance documents, in collaboration with the BWP, QWP and/or GMDP IWG, as well as to the training and quality-related workshops for EU quality assessors and GMP inspectors. Harmonisation of efforts within the entire EMA’s and Heads of Medicines Agencies (HMA) structures shall be enabled by the interaction with EMA’s ITF/Innovation Office/SME Office and the HMA Innovation Office. Communication with the external stakeholders (including the industry, academia and regulators) shall be supported by the creation of a dedicated set of communication platforms.


The main contributions to the consultation on the revision of the pharmaceutical legislation

March 4, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The European Commission has published the summary of the outcomes of the public consultation on the Evaluation and revision of the general pharmaceutical legislation, which closed on 21 December 2021. A total of 478 contributions were received, mostly by companies and business organisations (25.10%), non-governmental organisations (19.67%) and business associations (14.02%). At the geographical level, Germany contributed the 18.2% of feedbacks, followed by Belgium (16.7%), and France (9.2%); 12.8% of contributions came from non-EU countries.

Almost half of the respondents (48.1%) are registered in the EU Transparency Register; one third (33.1%) provided also separate position documents. The Summary Report and single contributions to the consultation are available at the Commission’s dedicated webpage.

Large companies represented the main industrial contributors (39%). Feedback from the pharmaceutical sector accounts for 28.4%, those from patient or consumer organisations 13.8%. A great part of the comments from public authorities (26 respondents in total) came from public authorities at national level (82.6%).

The main themes emerged from the answers

The Summary Report provides an outlook of the received comments from the perspective of the different categories of stakeholders.

Key topics of interest for the Industry included the decline of R&D investment and clinical trials in Europe, paralleled by the need of a more attractive regulatory framework for global investment and a facilitated access to value-added products and over-the-counter switching. Slow response rates of regulatory agencies, high administrative costs, convergence of data requirements of EMA and HTA, digitalisation of regulatory processes and optimisation of regulatory pathways for vaccines are other issues looking for solutions.

The impact of parallel trade on the security of supply, a predictable system of incentives for innovative products and unmet medical needs, a strong framework for intellectual property (IP) protection, and attention to the EU manufacturing of active pharmaceutical ingredients (APIs) were also reported.

Some of these topics were also addressed under the perspective of public authorities and healthcare payers. Comparative safety assessments, coherence with the blood, tissues and cells (BTC) legislation, affordability issues due to high prices/monopoly positions, transparency of medicinal product R&D and market launch costs, and abuse of existing incentives are other issues on the table, together with incentives for APIs manufacturing in the EU and a clear framework for medicine repurposing. On the clinical perspective, regulators ask for the inclusion of up-to-date clinical information in the Summaries of product characteristics, and for patient involvement in the definition of unmet medical needs.

The Summary Report also provides feedback on comments received by academics and research institutions, civil society organisations, citizens, healthcare professionals and other respondents. A total of six different campaigns were identified through the statistical analysis of the received answers, addressing respectively the need to update the radiopharmaceutical legislation, medicines shortages and the role of wholesale distribution, incentives for the innovative pharmaceutical industry and for generic manufacturers, access to treatments for rare diseases from the patient perspective, and the integration of microbiome science in the legislation.

EFPIA’s contribution

EFPIA, representing the innovator industry, highlighted the “significant interdependencies between the R&D policy environment and the manufacturing ecosystem downstream”. At the regulatory level, suggestions include the reinforcement of expertise-driven assessment and a more agile centralised authorisation framework, the improvement of expedited pathways framework supporting innovation, an expanded role of EMA in the assessment of drug-device/diagnostic combination products, and the replacement of the paper patient information leaflets with electronic versions.

The impact of further modifications of the EU SPC framework would need a careful assessment, while a Regulatory Data Protection (RDP) would support a better evaluation of products with lower development times, insufficiency/inadequacy of patent protection and new indications.

EFPIA also provides its vision on the sustainability of the off-patent market, including procurement practices and interchangeability of medicinal products. Actions to prevent and mitigate medicines shortages should be differentiated and coordinated at the European level, on the basis of a harmonised definition of shortage. Harmonisation should also represent a target for quality requirements at the global level, as well as for supply chain and GDPs. Other identified barriers at the manufacturing level include manufacturing site authorisations referring only to the local premises specified, full import testing, Official Medicines Control Laboratory testing for vaccines and biologics, and the revision of the Variations Regulation.

Comments from Medicines for Europe

Medicines for Europe, representing the off-patent industry, asks for a fit-for-purpose, efficient and fully digitalised regulatory framework. Among the priorities at the regulatory level are the optimisation of the Decentralised and Repeat Use Procedures. The regulatory framework should also avoid the unnecessary and unethical repetition of clinical studies, so to encourage generic and biosimilar medicines development. Global access and competition in the field of off-patent medicines should benefit of a single global development framework for multiple jurisdictions.

According to Medicines for Europe, the revision of the pharmaceutical legislation should also address the absence of rewards for manufacturers, in order to find a balance with their obligations of supply. As for IP protection, the association asks for the clarification of the Bolar exemption and the legal ban of patent linkage in all EU member states. The availability of multiple API suppliers should be encouraged through a single and efficient assessment of ASMP (Assembling Surfactants-Mucoadhesive Polymers) and API authorisations, and the separation between the regulatory dossier (regulatory assessment-subject of variations) and GMP (subject of inspection) should be introduced; a broader use of virtual inspections should also be promoted.

Other comments from industrial associations

AESGP, representing the self-care industry, considers the incentive of one added year of data protections not sufficient to reward investment in innovative switches. The burden posed by the Sunset Clause is also critical with regard to un-marketed licences, as well as extending the data exclusivity for a new indication or a switch. Stringent pharmacovigilance and post-approval change requirements are considered by AESGP unjustified or disproportionate, due to the limited gains in patient protection. The suggestion is for a risk-based approach for the submission of Risk Management Plans as a part of Market Access Authorisation, based on existing API safety info and provided there are no great differences in conditions of use. At the regulatory level, the applicant should be free to choose the procedure to authorise the product, and all procedures should perform equally and according to defined timelines. A broader definition of unmet needs would allow for more non-prescription medicines to be accessed; differences in the legal status of this type of medicines in different EU’s countries may also affect their availability to patients.

The European Healthcare Distribution Association (GIRP) addressed mainly issues related to medicines shortages. Among these are the need to strengthen the existing obligations for supply chain actors, and a better framework for the implementation of Article 81, paragraph 2 and 3 of Directive 2001/83 in member states legislation, so to place obligations on both marketing authorisation holders (MAHs) and pharmaceutical full-line wholesalers. The latter should be appropriately and continuously supplied by MAHs with the full range of products. Unjustified supply quotas based on legal and ethical grounds should be abolished.

A legal basis should be established for a EU-wide early warning system for anticipated/potential and verified/confirmed shortages for critical medicines. EU-wide harmonised categories for root causes of shortages should be implemented in the shortages databases managed by member states. GIRP also addressed access to market, suggesting pricing and reimbursement for centrally registered products should be separated from the availability of centrally registered products on national markets.

Market access has been addressed also by Affordable Medicines Europe, representing parallel distributors. The suggestion is for the Commission to develop a guidance on the launch of centrally approved products by parallel distributors in markets where the MAHs have not launched. An obligation for MAHs to supply entities launching in markets not covered by MAHs is also envisaged. To better manage withdrawals, Art 123 (2) of Directive 2001/83 should be amended, and a notification by MAHs should be made no less than 12 months before the withdrawal for commercial reasons. MAHs should also compulsory supply entities continuing marketing in markets undergoing commercial withdrawal; in this instance, guidance to member states should be provided on how to delegate pharmacovigilance tasks to another member state where pharmacovigilance data are available, so to limit technical measures aiming to reduce availability and ensure that products can still enter the market.

The Alliance of Regenerative Medicines (ARM), representing producers of advanced therapy medicinal products (ATMP), highlights the risk for Europe of loose positions in the competitive scenarios due to policy and regulatory barriers. According to ARM, all medicines falling under the ATMP definition should undergo the same regulatory requirements. A mandatory centralized procedure of authorisation should be maintained, in order to provide the level of expertise needed for the assessment of these complex products. GMP and pharmacovigilance aspects should be also coordinated at EU level. Bedside manufacturing models or other schemes should be avoided in order to prevent a two-tiered regulatory framework for ATMPs, leading to different quality and safety standards. Hospital Exemption (HE) should also be strictly regulated and harmonised across member states, with application only to individual patients on a case-by-case basis. Accelerated market approval procedures are expected to maintain rigorous regulatory requirements and high-quality standards for ATMPs. A pan-EU infrastructure and standards for collecting, storing and using ATMP-related real-world data, also for regulatory decision-making, is supported. The association asks for changes to the regulatory requirements for medicines containing genetically modified organisms (GMOs). Implementation of the EU cross-border healthcare legislation would support the administration of ATMPs to patients; HTA should be also coordinated at the EU-level.

Obligations accompanying any novel incentives should carefully take into considerations differences compared to traditional pharmaceuticals, as well as withdrawals due to market failures. A new business model is also recommended by ARM to address the shift in cost from chronic to one-time treatment. No modification of the current definition of ATMP to differentiate with respect to BTC products would be needed.

The position of community pharmacists

The Pharmaceutical Group of the European Union (PGEU) also contributed to the consultation with a position paper, providing the perspective of community pharmacists. The document suggests that issues of medicine shortages and patients’ access would require a “bold, ambitious, and coordinated actions at all policy levels”. According to PGEU, the revision of the pharmaceutical legislation should take the form of a new Directive, so to better respect the existing social, cultural and economic differences between European countries, which are reflected in the organisation of their healthcare systems.

An expanded role for EMA in the prevention and management of shortages, in coordination with the HMA, and the availability of a centralised EU monitoring system for (anticipated) shortages of all medicines in the EU would support the improved availability and access for patients. PGEU also asks for a better transparency and timely communication on shortages to affected stakeholders, as community pharmacists are deeply impacted; clarification of European and national laws related to the public service obligations of supply chain actors would also help to improve compliance.

A more effective redistribution mechanism for medicines available on the European market, irrespective of the country of residence of the patient, would help to face health crises and other special circumstances (i.e. the Brexit and its impact on medicines supply in Malta, Ireland and Cyprus). PGEU also suggests that pharmaceutical companies asking for a centralised marketing authorisation for their products should then commercialise them in all member states. Unmet needs of small patient populations may find an answer in pharmaceutical compounding by community and hospital pharmacists; this practice may also help to face shortages in cases where no suitable alternatives are available.

On their regulatory perspective, PGEU suggests that electronic Product Information (ePI) should complement, and not completely replace, printed leaflets. Digitalisation is deemed important also with respect to the exploitation of real-world data for regulatory decision making and Health Technology Assessment. To this instance, the association suggests to consider a rewarding for evidence generation in community pharmacies at the national level, so to better intercept data useful to evaluate the effectiveness, safety, off-label use and therapeutic added value of medicines in practice. According to PGEU, pharmacy organisations should also be better involved in integrated medicines development and post-authorisation activities, in coordination with other actors.

Repurposing of off-patent medicines should be targeted to areas where important public health benefits are likely to be achieved, but attention should be paid not to limit patients access to these medicines for the currently authorised indications. The association of community pharmacists also supports the reshoring of pharmaceutical manufacturing in the EU (e.g. active ingredients, excipients and basic chemical compounds particularly critical in terms of supply), a goal to improve European competitiveness and reduce the direct dependence from extra-EU countries. An improved diversification of the medicines supply chain is also envisaged.

Environmental issues should be tackled by the availability of innovative incentive and business models for the development of new antimicrobials and antibiotics, and a full compliance with environmental quality standards for pharmaceuticals. A coordinated approach among member states to the evaluation of cost-effectiveness and added therapeutic value of new therapies, including HTA, would support the affordability and fiscal sustainability of medicines. According to PGEU, pricing decisions in one country should not negatively impact on patient access in other countries. Cost-effective pharmaceutical care services at national level should be promoted as a mean to support the rational use of medicines through the adequate remuneration.


First steps of the HERA Authority and comments from industrial and medical associations

October 22, 2021 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The new European Health Emergency preparedness and Response Authority (HERA) has started its operative phase. Initially launched in February 2021, HERA has been modelled by the European Commission on the example of the US’s DARPA agency, and it will be in charge of anticipating threats and potential health crises.

The first three calls for tender to support HERA’s setup have been published on the Commission’s website and will remain open until 29 October 2021. They are targeted towards addressing different aspects of the management of Covid-19 therapeutics and antimicrobial resistance.

A total sum of €7 million from the EU4Health programme will fund these activities. An info session on the three calls was delivered on 14 October 2021 by European Health and Digital Executive Agency (HaDEA) in collaboration with DG Santé (see more at this link). A summary of HERA’s activities in the field of crisis preparedness and emergency response is also available here. A budget of €6 billion from the current Multiannual Financial Framework 2022-2027 is available to fund HERA’s setup and activities, plus additional support from other EU programmes, for a total of almost €30 billion. HERA will be part of the internal Commission structure, and it is expected to become fully operational in early 2022.

“HERA’s role is to improve the EU’s development, manufacturing, procurement and distribution of key medical countermeasures – said the Commissioner for Health, Stella Kyriakides, following the recent Informal Meeting of Health Ministers in Ljubljana, Slovenia -. HERA will also be crucial in ensuring accessibility and availability of medicines. As I said to Ministers today, HERA is a joint undertaking, with Member States, EU Agencies, the European Parliament and other concerned stakeholders, including industry and civil society. HERA’s strength and success will come from our joint preparedness and joint response, and our capacity to bringing joint solutions. HERA is now operational and should be fully up and running early next year.”

HERA’s first activities

The call for tender on antimicrobial resistancerefers to a service contract to run a study comprehensive of a technological review of the latest AMR medical-countermeasures (e.g.; medicines, medical devices, vaccines) and a gap analysis and assessment of needs amongst the EU Member States and key stakeholders. The study shall also include options for possible actions, funding and provision of support mechanisms, and exploration of available tools suitable to ensure the availability of safe and effective products in the European market. These products are expected to be immediately available to the EU and member states in the event of a public health emergency. The estimated total value of the tender is €1 million.

Stockpiling of medical countermeasures in the area of AMR is the subject of the second feasibility study (estimated total value €1 million). The study shall analyse physical stockpiling solutions compared to other options, providing identification and assessment of all available opportunities. The needs and availability of AMR countermeasures shall be also assessing, both at member states and EU level, as well as the mapping of relevant stockpiling systems currently operated at EU and/or global level (e.g. WHO). Possible funding mechanisms (including procurement options), identification and assessment of operational deployment mechanisms and considerations on liability and regulatory aspects and/or constraints are also to be included in the study.

The third feasibility study has the higher estimated total value (€5 million) and will focus on the design and prototype development for a mapping platform on Covid-19 therapeutics in the EU. The platform is expected to map the production capacity and supply of products intended to treat Covid-19, both already on the market and in R&D phases. Possible examples include ICU medicines, heparin, dexamethasone and antibiotics, in vitro diagnostics devices and/or companion diagnostics.

Comments from stakeholders

Many stakeholders released their comments to welcome the creation of the new Authority.

“The creation of HERA is a first step to putting Europe on the front foot in addressing global health threats.”, said EFPIA Director General, Nathalie Moll. “The speed at which Europe became the epicentre of the Covid-19 crisis meant, as a region, we were simply reacting to issues as they arose, working together to find solutions as quickly as possible”.

The lessons learnt during the pandemic revealed a number of weaknesses in Europe’s ability to respond to a public health crisis. HERA’s ability to balance coordination and unity with agility and responsiveness as threats emerge shall be central to its success, according to EFPIA. The Federation, together with Vaccines Europe, supports an end-to-end approach to govern HERA’s activities, and a collaborative, partnership-based model to maximise the strength of each stakeholder in a highly coordinated approach.

The association representing the generic and biosimilar industry, Medicines for Europe, wrote in a note that HERA should “be an efficient agency with strong links to healthcare industries”. A joint industrial cooperation forum to coordinate interactions of manufacturing associations and EU authorities, a regulatory framework able to prioritise the supply of essential medicines and the elimination of the proposal for redundant manufacturing capacity are just some suggestions made by the Association, which is more favourable towards manufacturing investment in a wide range of medicine production types, as outlined in the Structured Dialogue.

Reserve policies should be also revised in order to avoid waste, costly destruction, and distorting supplies of medicines to certain (smaller) EU countries. The functioning of joint procurement system should be also addressed and improved by the Commission, to avoid distortions in the internal market and provide accurate demand estimates.

The Federation of the European Academies of Medicine (FEAM) published in May 2021 a report jointly prepared with the Wellcome Trust, highlighting the opportunity in the short term not to overstep HERA’s role in relation to others European authorities (e.g. the European Centre for Disease Prevention and Control) as a pre-requirement to ensure its success.

The new-born Authority should also try to harmonise the European research and development landscape for pandemic preparedness and response, in order to remain “relevant and active between emergencies”.


Consultation on the reform of the European pharmaceutical legislation

October 15, 2021 , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

A new step in the review of the overall framework governing the pharmaceutical sector has been announced by the European Commission on September 28th: the launch of a first phase of public consultation will enable to collect opinions from all the stakeholders of the pharmaceutical sector as a pre-requisite for the revision of the existing general pharmaceutical legislation on medicines for human use.

The initiative builds on the previous public consultation which represented the basis for the drafting of the Pharmaceutical Strategy for Europe released by the Commission in November 2020. The final target is the creation of a future-proof and crisis-resilient regulatory framework for the pharmaceutical sector. The pharmaceutical industry represents one of the main contributors to the European economy, with 800.000 direct jobs and €109.4 billion trade surplus in 2019, and €37 billion contribution to research investment.

“Today we take an important step for the reform of EU’s pharmaceutical legislation by the end of next year. A regulatory framework for pharmaceuticals, which is modernised and fit for purpose, is a key element of a strong European Health Union and crucial to addressing the many challenges this sector is facing. I call on all interested citizens and stakeholders to help us shape EU rules for the future, responding to patients’ needs and keeping our industry innovative and globally.”, said the Commissioner for Health and Food Safety, Stella Kyriakides.

Details of the consultation

The consultation is open until 21 December 2021 and is published in the form of an online questionnaire to be filled in by stakeholders and members of the general public, including patients and patient’s organisations, pharmacists and doctors, associations active in public health, healthcare professionals and providers, academia, researchers, regulators, EU’s institutions and the pharmaceutical industry. A combined evaluation roadmap/Inception Impact Assessment published in April 2021 is also available at the consultation’s webpage, together with a document on the consultation strategy (link).

The main issues touched by the consultation include all the 4 pillars of the Pharmaceutical Strategy, for each of which both legislative and non-legislative actions are envisaged.

A main area of interest looks to address unmet medical needs and ensure access to affordable medicines for patients, namely in the areas of antimicrobial resistance and rare diseases. The commitment to respond to environmental challenges is another key point of attention. New incentives for innovation and future-proofing the regulatory framework for novel products shall support the availability of next-generation therapeutics for European citizens and the competitiveness of the European markets. Quality and manufacturing of medicines, and the repurposing of older products are other topics looking for innovative approaches to be defined within the revision of the pharmaceutical legislation.

The Covid pandemia showed the importance to developed measures to enhance crisis preparedness and response mechanisms in all European countries, and to ensure diversified and secure supply chains are in place to reduce dependency of supply from extra-EU countries. A stronger EU voice on the theme of medicines shortages shall be also pursued by promoting a high level of quality, efficacy and safety standards.

The consultation aims to better understanding of all implications of the possible policy options, and to provide evidence to the Commission on the functioning and delivery of the current legislation with respect to its initial objectives. The impact of new potential options on the different stakeholders shall be also assessed. The exercise aims to identify areas of broad agreement among stakeholders as well as differences of views on other topics, and the causes of contention.

A brief overview of the legislative process

The revision of the pharmaceutical legislation is just one of the many legislative actions undertaken by the von der Leyen Commission in order to completely innovate the reference framework for medicines’ development, production, authorisation, commercialisation and postmarketing monitoring. The last revision of the pharmaceutical legislation occurred almost 20 years ago.

The Pharmaceutical Strategy defines the general targets, to be then synergistically implemented by mean of actions specific to the different fields. The revision of the general pharmaceutical legislation is one of the main flagship initiatives towards this target, and it is also being supported by an ongoing study run by an external contractor and expected to close in Q1 2022.

Among other actions which shall contribute to the goals of the Strategy are the proposal of the new regulation on Health Technology Assessment, the EU Health Data Space, the revision of the current legislation on rare diseases and paediatric medicines and actions to address shortage of medicines in the EU’s market.


Medical Cannabis in Europe

September 24, 2021 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

Business based on medicinal products containing cannabis-derived substances has greatly developed in Europe in recent years, due to the many beneficial pharmacological properties offered by the plant Cannabis sativa. The global medical cannabis market is rapidly expanding (36% compound annual growth rate/CAGR 2017-2024), with Germany as the leading country (49,5% CAGR).

The medical use of cannabis in Europe refers to the EU Parliament’s resolution 2018/2775 of 13 February 2019, aimed to clearly and unambiguously distinguish between “medical cannabis” and “cannabis-based medicines”. The second ones have undergone clinical trials as all medicinal products and have been assessed by competent regulatory authorities to achieve approval. Only cannabis-based medicinal products should be considered for a safe and controlled medical use, suggests the Parliament resolution.

According to an article by Lipnik-Štangelj and Razinger (Arh Hig Rada Toksikol 2020;71:12-18), just one medicine characterised by a 10% concentration of cannabidiol (CBD, one of the main active components of cannabis) was centrally approved in 2019 by EMA for the therapy of intractable childhood epilepsy. Other medicinal products containing other types of cannabinoids have received approval through mutual recognition procedure or at the national level.

EU’s member states have not yet adopted a uniform approach on how to regulate the cultivation, manufacturing and use of medical cannabis; there is also a lack of uniform indications as for the modalities and contents of the labelling of cannabis-derived medicinal products. An extensive discussion of different legislative and regulatory frameworks relevant to the medical use of cannabis and cannabinoids have been addressed by a report published in 2018 by the European Monitoring Centre for Drugs and Drug Addiction.

The German approach

One of the first European countries to invest in medical cannabis has been Germany, where cultivation is allowed exclusively for medical purposes. A targeted Cannabis Agency (Cannabisagentur) was created in 2017 as a part of the local regulatory agency German Federal Institute for Drugs and Medical Devices (BfArM), in parallel with the coming into force of the Cannabis as Medicine Act.

The Agency has selected by a tender procedure three companies allowed to cultivate cannabis in Germany (Aphria RX GmbH, Aurora Produktions GmbH and Demecan GmbH), for a total production of approx. 2600 kg per year. BfArM started in July 2021 the state sale of medical cannabis from German cultivation, maintaining also open the possibility to import the plant for medical use.

The characteristics of the standardised cannabis extracts are described in a dedicated monograph of the German Pharmacopeia; the cultivation of the plant and the manufacturing of medical cannabis, which is a prescription drug, is also subject to the German narcotics law regulations (BtMG), to Good Agricultural and Collection Practices (GACP) and to Good Manufacturing Practices (GMP). German pharmacies can buy medical cannabis directly from the dedicated portal of the Cannabis Agency; a GMP/GDP-certified company is in charg of distribution. The price established by BfArM for pharmacies is 4,30 €/g.

The case in Greece

Greece also approved in 2018 a specific legislation on cannabis for medical use (Law 4523/2018, amending Law 4139/2013), providing the full reference framework for the cultivation, manufacturing, regulatory approval and distribution of cannabis-based medicinal products.

According to data by the Greek Ministries of Development and Investments and Rural Development and Food published in April 2020 by the Medical Cannabis Network, estimates of investments in the sector are reaching €1,68 billion and more than 8.000 employees.

The government aims to improve the attractiveness of Greece for cannabis cultivation and instalment of manufacturing plants – thanks to the favourable climatological and working conditions – as a way to support the expansion of the national economy. To this regard, possible competitors are Portugal, Malta or Cyprus, all countries characterised by similar favourable conditions.

Greece currently allows for the cultivation of cannabis with a THC content not exceeding 0,2%. A new law has passed in the Greek Parliament to regulate the production, export and distribution of final medical cannabis products with a THC content of more than 0,2%.

The new law is expected to create a special framework for cannabis businesses based in Greece and devoted to export only; their activities may be also subject to laws, regulations and GMP/GDP guidelines of the importing country.

Companies interested in establishing this sort of productions currently need to fulfil a wide set of conditions in order to receive permits for cultivation and authorisation by the Greek National Organisation for Medicines (EOF) to produce and market their products, which are classified as medicines. Criteria for authorisation are listed in the joint Ministerial Decision released in connection to the 2018 Law. The issuing of the permit by Greek authorities usually needs about three months time.

The common licence level allows for the initial establishment of a new manufacturing facility; the majority of companies which applied so far have received this type of licence (57/100). The second level of the licence refers to the authorisation to operation.

According to the experts interviewed by Medical Cannabis Network, current issues still to be solved include “establishing a clear definition of the type of greenhouses needed for a particular crop and the specific type of finished medicinal products that will eventually be allowed to circulate commercially”.

Malta, the QP for cannabis medicine production needs to be a pharmacist

Malta has issued in 2018 the Production of Cannabis for Medicinal and Research Purposes Act, the law governing the sector of medical cannabis for prescription.

The document provides detailed information on Quality & Stability of cannabis-based medical products (Appendix I), Security & Transportation (Appendix II) and Cultivation, Harvesting & Packaging (Appendix III).

Malta’s Medicines Authority is responsible for the evaluation of the technical and scientific documentation submitted by the applying companies, and for the issuing of the authorisations for import and wholesale distribution of cannabis-based products for medicinal use. Only finished products are allowed, they must also comply to the relevant legislation of the destination country.

The Maltese framework for the production of medical cannabis is characterised by the fact the Qualified Person (QP) responsible for the manufacturing plant has to be engaged by the license holder and must be a pharmacist registered with the Maltese Pharmacy Council and resident in Malta. This provision differs from the requirements outlined in Directive 2001/83/EC governing the manufacture and import of medicinal products for human use, transposed into the local Medicines Act and subsidiary legislation, where many other types of degrees (Pharmacy, Medicine, Veterinary, Chemistry, Pharmaceutical Chemistry and Technology, or Biology) are also considered.

Medical cannabis products licensed under the Medicines Act (Chapter 458 of the Laws of Malta) or manufactured under GMP can be sourced by licensed importers or wholesale distributors, provided the possession of the necessary approvals and permits. A Letter of Intent (LOI) from a Malta Enterprise is also needed to run operations related to medicinal cannabis production, analysis and research. The local regulatory agency can run inspections of the manufacturing facilities to verify their compliance to GxP; EU-GMP certification is needed prior to the starting of the manufacturing activities.

Research activities on medical cannabis is also supported through the Advanced Scientific Initiatives Directorate, in particular in the case of established organisations for scientific collaboration.

A pool of beneficial active ingredients

The plant Cannabis sativa contains a very rich pool of more than 480 compounds, among which are more than 100 cannabinoids. D9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main cannabinoid substances present in cannabis, the first one representing the main psychoactive and addictive constituent of the plant. On the other hand, CBD has no intoxicating or addictive properties. Many other cannabinoids possess an interesting pharmacological and therapeutic profile, and have been studied for possible use as neuroprotective agents (e.g. in case of anxiety disorders, depression, post-traumatic stress disorder), and for their effects as anti-emetics or on chronic pain (e.g. in cancer disease), inflammation, bacterial infections, etc.