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The EU Parliament voted its position on the Unitary SPC


by Giuliana Miglierini The intersecting pathways of revision of the pharmaceutical and intellectual property legislations recently marked the adoption of the EU Parliament’s position on the new unitary Supplementary Protection Certificate (SPC) system, parallel to the recast of the current Read more

Reform of pharma legislation: the debate on regulatory data protection


by Giuliana Miglierini As the definition of the final contents of many new pieces of the overall revision of the pharmaceutical legislation is approaching, many voices commented the possible impact the new scheme for regulatory data protection (RDP) may have Read more

Environmental sustainability: the EIPG perspective


Piero Iamartino Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the Read more

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The first Union list of critical medicines

December 21, 2023 , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The first version of the Union list of critical medicines was published on 12 December 2023 by the European Commission, the European Medicines Agency (EMA) and the Heads of medicines Agencies (HMA).

The initiative is part of the actions planned according to the Pharmaceutical Strategy and the Communication on addressing medicine shortages in the EU. A Q&As documentwas also published to illustrate the main features of the list, together with the methodology to identify critical medicinesto be included in the list (see the dedicated webpage of EMA’s website). The first version of the Union list of critical medicines is comprehensive of approx. 200 active substances, selected starting from a pool of more than 600 referred to in the national lists of critical medicines of Finland, France, Germany, Portugal, Spain, and Sweden. These six countries were chosen as their lists were based on criteria aligned with those agreed for the Union list. The process also comprised consultations of key stakeholders, including patients and healthcare professionals’ organisations and industry associations.

The list will be updated annually, and further references will be added in 2024. The final list will also include the separate assessment of the vulnerability of the supply chains to be run by the European Commission.

The Union list will not replace existing national lists of critical medicines, that will continue to support national policy decisions. EU member states may also use the Union list to create their own national lists, if not yet available.

“Ensuring an uninterrupted supply of critical medicines is essential for a strong European Health Union. With the publication of the first Union list of critical medicines today, we are delivering on our promise to accelerate work in this area and to take every possible measure to avert the risk of shortages for our citizens”, said Stella Kyriakides, Commissioner for Health and Food Safety.

A list to prevent shortages

The Union list of critical medicines represents a warning about the importance of avoiding shortages for specific medicines, as they would highly impact both patients and healthcare systems. No immediate effect is expected on shortages, but the risk might decrease in the longer term.

The Union list specifies human medicines (both innovators and generics, vaccines, and medicines for rare diseases) those continued supply is considered a priority in the EU. It will be used by the EU Commission, EMA and HMA for the definition of proactive measures to strengthen the supply chain and minimise the risk of supply disruptions (see more on EMA’s webpage on Availability of critical medicines).

The Union list of critical medicines will also serve as the basis for the Commission to run the analysis of vulnerabilities, followed by recommendation of suitable measures in consultation with the Critical Medicines Alliance (we wrote about this part 1 and part 2). The Commission may issue recommendations for companies to diversify suppliers or increase production within the EU. Incentives to invest may also be used to favour the resilience of European manufacturing. As for procurement, strong contractual obligations for delivery may apply.

Medicines included in the Union list will also be prioritised for actions by the European medicines regulatory network, in charge of monitoring their availability and implementing measures to minimise the risk of supply disruptions. To this instance, existing processes and structures will be used as defined in the mandate of EMA’s Medicine Shortages Single Point of Contact (SPOC) Working Party and EMA’s Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG).

No additional obligations have been introduced by now for marketing authorisation holders and national competent authorities. This will be a topic of discussions during the final phase of negotiations on the proposed revision of the EU pharmaceutical legislation.

The methodology to select critical medicines

The therapeutic indication and the availability of alternative medicines are the two main criteria for the insertion of a certain medicinal product in the Union list of critical medicines. Additionally, it has to be classified as critical in at least one-third (33%) of EU/EEA (European Eco-nomic Area) member states.

National lists of critical medicines may differ from one another, reflecting differences of the internal evaluation criteria used to assess criticality. For example, some products are marketed just in some countries, or alternatives are available in some countries and not in others. Furthermore, the Union list is still incomplete, as some important medicines have not yet been assessed at the central level. The Union list does not include as well products mentioned in the WHO list of essential medicines. Orphan medicines are included in the Union list if they meet the above-mentioned assessment criteria.

The document on methodology further clarifies the governance of the process and the matrix for identifying medicines to be included in the Union list of critical medicines. The methodology was created starting in 2021 (European Commission Structured Dialogue initiative), finalised by the HMA/EMA Task Force on the availability of authorised medicines for human and veterinary use (HMA/EMA TF-AAM), and finally adopted in June 2023.

The medicinal product criticality is evaluated on the basis of a risk assessment. As for therapeutic indications (criterion 1), all authorised medicines in a member state should be classified, irrespective of their marketing status. Criterion 2 refers to the availability of alternatives, and only authorised medicines marketed in the respective member state should be classified.

A low, medium or high-risk level is assigned for each of the two above-mentioned criteria, thus resulting in a risk matrix. The exercise allows to assign the medicine in one of the following categories: critical medicines, medicines at risk, other medicines.

Medicines considered at high risk with respect to their therapeutic indication refers to products those use may have very serious implications for the health of individual patients or public health (general life-threatening acute conditions, specific life-threatening acute conditions, or irreversibly progressive conditions). Evaluation parameters include the fact the disease is potentially fatal, irreversibly progressive or, if left untreated, will pose an immediate threat to the patients. Furthermore, the treatment must be administered immediately or within regular dosing intervals, and the product has to be part of a national disease control program.

Appropriate alternatives are identified according to the fact they are authorised for the same therapeutic indication and are available on the market in the respective member state. Furthermore, alternative treatment has to be clinically possible, without negative impact on the patient’s health and providing the same quality of care standard. As for criterion 2, high risk cri-tical medicines refer to products for which no appropriate alternative is available, or only one appropriate alternative (product) on ATC level 4 or 5 (same active substance or alternative is within the same ATC level 4 group or in another ATC level 4 group) is available.

Public consultation for the review of HERA

We inform all interested EIPG’s members that the public consultation for the review of the Health Emergency Preparedness and Response Authority (HERA) is open until 19 February 2024 and it can be accessed through the dedicated webpage of the EU Commission website.

The consultations aim to assess how HERA’s mandate and tools contributed to achieve EU’s political objectives, and how the Authority complements the work of other EU bodies and responds to the current health challenges.


ACT EU’s Workplan 2022-2026

September 16, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The implementation phase of the Accelerating Clinical Trials in the EU (ACT EU) initiative, launched in January 2022 by the European Commission, started with the publication of the2022-2026 Workplan jointly drafted by the Commission, the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA).

The final target is to renew how clinical trials are designed and managed, so to improve the attractiveness of Europe for clinical research and the integration of results in the current practice of the European health system.

The 2022-2026 Workplan details the actions and deliverables planned according to the ten priorities identified by ACT EU. The drafting of the document took as primary reference also the recommendations of the European Medicines Regulatory Network (EMRN) strategy to 2025 and the European Commission’s Pharmaceutical Strategy for Europe.

Steps towards the full implementation of the CTR

The first priority of action should see the completion by the end of 2022 of the mapping of already existing initiatives within the EMRN and ethics infrastructure. This exercise represents a fundamental step to achieve a detailed picture of the current clinical trials regulatory landscape, characterised by the presence of various expert groups working in different areas.

The results of the mapping will form the basis to plan and implement a new strategy for the governance of the entire framework governing clinical trials, including the clarification of roles and responsibilities to the Network and its stakeholders. The expected outcome is the rationalisation and better coordination of the work done by different expert groups and working parties, as reflected by a new regulatory network responsibility assignment (RACI) matrix. The analysis and setting up of the new framework should start from the core governance bodies (Clinical Trials Coordination and Advisory Group (CTAG), Clinical Trials Coordination Group (CTCG), Commission Expert Group on Clinical Trials (CTEG) and Good Clinical Practice Inspectors Working Group (GCP IWG)), to then extend to other parts of the Network further.

The full implementation of the Clinical Trials regulation (Reg. (EU) 536/2014) by mean of the launch of monthly KPIs tracking of the planned activities is another key action. A survey to identify issues for sponsors and the consequent implementation of a process to prioritise and solve them are planned for the second half of 2022. The beginning of 2023 should see the launch of a scheme to better support large multinational clinical trials, particularly those run in the academic setting. One year later, at the beginning of 2024, a one-stop shop to support academic sponsors should also be launched.

An important action for the success of ACT EU should see the creation of a multi-stakeholder platform (MSP) to enable the interaction and regular dialogue of the many different stakeholders working in the field of clinical trials under different perspectives, both at the European and member state level. The platform should be launched by Q2 2023, with the first events run under its umbrella planned for Q3 and is expected to help in the identification of key advances in clinical trial methods, technology, and science.

Methodological updates in clinical trials

Another key step in the renewal of the European framework for clinical trials is linked to the updating of the ICH E6(R2) guideline on “Good Clinical Practice” (GCP). A targeted multi-stakeholder workshop on this theme is planned for Q1 2023, while the resulting changes should be implemented in EU guidance documents by Q3 2023. New GCPs should take into better consideration the emerging designs for clinical trials and the availability of new sources for data and are expected to “provide flexibility when appropriate to facilitate the use of technological innovations in clinical trials”. This action also includes the development of a communication and change management strategy to support the transition to the revised GCP guideline, and the updating of other relevant EU guidelines impacted by the change.

The opportunity to introduce innovative clinical trial designs and methodologies shall be addressed starting from decentralised clinical trials (DCT), with the publication of a DCT recommendation paper by the end of 2022. A workshop on complex clinical trials should be also organized to discuss issues linked to study design, such us umbrella trials and basket trials or master protocols. New technologies may support innovative approaches to the recruitment of eligible study participants and new ways to capture data during clinical trials. The publication of key methodologies guidance is an expected deliverable, together with a improved link between innovation and scientific advice.

A new EU clinical trials data analytics strategy is expected to be published by the end of 2022, while the first half of next year should see the development of a publicly accessible EU clinical trials dashboard and a workshop to identify topics of common interest for researchers, policy makers, and funders. These activities are targeted to fully exploit the opportunities offered by data analytics, so to identify complex trends from the large base of data about clinical trials collected by the EMRN. The existence of multiple data sources is a main barrier currently affecting the possibility to access, process and interpret these data.

Another priority is to plan and launch a targeted communication campaign to engage all enablers of clinical trials, including data protection experts, academia, SMEs, funders, Health Technology Assessment (HTA) bodies and healthcare professionals. Up to 2024, this action will also support sponsors in remembering the importance of training linked to the application of the CTR and the mandatory use of the Clinical Trials Information System (CTIS). All other communication needs across all priority actions will also be handled under this action.

Scientific advice, safety monitoring and harmonised training

The current framework sees the involvement of different actors who interact with sponsors at different stages of product development to provide them with scientific advice. A simplification of the overall process should be pursued by grouping of key actors in clinical trials scientific advice in the EU, “with the aim of critically analysing the existing landscape in line with stakeholder needs”. The Workplan indicates several pilot phases should be run to identify the better way to address this topic, which should benefit especially academic or SMEs sponsors that may have less experience of regulatory processes. Planned activities include a enhanced intra-network information exchange, the running of a survey among stakeholders and the operation of a first pilot phase by Q4 2024, to then optimise and expand the advice process upon results.

The establishment of clinical trial safety monitoring is another central theme of action, that should see member states involved in a coordinated work-sharing assessment. Key activities should include the identification of safe CT KPIs by the end of 2022 and a review of IT functionalities for safety, and it will be run in strict connection with the EU4Health Joint Action Safety Assessment Cooperation and Facilitated Conduct of Clinical Trials (SAFE CT). Training of safety assessors and the development of a harmonised curriculum thereof shall be also considered, as well as the alignment of safety procedures for emerging safety issues potentially impacting clinical trials.

The development of a training curriculum informed by regulatory experience should support the creation of a renewed educational ‘ecosystem’ characterised by bidirectional exchanges to enable training on clinical trials. This action is target mainly to better engage universities and SMEs, and it should include also training provided by actors other than the regulatory network.


The European Medicines Regulatory Network Data Standardisation Strategy

January 28, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The availability of interoperable data is a “must” to ensure the smooth sharing, use and re-use of data along the entire regulatory process. A new document – the European Medicines Regulatory Network Data Standardisation Strategy – has been issued by the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) to provide guidance to all authorities members of the European Medicines Regulatory Network (EMRN) on how to approach issues related to the definition, adoption and implementation of international data standards.

As data contains the higher informative value, regulatory procedures are undergoing a phase of deep rethinking in order to pay greater attention to the underlying data, leaving behind the traditional assessment of regulatory documents prepared using those data. Furthermore, the secondary use of data may support optimised regulatory decision-making processes.

The EMRN Data Standardisation Strategy – one of the main deliverables of the HMA-EMA Joint Big Data Steering Group (BDSG) workplan – builds upon the EU Data Strategy and the goals of the EMRN Strategy 2025. The FAIR principles (Findable, Accessible, Interoperable and Reusable) have been identified to govern the acquisition, conservation and use of data.

A more standardised approach to be adopted by the EMRN shall make possible to reduce the current manual and technical workload needed to manage regulatory documents and data, which are often submitted using a variety of different formats. According to the Strategy, a review of the mechanisms of data governance is also needed to include the responsibilities for oversight of data standardisation work and for the periodic updating of the EMRN data strategy. Further assessment of the expected costs and benefits is needed to make available the final roadmap for the implementation and prioritisation of measures suggested by the Data Standardisation Strategy.

Adopt, adapt, develop

The document was drafted on the basis of initial internal consultations on current practices for the management of scientific data; the inventory of the current IT systems in use by members of the EMRN was also created. In a second phase, a public survey was conducted among all stakeholders; current and new standards under development were identified by analysis of a selection of Standards Development Organisations (SDOs) active in the healthcare sector.

The exercise led to the identification of three different categories of actions, respectively referred to the adoption by the EMRN of currently available standards, the adaptation of available standards to include additional requirements, and the development of entirely new standards.

A total of eight principles have been identified to guide the standardisation of data to be used for regulatory purposes. First of all, high-quality data standards developed by accredited SDOs should always be adopted, on the basis of voluntary and consensus-based processes. EMA-HMA’s suggestion is to use such standards in place of (unique) local or proprietary standards, unless not compatible with the EU legislation or otherwise impractical. This would also support the creation of the European Health Data Space (part of the EU digital strategy) and facilitate the sharing and re-use of data and the governance of data privacy according to the draft EU Data Governance Act. The principles of data protection and data ethics by design are another fundamental requirement, as well as the collaboration with stakeholders in order to be informed about their needs. An alignment and consolidation of requirements from other regulations and guidelines is also envisaged; assessment of requirements for both human and veterinary regulatory practices should be run in order to avoid duplication of efforts or creation of competing standards.

Four domains for the management of data

The EMRN Data Standardisation Strategy identifies four different domains for the adoption of common standards: Medicinal Product, Healthcare & study data, Safety & risk management and Submissions. Recommendations for each of the four domains are discussed in the document.

The Medicinal Product domain includes product information, substance information, manufacturing and quality information.

Standards such as the ISO IDMP (IDentification of Medicinal Products) – based on the HL7 FHIR (Fast Healthcare Interoperability Resources) standard – are already in place, for example, to feed EMA’s SPOR system, but additional FHIR resources would be needed to structure key product information in already existing projects. To this regard, the Strategy suggests to implement and adapt ISO IDMP specified substance group levels 2 and 4 by the associated HL7 FHIR message exchange format, so to capture active substances and excipients in a structured format. This approach would also better support inspections (together with the availability of a standardised template for all inspections data), traceability of the origin of all substances used to manufacture a certain medicinal product, and the adoption of risk-based tracking procedures to assess the interactions between product quality and inspections of manufacturing sites.

The Healthcare and study data domain refers to data acquired during clinical development (i.e. data from interventional and/or observational studies) and the development of a common data model (CDM) for individual patient data and mobile health (mHealth) devices.

Many projects are already active, e.g. the ICH M11: Clinical electronic Structured Harmonised Protocol (CeSHarP), an initiative that would need further tuning to include some additional requirements. The possible use of raw data from interventional studies is also under assessment (e.g. CDISC SDTM – Study Data Tabulation Model, and ADaM-Analysis Data Model).

A new CDM standard would also be needed to exploit the full and harmonised potential of real-world data (RWD) and metadata obtained from healthcare records and disease registries. To this instance, a particular attention should be paid to mHealth applications installed on personal smart-devices, a fast-growing segment giving rise to the availability to big quantities of data.

The Safety and risk management domain refers to pharmacovigilance activities and includes Individual case safety reports (ICSR), Product safety update reports (PSUR), and environmental risk assessment (ERA) and risk management plans (RMP).

ICSR might be optimised by adoption of the HL7 FHIR based messaging standard and the inclusion of -omics data (genomics, proteomics and metabolomics) of patients. According to the Strategy, a new structured, electronic format for PSURs built upon the ICH E2C (R2) periodic benefit- risk evaluation report guidelines would be also beneficial for the work of regulatory authorities. The CDISC SDTM8 standard for data collection of risk assessment data represents a possible option to better handle data referred to environmental risk assessments. A structured, electronic risk management plan (eRMP) format should be also created to overcome the current paper template format; the new standard may find inspiration in the ICH E2E Pharmacovigilance Planning guideline and the EU Guideline on good pharmacovigilance practices (GVP) Module V – Risk management systems.

The Submissions domain includes the dossier management and the structured application form. Version 4.0 of the electronic Common Technical Document (eCTD v4.0) is more flexible compared to the previous one; for example, it supports the re-use of Pdf documents across sequences and eCTD dossiers and the submission of other data formats within the dossiers. The wider use of structured data will make the use of Pdf files less common, in favour of electronic Application Forms (eAF) based on data exchange standards such as HL7 FHIR to manage regulatory application along the entire life cycle of a medicine.