scientific advice Archives - European Industrial Pharmacists Group (EIPG)

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

How AI is Changing the Pharma Industry and the Industrial Pharmacist's Role


Svala Anni, Favard Théo, O´Grady David The pharmaceutical sector is experiencing a major transformation, propelled by groundbreaking drug discoveries and advanced technology. As development costs in the pharmaceutical industry exceed $100 billion in the U.S. in 2022, there is a Read more

Generative AI in drug development


by Giuliana Miglierini Generative AI is perhaps the more advanced form of artificial intelligence available today, as it is able to create new contents (texts, images, audio, video, objects, etc) based on data used to train it. Applications of generative Read more

EMA’s pilot scheme for academic and non-profit development of ATMPs

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by Giuliana Miglierini

Advanced therapy medicinal products (ATMPs) are often developed by academic and non-profit organisations, because of their high level expertise in the biotechnological techniques that underpin many new therapeutic approaches. On the other hand, these organisations often lack sufficient understanding and experience to face the complexity of the regulatory development.

To improve the possibility for non-commercial developers to access regulatory and scientific support related to promising ATMPs addressing unmet medical needs, a pilot was launched by EMA in September 2022. Three projects have been already selected to participate to the pilot. ARI-0001, a chimeric antigen receptor (CAR) product based on patients’ own T-cells, developed by the Hospital Clínic de Barcelona, was the first project to access the pilot. The product was granted eligibility to the PRIME scheme in December 2021, and is targeted to treat patients older than 25 years with relapsed/refractory acute lymphoblastic leukaemia.

The second call closed in December 2023 and saw the participation of 11 candidates, among which two new academic organisations were selected. The Berlin Center for Advanced Therapies (BeCAT) – Charité is developing TregTacRes, a gene therapy based on modified T-cells, for use as add-on therapy after transplantation. Fondazione Telethon’s gene therapy Telethon 003 (etuvetidigene autotemcel) targets the Wiskott-Aldrich syndrome, a rare, life-threatening immunodeficiency.

The new phase of the project will now recruit a total of 5 new participants by the end of 2024. The first results of the pilot are expected in 2025.

How to apply
Interested academic organisations can find all information together with the ATMP Pilot Application Form on the dedicated EMA webpage; applications are open up to the end of April 2024. The email address [email protected] is also available to request more information or to express interest in participating. A guideline document on fee incentives for scientific advice, marketing authorisation (MA) applications and pre-authorisation inspections for academic participants is available, together with Q&As on the pilot.

Pre-selected candidates will be invited to a meeting with EMA’s Innovation Task Force (ITF) to provide further information on their projects before final selection. At this stage, interactions between EMA and applicants would mainly take place via the online platform IRIS. Therefore, interested organisations will need to register to the platform and request a research product identifier (RPI).

Requirements and procedure for the application
Academic developers active in the EU can apply to the pilot provided they have already generated some proof-of-principle data on the interested ATMP. The academic status of the organisation will be checked by EMA during the selection phase. Applicants may include public/not-forprofit hospitals or research organisations and hospitals, Higher Education Institutions (HEI), public-private partnerships/consortia, and international research organisations, provided they are establish in the EU. In case of projects comprehensive of non-EU participants, the principal investigator has to be located in the EU, and clinical trials must include EU patients. The academic sponsor must be free from operating agreements with any pharmaceutical company, and it can freely operate via intellectual property rights on the product.

The support provided by EMA aims to ensure that development activities would meet regulatory standards as for quality, safety and efficacy of the ATMP product. A smooth path towards the submission of the MA application based on existing regulatory procedures and tools should therefore be possible. The pilot also aims to identify potential gaps in existing tools and procedures, from the perspective of academic sector developers.

Key principles used to select the new participants are listed in the Q&As document. As for individual ATMPs under development, they must address an unmet medical need, represent a major therapeutic advantage over existing treatments, or offer a new option in orphan areas. Previous eligibility to the PRIME scheme is not a prerequisite to apply for the pilot. The Q&As also specify that there is no direct link between the product having received an hospital exemption (HE) and access to the academic pilot.

Preliminary clinical evidence in patients is needed to support the application, as well as information on the mechanism of action gained by non-clinical studies. A sufficiently mature quality development, to be assessed against the pharmaceutical process and the planned GMP manufacturing process, should be also available to better support later stage clinical development and/or a MA application in the EU.

The academic sponsor must also have full access to the data related to the development and manufacture of the product, e.g. control of critical starting materials. The knowledge needed to successfully interact with EMA may be ideally provided by a specific person (also a consultant) appointed by the sponsor and with experience in the field of product development and regulatory affairs.

Benefits and fee reductions
Selected academic organisations will benefit by a dedicated EMA’s point of contact in the relevant therapeutic area office. A EMA Support team may be also appointed to provide regulatory and scientific support depending on the stage of development and nature of the program. Activities to be part of the pilot may include preparatory teleconferences to check planning, identify potential needs for additional support and complement interaction mechanisms under existing tools. The optimisation of pre-submission meetings is another goal of the pilot, together with debriefings before and/or after regulatory interactions. A particular attention will be payed to the regular assessment of the level of maturity of the projects, including co-decisions and stopping points.

EMA will also provide financial support to the selected academic applicants for the activities concerning the five selected ATMPs. More in particular, the Agency will grant the same incentives as for micro-, small- and medium-sized enterprises, with respect to fees established by the Council Regulation (EC) No 297/95 and its Implementing Rules.

To qualify for the fee incentives, selected academic organisations must continue to fulfil all the above mentioned criteria for accessing the pilot also at the time of the request for a fee incentive related to a procedure or service to be provided as a part of the pilot itself. To this instance, applicants shall submit a declaration to EMA, inclusive of the fulfilment of requirements and establishment in the European economic area.

Incentives for academic organisations participating to the pilot include a 90% fee reduction for both initial scientific advice and follow-up, and pre-authorisation inspections. MA applications for designated orphan medicinal products for human use will benefit a 100% fee reduction, while MA applications not covered under this occurrence will see deferral of payment until the notification of the final decision on the MA for the concerned ATMP is issued.

The document on fee incentives specifies also that remuneration of national competent authorities for those activities shall not be reduced.

The granting of fee incentives will follow EMA’s verification of the documentation submitted by the applicants. After confirmation by the Agency the applicant qualifies for the fee reduction, participants to the pilot will have a six months period to submit their requests for scientific advice and/or marketing authorisation. Ex–post controls and prove of evidence confirming the fulfilment of criteria for the fee reduction may also be required at any time until the finalisation of the concerned procedure.



EMA’s 3-year work plan for the Quality domain

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by Giuliana Miglierini

The European Medicines Agency has released the input notes made by the GMDP Inspectors Working Group (IWG) as for the drafting of the 3-year workplan for the Quality domain. The document, which reflects the objectives of the Network Strategy and Regulatory Science Strategy, addresses many aspects which may affect the overall efficiency of the pharmaceutical supply chain, both at the routine and specific level.

The document identifies a number of strategic goals aimed at improving the overall integrity and resilience of the pharmaceutical supply chain and the product quality, and to optimise the im-pact of new technologies. Description of the tactical goals follows, i.e., the projects and actions to be activated in order to reach the above-mentioned strategic objectives.

Improved traceability of the supply chain

Strategical goals include the enhancement of traceability, oversight and security for both the human and veterinary medicine supply chain. Four different actions are planned at the tactical level, starting from a better sharing of information regarding manufacturers, distributors, pro-ducts and their respective compliance. To this instance, actions to improve EudraGMDP records are expected.

Inspections of the repositories system should also be tackled by means of a liaison with the Ex-pert Group in inspectional procedures. The implementation of the new Veterinary Regulation should be addressed paying attention both to GDP for veterinary medicines and active substances. Improvement of the inspection capacity may benefit from the development of a specific training curriculum for GDP inspectors; to this instance, the IWG suggests a possible collaboration with PIC/S, through the EU4Health Joint Action 11 and the associated Work Programme 6.

Enhanced inspector capacity

Another strategic goal set forth by the GMDP IWG aims to improve inspector capacity building at EU and international level. To this regard, suggested actions include the support to the international API programme, comprehensive of the provisions of the new Veterinary Regulation related to API inspections and controls. Veterinary specific GMP guideline annexes 4 and 5 should be harmonised in collaboration with PIC/S. The collaboration should also include ongoing initiatives on inspection reliance, in order to better identify barriers preventing member states from accepting inspection results from other trusted authorities. PIC/S and the International Coalition of Medicines Regulatory Agencies (ICRMA) should also collaborate with the GMDP IWG to reach an agreement on shared definitions, best practices and harmonised approaches for distant assessment and hybrid inspections. The pilot programme for sterile inspections should be also finalised, with participation of all member states. Routine assessor-inspector joint inspections are suggested, as well as a training course specific to the new Annex 1.

The development of a harmonised, EU level guidance on data integrity is the tool identified by the GMDP IWG to reinforce responsibility of marketing authorisation holders (MAHs) for product quality. This goal may be achieved by adapting the current guidance published in the form of Q&As into Chapter 4 and Annex 11 of the GMP Guide, in collaboration with the WHO and PIC/S. A better attention on MAHs responsibilities and to the supervision of API manufacturers should also build upon the recommendations contained in EMA’s lessons learnt report (LLE) on Nitrosamines.

Critical manufacturing sites and new technologies

The review of long-term risks resulting from dependency on limited number of manufacturers and sites should support a better supply chain resilience. The review should be aimed to the identification of sites manufacturing a significant number of products or producing medical pro-ducts for a significant number of markets within the European economical area (EEA). The GMDP IWG also suggests performing cooperative supervision of these sites between member states and other strategic partners.

A better understanding of the possible implications resulting from the introduction of new manufacturing technologies has been also deemed important to regulate the new supply chains. To this instance, the indication of the IWG is to consider if a specific GMP annex would be re-quired in order to support the adoption of new and innovative technologies. As for decentralised manufacturing, this topic should also be evaluated in the GMP Guide to medicinal products other than advanced therapies.

Amendments to current guidelines

The document of the GMDP IWG details the specific guidelines that would need consideration in view of the proposed interventions.

Many actions are planned to achieve their objectives by the end of 2023. More specifically, the IWG expects to provide the EU Commission with the final text of the GMP for novel veterinary medicinal products and for autogenous veterinary vaccines. GMPs should be also revised to include Nitrosamines LLE recommendations to MAHs, so to ensure adequate quality agreements are in place with manufacturers.

The same deadline should apply to the development of specific training material on ICH Q9, addressing risk identification and risk management. This action would support EU members of the Expert Working Group (EWG) and should be coordinated with the dedicated PIC/S expert circle. A similar action is planned with respect to ICH Q12 on lifecycle management and ICH Q7 (GMP for active substances), as well as to other quality guidelines for veterinary medicines. The GMDP IWG is also expected to support the EWG in developing the new ICH Q13 guideline on continuous manufacturing.

Annex 15 on the Qualification and Validation may be revised by Q2 2024 in order to include considerations on new technology in facilities, products and processes, including also the possible extension of LLE recommendations to APIs.

The end of 2024 is the date indicated for the review of GMPs for advanced therapy medicinal products in order to include the new provisions of the revised Annex 1. The same deadline applies to the possible revision of Annex 16 on the certification by a Qualified Person and batch release, in order to provide further guidance on batch traceability according to LLE recommendations. The end of next year may see also the drafting of the final text of Annex 4 on the manufacture of veterinary medicinal products other than the immunological ones, based on comments received on the concept paper and the resulting draft text. A similar action is planned for Annex 5 on the manufacture of immunological veterinary medicinal products.

Chapter 4 (Documentation) and Annex 11 (Computerised systems) of the GMP Guide should be revised to assure data integrity in the context of GMP. The proposed deadline for these actions is Q1 2026.

Support to scientific advice and communication

A specific chapter of the GMDP IWG document is dedicated to actions deemed to support scientific advice activities. In this case too, target dates are provided for the completion of the different actions. These include the provision to the EU Commission of scientific advice on GMP standards to be included in the implementing act on GMP for veterinary medicinal products and active substances.

At the international level, the IWG plans to continue its efforts to reach a better convergence through existing mutual recognition platforms and programmes and to support the EU Commission to establish and maintain mutual recognition agreements. Collaborations with ICRMA, the EDQM, Chinese and Indian regulators should be also continued, as well as the dialogue with interested parties and stakeholders.



ACT EU’s Workplan 2022-2026

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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.


EMA’s Industry stakeholders group (ISG)

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by Giuliana Miglierini

The Industrial Stakeholder Group (ISG) is a new initiative recently launched by the European Medicines Agency (EMA) in order to favour the dialogue with the industrial stakeholders. The first meeting of the ISG, the 21 June 2022, focused on the mandate of the Group and on the three priority topics to be addressed during the pilot phase: the Emergency Task Force (ETF), the issue of shortages of medicines and medical devices and the medical device expert panels.

The initiative is part of the activities planned by EMA for the implementation of its extended mandated, as for Regulation (EU) 2022/123.

The mandate of the ISG

The main scope of the ISG is to provide a dedicate forum to capture the industrial point of view and proactively inform on open issues during the implementation of EMA’s extended mandate. The ISG will focus on human medicines and will complement other existing tools, such as industry platform meetings, bilateral meetings, topic or project related meetings. The outcomes obtained from the pilot phase will form the basis of an analysis to evaluate if to extend the scope to other initiatives.

The Chair of the ISG is nominated by the Agency’s Executive Director; the group is composed by one member and one alternate from selected EU industry organisations relevant to the subject of discussion, on the basis of a call for expression of interest. Additional representatives of selected organisations and observers may also participate to specific meetings, according to the topics on the agenda. Observers include the European Commission, EMA’s committees (e.g. CHMP, ETF, CMDh, SPOC WP, SMMG), the EU Network, Notified bodies; ad-hoc observers may be also invited from member states and stakeholder groups.

Appointed members will be responsible to liaise with the respective industrial rganisations, so to contribute the discussion with their point of view and to keep them updated on the outcomes of the ISG meetings. The current schedule includes four quarterly meetings per year; the next two are fixed for the 26 September and 22 November 2022. The summary report of each meeting will be available in EMA’s website.

The Emergency Task Force

The new Emergency Task Force (ETF) builds upon the experience gathered during the pandemic and acts within EMA to advise and support on medicines for public health emergencies and preparedness.

The ETF is in charge of coordinating all efforts following the declaration of a public health emergency by health authorities, in strict coordination with all other relevant bodies including the European Health Emergency preparedness and Response Authority (DG HERA), the European Centre for Disease Prevention and Control (ECDC), the WHO and the European Commission.

The new ETF started operating on the new mandate on 22 April. Its composition is based on expertise, and it includes representatives of EMA’s Scientific Committees and Working Parties as well as selected patients and healthcare professionals and clinical trials experts from various member states.

There are three distinct area of activities for the Task Force. Scientific advice and support to clinical trials for the development of medicines to be used during the emergency will be directly managed and assessed by the ETF, free of charge and flowing a fast-track procedure. The new streamlined procedure should lead to the outcome in 20 days; deceleration criteria are also considered, i.e. premature evidence to address the medical need, high workload or lack of urgency. Expected benefits include the reduction of the use of medicines with insufficient evidence of efficacy and the increase of safe and harmonised use across the EU of new products from the pipelines ahead of authorisation. Activities of the ETF will cover all stages of development, from pre-authorisation (e.g. rolling applications or paediatric plans) to post-authorisation (e.g. major changes), investigational products and compassionate use.

The systematic assessment of the available evidence on medicines will be the focus of the scientific reviews, while recommendations will target medicines not yet authorised or topics of particular scientific or public interest. These may include, for example, the monitoring of new outbreaks and epidemics and the information on potential radiological, chemical or bioterrorism agents.

All lists of medicines under assessment to address a declared emergency will be made public to increase transparency, as well as the CHMP opinions on the use of medicines not yet authorised, Product Information, EPARs end Risk Management Plans.

Two dedicated mailboxes are also available, the first for sponsors of clinical trials to request EMA/ETF support for facilitating CTA and approval and sponsors agreement to conduct larger multinational trials ([email protected]), the second for manufacturers to discuss with EMA/ETF their development programs or plans for scientific advice prior to any kind of formal submission ([email protected]).

Shortages of medicines

EMA’s extended mandate in this area include the monitoring and mitigation of shortages of critical medicines and medical devices, and the setting up, maintenance and management of the European Shortages Monitoring Platform (ESMP). The action also includes the establishment of the Medicines Shortages Steering Group (MSSG), which will be supported by the Working Party of singles points of contacts in the members states (the EU SPOC Network) and a network of contact points from pharmaceutical companies (the i-SPOC system). A corresponding Executive Steering Group on Shortages of Medical Devices (MDSSG), to be created by February 2023, will be in charge of adopting the list of categories of critical medical devices and to monitor their supply and demand.

According to Regulation (EU) 2022/123, pharmaceutical companies are required to identify a i-SPOC to act as the reference contact for EMA should the Marketing Authorisation Holder (MAH) have medicinal products be included in the lists of critical medicines. All information has to be provided through the IRIS platform; the registration process opened on 28 June 2022 and is comprehensive of two steps (the IAM preliminary requirement for the creation of the account and the following IRIS submission).

Scheduled milestones will see the establishment of a list of the main therapeutic groups for hospital care (due by 2 August 2022), the registration of i-SPOCs from MAHs (by 2 September 2022), and the definition of shortages of medical devices and in vitro diagnostics (by 2 February 2023). The ESMP platform is expected to go live by 2 February 2025, and will represent a single reference point to make information available on shortages, supply and demand of medical products, including the marketing status and cessation.

Expert panels on medical devices

Regulation (EU) 2022/123 establishes the hangover of expert panels on medical devices from the Joint Research Centre (JRC) to EMA, thus adding a completing new type of activity for the Agency.

The new Secretariat is coordinating the activities of the Screening panel composed by 70 experts in charge of the decision whether to provide a scientific opinion, eleven thematic expert panels and expert panels sub-groups (for a total of approx. 130 experts), and a Coordination Committee inclusive of the Chair and vice-Chair of all the expert panels.

The main task of the expert panels is to provide opinion to the notified bodies for certain high-risk medical devices and in-vitro diagnostic, for the assessment of their clinical and/or performance evaluation. EMA is specifically involved in the coordination of the Clinical Evaluation Consultation Procedure (CECP) for medical devices and Performance Evaluation Consultation Procedure (PECP) for in-vitro diagnostics. Further details on the procedures and their interfaces with the ETF is available here.


Steps forward towards the new framework for HTA

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By Giuliana Miglierini

The long-waited European regulation on Health Technology Assessment (HTA) was adopted by the Council of Europe on November 9, and it has now to pass through the final endorsement of the European Parliament as the last step before publication in the EU Official Journal. The regulation will entry into force three years and twenty days after publication.

The first proposal of a new HTA regulation was made in January 2018 by the EU Commission; the final political agreement between the Council and the EU Parliament was reached in June 2021. The position of the Council of Europe on the draft regulation at first reading was also published.

The provisions of the new HTA regulation will apply to medicinal products, medical devices (for example pacemakers, dialysis equipment or infusion pumps) or medical and surgical procedures, as well as measures for disease prevention, diagnosis or treatment used in healthcare.

The adoption of this law is another demonstration of how EU countries, when acting together, can achieve very practical results for their citizens. This new law will benefit patients, producers of health technologies and our health systems.”, said Janez Poklukar, the Slovenian minister for health.

Cooperation and joint activities

Joint clinical assessments and joint scientific consultations are central concepts of the HTA regulation: a target that would require the active cooperation of all member states in order to efficiently identify emerging health technologies. Administrative procedures shall be greatly simplified and become more cost-efficient, as manufacturers of health technologies (especially small companies) should be required to submit once-only all data and documentation for a certain technology at the EU level. These will form the basis for national competent authorities to run all joint activities, including scientific advice and clinical assessment.

The added value of new health technologies compared to the existing ones will be a main driver to guide the assessment activities, so to take informed decisions on pricing or reimbursement.

Joint scientific consultations may also include the exchange of relevant information between national authorities and manufacturers on development plans for the technology under assessment, so to favour the availability of all the evidence required to meet regulatory expectations.

The new Heads of Agencies Group

While waiting for the formal adoption of the new HTA regulation by the EU Parliament, other activities are ongoing to set up the operative framework needed to guarantee the smooth activation of all planned collaborative efforts.

The newly formed Heads of Agencies Group (HAG) is an initiative aimed to support the implementation of common joint work approach on all HTA activities at the EU level, according to the new model of cooperation among national authorities established by the regulation.

The new HTA-focused collaborative network for high-level strategic exchange and discussion was launched on 29 September 2021 by the heads of 19 European HTA agencies, which elected Prof. Rui Santos Ivo (INFARMED, Portugal) as its Chair, and Prof. Dominique Le Guludec (HAS, France) and Dr. Trygve Ottersen (NIPH, Norway) as Vice-Chairs. The secretariat of the Group has been established at the Dutch Health Care Institute (ZIN).

All HAG’s activities will be based on a joint Memorandum of Understanding. The Group will work during the next three years to support national systems to be prepared for the entry into force of the HTA regulation, including the availability of the needed capacity. HAG will also support the joint technical and scientific work performed by HTA bodies across Europe, and it will advise policymakers and other relevant institutions – both at the EU and national level – on issues related to cooperation in HTA.

Current members of the group include the following national authorities involved in HTA activities: AEMPS (Spain), AIFA (Italy), AGENAS (Italy), AIHTA (Austria), INFARMED (Portugal), KCE (Belgium), NIPH (Norway), G-BA (Germany), HAS (France), HIQA (Ireland), IQWiG (Germany), FIMEA (Finland), NCPE (Ireland), REDETS (Spain), RER (Italy), RIZIV-INAMI (Belgium), NOMA (Norway), TLV (Sweden) and ZIN (The Netherlands).

The EUnetHTA 21 consortium

After the closing of its third Joint Action (2016-2020), which paved the way to the permanent HTA working structure for Europe (encompassing more than 80 HTA bodies), the European Network for Health Technology Assessment (EUnetHTA) has published a HTA White Paper as the final document resuming lessons learned up to now that may prove relevant for the implementation of the next phase of the HTA joint cooperation.

This new phase in the life of the Network, that now goes under the name of EUnetHTA 21, is no more a Joint Action; a joint consortium has been created instead, led by the Dutch HTA body ZIN and including the following HTA agencies: AEMPS (Spain), AIFA (Italy), AIHTA (Austria), GBA (Germany), HAS (France), INFARMED (Portugal), IQWIG (Germany), KCE (Belgium), NCPE (Ireland), NIPN (Hungary), NOMA (Norway) and TLV (Sweden). The consortium will provide support to the future European HTA system to be established according to the upcoming regulation.

EUnetHTA 21 is funded by a two-years’ Service Contract for the Provision of Joint Health Technology Assessment (HTA) Work Supporting the Continuation of EU Cooperation on HTA, signed on 17 September 2021 by the European Health and Digital Executive Agency (HaDEA).

The first Stakeholder Kick-Off online meeting of the consortium is scheduled on 3 December

2021; the discussion will focus on the illustration of the governance principles, the planned interactions with stakeholders in the form of public consultations and the presentation of deliverables planned for the next two years.

The first Open Call for consultation

EUnetHTA 21 has already launched its first Open Call , targeted to the pharmaceutical industry with reference to four different Joint Scientific Consultations (JSC, previously referred to as Early Dialogues). The Call is open until 7 December 2021; some other four slots for JSC are expected to be activated during the period of activities of EUnetHTA 21.

The medicinal products to access these four first slots will be selected on the basis of the results of the Open Call, within two weeks from its closure; the following Joint Scientific Consultations are expected to start in January 2022. According to EUnetHTA, the procedure to be used for JSC shall remain essentially unchanged, with just minor adjustments; an updated guidance document should be soon available.

JSCs are a pillar of the new HTA regulation, aimed to provide non-binding scientific advice to developers of new products, after completion of the feasibility or proof of concept studies and prior to the activation of pivotal clinical trials, in order to improve the quality and appropriateness of the data to be used for future HTA assessment. This type of evaluation will run in parallel to EMA’s scientific advice procedures.

Early exchange of relevant information between applicants and both regulatory (EMA) and HTA agencies represents the core of the process, so to optimise the integration of the different requirements to be included in the study design across multiple European member states. These might refer, for example, to the choice of comparators or relevant outcomes, to the quality of life and/or patient groups (both for pivotal trials and post-launch studies), as well as to the economic evidence generation plan.


A new role for EMA and a pilot project for the repurposing of medicines

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by Giuliana Miglierini

A draft agreement was reached at the end of October between the Council of the European Union and the European Parliament to reinforce the mandate of the European Medicines Agency (EMA) with reference to crisis preparedness and management for medicinal products and medical devices. “EU-level preparation and coordination are two essential ingredients to fight future health crises. Thanks to this deal we are adding an essential new building block to upgrade the EU’s health architecture. It will allow the EU’s Medicines Agency to make sure we have the medicines needed to deal with public health emergencies”, said Janez Poklukar, the Slovenian minister for health.

The revision of EMA mandate is part of the broader activities announced by the EU Commission in November 2020 to achieve the European Health Union; these also include the reinforcement of the European Centre for Disease Prevention and Control and a draft law on cross-border health threats. The establishment of the new Health Emergency Preparedness and Response Authority (HERA), announced in September 2021, is also part of the package. The draft agreement shall now be endorsed both by the Council and the Parliament before entering into force.

Three new key targets for EMA

The draft agreement reached by the Council and Parliament negotiators focuses on three main areas. The first one refers to the definition of a major event and how to recognise it: these shall be events likely to pose a serious risk to public health in relation to medicinal products, as acknowledged by a positive opinion from the Medicines Shortages Steering Group, and which may trigger specific actions such as the adoption of a list of critical medicinal products to fight the health threat.

Solid funding from the Union budget shall be also provided to EMA in order to support the work of the new steering groups, task force, working parties and expert panels. The availability of provisions for adequate data protection is important to guarantee the full compliance to the GDPR regulation and other EU data protection rules, and the safe transfer of personal data relevant to EMA’s activities (e.g. data from clinical trials).

EMA shall play an improved role in the monitoring and management of shortages of medicines and medical devices, a critical activity for the availability of the products needed during public health emergencies. Other points of the agreement include the timely development of high-quality, safe and efficacious medicinal products, and the creation of a new EMA’s structure specific for expert panels in charge of the assessment of high-risk medical devices and of essential advice on crisis preparedness and management.

How to tackle shortages of medicines

According to the EU Parliament, two “shortages steering groups” (for medicines and medical devices, respectively) shall be created by EMA; if needed, these groups may also include expert advice from relevant stakeholders (e.g. patients and medical professionals, marketing authorization holders, wholesale distributors, etc.).

Parliament negotiators highlighted the importance to achieve a high transparency of the process, including avoidance of interests related to industry sectors for members of the two groups; summaries of the proceedings and recommendations shall be also made publicly available.

A European Shortages Monitoring Platform shall be created by EMA to facilitate the collection of information on shortages, supply and demand of medicinal products; a public webpage with information on shortages of critical medicines and medical devices shall be also made available.

As already occurred during the Covid pandemic, future public health emergencies may boost the development of new medicines and medical devices. Sponsors of clinical trials conducted during health emergencies will be required to make the study protocol publicly available in the EU clinical trials register at the start of the trial, as well as a summary of the results. Following the granting of the marketing authorisation, EMA will also publish product information with details of the conditions of use and clinical data received (e.g. anonymised personal data and no commercially confidential information).

With this agreement, Parliament makes both the Agency and all actors in the supply chain more transparent, involving them more in the process and fostering synergies between EU agencies. Moreover, we pave the way to promoting clinical trials for the development of vaccines and treatments, boosting transparency on those issues. In short, more transparency, more participation, more coordination, more effective monitoring and more prevention”, said Rapporteur Nicolás González Casares (S&D, ES).

EMA’s pilot project for the repurposing of medicines

The repurposing of already approved and marketed medicines is another key action put in place to ensure improved response capacity in case of future health emergencies.

A new pilot project to support the repurposing of off-patent medicines has been launched by EMA and the Heads of Medicines Agencies (HMA), with special focus on not-for-profit organisations and the academia as the main actors to carry out research activities needed to support the regulatory submission for the new indication. The initiative follows the outcomes reached by the European Commission’s Expert Group on Safe and Timely Access to Medicines for Patients (STAMP).

Interested sponsors may access EMA’s specific scientific advice upon submission of the drug repurposing submission form to the e-mail address [email protected] by 28 February 2022. More information is available in a Question-and-Answer document. The pilot will last until scientific advice for the selected repurposing candidate projects; filing of an application by a pharmaceutical company for the new indication is another target. Final results of the project will be published by EMA.

Comments from the industry

The European Federation of Pharmaceutical Industry Associations (EFPIA) welcomed the proposed framework for the repurposing of authorised medicines. “This pilot launch comes at a timely moment to test whether a streamlined and more transparent regulatory pathway for repurposing of off-patent established products increases the chances of including existing scientific evidence into regulatory assessment. One of the goals of the pilot is to raise awareness regarding the standards required for regulatory-ready evidence on the road to further increase availability of authorised therapeutic use”, said the chair of EFPIA’s Regulatory Strategy Committee Alan Morrison.

Innovation on existing, well-known molecules through repurposing can deliver huge benefits for patients, according to Medicines for Europe. The Association of the generic and biosimilar industry supports the pilot project as a way to generate robust data packages and to translate research into access for patients. A sustainable innovation ecosystem for off-patent medicine is the expected final outcome, possibly including also reformulation of existing medicines, new strengths or adaptation for specific patient groups (i.e. paediatric populations). “These investments must also be recognised in pricing and reimbursement policies to make access a reality for all patients”, writes Medicines for Europe.