European Commission Archives - Page 2 of 4 - 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

The proposals of the EU Commission for the revision of the IP legislation

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By Giuliana Miglierini

In parallel to the new pharmaceutical legislation, on 27 April 2023 the EU Commission issued the proposal for the new framework protecting intellectual property (IP). The reform package impacts on the pharmaceutical industry, as it contains proposals on Supplementary Protection Certificates(SPCs) and compulsory licensing (CL) in crisis situations. It also includes a new Regulation on Standard Essential Patents(SEPs).

The proposed reform, which is part of the EU Industrial Strategy, will now undergo the scrutiny of the European Parliament and Council. It aims to improve European competitiveness, innovation and technological sovereignity, with a special attention to the role played by SMEs. The proposal is based on comments received during the consultation on the Action Plan on Intellectual Property issued in November 2020. The IP legislative framework will complement the Unitary Patent system, that will fully entry into force on 1 June 2023.

Supplementary Protection Certificates

Central to the reform of the SPC system is the creation of a unitary SPC to complement the Unitary Patent. The aim is to reduce the current fragmentation in the issuing of SPCs at the national level, which often leads to complex interpretation of patents’ expiry dates, and consequent legal uncertainty. The new system would not replace the existing national SPC schemes.

Procedures should be simplified, with a single application to be submitted to the EU Intellectual Property Office (EUIPO), which would be responsible for its central examination in close cooperation with EU national IP offices. The process would lead to national SPCs granted for each of the designated member states (MS), plus a unitary SPC if required by the applicant (here the Q&As).

According to the Commission, approx. 25% of current SPC procedures have contradictory outcomes. The mean number of annual SPC applications is 81 per MS, with a total cost of €192,000 over the 5 years of duration (compared to roughly €3,000 in the US and €4,200 in Japan). Savings from the new procedures may amount to up €137,000 for the EU27 wide, five years long SPC protection. A central SPC database is also planned in order to increase transparency.

The proposed reform is comprehensive of a Regulation specific to medicinal products and a second one focusing on plant protection products, plus parallel recasting regulations to review the current legislative provisions (i.e. Regulation (EC) No 469/2009). Innovators would be incentivised to use unitary SPCs, since otherwise a unitary patent could be extended at higher costs only by means of national SPCs. Infringements of unitary SPCs would fall under the judgement of the UPC Court.

The Commission expects the development and access to generic medicines will be facilitated. In particular, SMEs will be able to submit observations during the examination of a centralised SPC application, and to file an opposition in order to centrally challenge the validity of the SPC protection, if justified. The new framework complements the proposed pharmaceutical legislation, for example on the Bolar exception. This should allow the generic industry to perform research and testing for preparing regulatory approval also while a patent/SPC is still in force.

Compulsory licensing

Compulsory licensing may be used during crisis in order to provide access to relevant products and technologies, should result in impossible (or not adequate) to close voluntary licensing agreements with owners of IP rights. The current fragmentation of procedures at the national level results in a wide legal uncertainty (see also the published Q&As). The new framework would complement other EU crisis tools, such as the Single Market Emergency Instrument, HERA regulations and the Chips Act.

According to the proposal, a Union compulsory licence can only be granted after activation of an emergency or crisis mode at EU level. Instruments to trigger this fundamental passage are listed in an Annex, so to improve legal certainty. A remuneration scheme for IPR holders is also included, on the basis of successive steps in the activation and termination of compulsory licensing.

The existing national frameworks on compulsory licensing will continue to operate, and they may be used to manage local crisis. Compulsory licensing of exported products would not be allowed.

Standard Essential Patents

SEPs refer to technologies essential for the implementation of a technical standard adopted by a standard developing organisation. They are typical of the ITC industrial sector, and central to building the Internet of Things.

To improve the transparency and legal certainty of SEPs, the proposal aims to ensure innovation would be run in the EU by both EU SEP owners and implementers. End users would benefit from products based on the latest standardised technologies at fair and reasonable prices. SEPs licensing is based on the FRAND scheme (fair, reasonable and non-discriminatory) for the remuneration of patent holders.

Comments from the stakeholders

EFPIA granted positive feedback on the simplification and harmonisation of the SPC system and to the opportunities offered by the unitary SPC. On the other hand, the proposals on compulsory licensing didn’t find the agreement of the research-based pharmaceutical industry.

According to a note, voluntary licensing would be the preferred instrument for innovators, as it allows for the choice of the best-positioned and trusted partners to speed up production and distribution of medicinal products during health crisis. On the contrary, compulsory licensing is seen as a threat to investment stability of the EU’s IP system and to the overall innovation pipeline.

Protecting the EU’s intellectual property framework could not be more important if we are to close the investment gap between Europe, the US and increasingly China and continue to offer patients the best possible treatments. Yet we are seeing multiple proposals emerging from the European Commission in the pharmaceutical legislation and patent package which tend towards the opposite”, said EFPIA Director General Nathalie Moll.

Medicines for Europe (MfE), on behalf of the generic and biosimilar industry, said that while “voluntary licensing agreements are relevant for health crises, we will contribute constructively to the EU-wide compulsory licensing system”. The request to the Commission is to make it a remedy also for anti-competitive abuses of the patent system, according to art. 31(k) of the TRIPS Agreement.

As for new SPCs, MfE highlights the new regime would extend their geographical scope from the current 20 out of 27 MS covered on average. “The proposal for a reform in the SPC system has the potential to reduce fragmentation in Europe but the legislation must ensure improved quality and transparency of granting procedures to prevent misuse by right holders to delay competition”, said MfE Director General Adrian van den Hoven.

Critics of the proposed scheme for compulsory licensing also came from EUCOPE, representing pharmaceutical entrepreneurs. According to the Confederation, the Commission’s proposal would further weakening the value of intellectual property rights within the EU. “Together with the proposal on the revision of the general pharmaceutical legislation, it is another indicator that the development of an innovation-friendly environment is not a priority, contrary to statements in the Intellectual Property Action Plan”, it states in a note.

For EUCOPE, the proposed SPC regime would not amend the substantive elements of the current system. Furthermore, a centralised SPC application would only be possible on the basis of a European patent, including a unitary patent, and for products with a centralised marketing authorisation. EUCOPE position goes for an optional EU-wide SPC, so to allow flexibility for IP owners in deciding their strategy for the protection of IP rights.


The EU Commission proposal of the new pharmaceutical legislation

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By Giuliana Miglierini

After a five-months delay, the European Commission has announced on 26 April 2023 its proposal for the revision of the European pharmaceutical legislation. The package is comprehensive of a Directive governing authorisations and other regulatory procedures, and a Regulation focused on central authorisation procedures. A Council Recommendation on antimicrobial resistance is also included. The entire reform package shall now undergo the scrutiny of both the European Parliament and Council in order to gain final approval and adoption.

In this first article, we will resume the main features of this highly complex reform, leaving to following posts a more detailed discussion of the single lines of intervention.

The experienced delays acknowledge of the many difficulties encountered by the Commission in reaching a balance between forces representing different perspectives within the pharmaceutical sector. Among the main areas of debate was the exclusivity protection: an issue not yet re-solved, judging from the first reactions from industrial associations, and that should be addressed during the incoming negotiations at the EU Parliament and Council.

A single market for medicines

Central to the entire reform package is the creation of a single European market for medicines, aimed to facilitate the fair and rapid access to patients of all member states. Regulatory procedures for approval of generic and biosimilar medicines should be simplified. Patients are also expected to benefit from more innovative medicines, thanks to a wide array of incentives, and from the repurposing of products already on the market.

Patient centricity should also address rare diseases and new therapeutic options for paediatric patients, including the creation of a EU network of representatives of patients associations, academics, developers and investigators. Patient representatives should be appointed to the EMA Committees, and thus involved in the approval of new medicines. A more extensive use of electronic Product Information is expected to facilitate access to updated information, while reducing costs for manufacturers.

A greater transparency on public funding for R&D should better support price negotiations with national authorities, so to make medicines more affordable to patients.

The long lasting issue of medicines shortages should be tackled from different perspectives. Pharmaceutical companies should be responsible for the emission of earlier warnings on shortages and withdrawals, and for the establishment of prevention plans. European authorities should create a list of critical medicines, to be used to identify supply chain vulnerabilities and improve security of supply. National and central competent authorities are called to a better monitoring of shortages, while EMA should play a stronger guiding role on security of supply.

The One Health approach should inspire actions to improve the environmental sustainability of medicines. From this perspective, the proposed reform includes a strengthened environmental risk assessment for all medicines, including those already on the market. Actions to improve environmentally friendly production technologies and to reduce the release of drugs into the environment are also considered.

Actions supporting innovation

The reform package completely redesigns the duration of regulatory protection, reducing the standard length to 8 years (6 years of data protection + 2 years of market protection), but offering a wide range of incentives to reach a cumulative maximum of up to 12 years of protection. The true novelty is the 2-year incentive for companies launching a new product in all EU markets at the same time. Other incentives are targeted to unmet medical needs (6 months), comparative clinical trials (6 months), and for a new indication to treat another disease (1 year).

The standard market exclusivity should reach 9 years for medicines for rare diseases. In this case too, a wide range of incentives may extend protection to up to 13 years.

The Transferable data exclusivity voucher is the tool identified to support the development of new antimicrobial medicines: the voucher would be transferred to another of the company’s products, extending its protection by 1 year. The Commission plans to issue no more than 10 vouchers over a 15 year period, under strict conditions, so to limit the impact of the measure on healthcare systems. Reshoring of pharmaceutical productions and EU’s strategic autonomy are not included in the reform. A number of other actions are ongoing to support specific lines of intervention, i.e. the EU FAB flexible manufacturing network of vaccines producers, HERA’s Joint Industrial Cooperation Forum on vulnerabilities along the supply chain, and the Important Project of Common European Interest on Health to allocate state aid to support for innovative EU projects.

A more flexible regulatory framework

A higher regulatory flexibility should support fast approval of medicines. Regulatory assessment for centralised procedures should shorten to 180 days (from the current 210); the time should be reduced further to 150 days for products needed for health emergencies.

Simplification of procedures will include full electronic submission of applications. Rolling re-views and temporary emergency marketing authorisations at the EU level for public health emergencies will fully enter the set of available procedures. Simplification should also include the abolishing of the marketing authorisation renewal in most cases.

A reform of EMA’s Committees is also envisaged: only the Committee for Human medicinal pro-ducts (CHMP) and the Safety Committee (PRAC) should continue to exist, while the orphan, paediatric and ATMP committees would be abolished.

Generic and biosimilar medicines shall also benefit from simpler rules for approval, while regulatory sandboxes are the tool to support testing of particularly new and innovative therapies. These may also benefit of additional early scientific advice and regulatory support by EMA, particularly for unmet needs. Dedicated pathways are also planned to support repurposing, especially for SMEs and not-for-profit organisations.

Clinical development may be improved thanks to a wider use of adaptive clinical trials, real world evidence and health data. The reform is also expected to make easier the interaction with other relevant healthcare frameworks, e.g. for medical devices and health technology assessment.

The first comments from interested parties

A very negative opinion on the proposed reform has been issued by the European Federation of Pharmaceutical Industrial Associations (EFPIA), representing the innovator industry.

Unfortunately, today’s proposal manages to undermine research and development in Europe while failing to address access to medicines for patients”, said EFPIA’s Director General Nathalie Moll. The main point of criticism is the 2-year incentive for the contemporary launch of a new medicine in all 27 member states, that for EFPIA would represent an impossible target for companies. According to President Hubertus von Baumbach, “the ‘net’ impact of policies set out across these proposals, in their current form, puts European competitiveness at risk: overall, it weakens the attractiveness for investment in innovation and hampers European science, research and development”. A comprehensive competitiveness checks on the impact of the revised pharmaceutical legislation is EFPIA’s request.

The Association also published a series of reports supporting its vision on the availability of new medicines throughout Europe, as its first action to stimulate the debate in view of the assessment of the proposal by the EU Council and Parliament.

We strongly support the proposal’s intention to stop the well documented patent games manship and evergreening and the adaptation of incentives to necessary equity of access across the EU. Moreover, there should not be an accumulation of regulatory incentives that would extend the regulatory data protection period beyond the existing system (8 years) which is already the longest in the world. Regarding AMR, the Commission proposal for a reserve fund is the correct alternative to transferable vouchers and most efficient policy to protect against future risks”, wrote in a note Medicines for Europe, representing the generic, biosimilar and value added medicines industry. “The central role of the off-patent medicines industry for the patient is clearly reflected in the intentions of the draft legislation. We are still lacking an industrial strategy to strengthen the European off- patent sector and improve open strategic autonomy in health”, said Medicines for Europe President Elisabeth Stampa.

EuropaBio, on behalf of the biotech sector, welcomed the provisions improving the EU’s regulatory framework and promoting novel technologies. In this case too, the main concern is the proposed new set of incentives, that according to EuropaBio may undermine the predictability and stability of the European landscape for innovation. “It is essential that EU policies meaningfully improve patient access to medicines across the EU without undermining the EU’s attractiveness for life science investments”, said EuropaBio Healthcare Public Affairs Director Vlad Olteanu.

AESGP supports the revision of the EU pharmaceutical legislation in principle. While we welcome the regulatory simplifications introduced by the revision, we are voicing some concerns on behalf of non-prescription medicines manufacturers that may have unintended negative consequences”, said Jurate Svarcaite, AESGP Director General. The Association resumed its worries in a statement published in its site.

These include the proposed two new prescription criteria for antimicrobial products and medicines containing an active substance which may have an environmental impact. As for incentives, according to AESGP a longer data exclusivity period (3 years instead of 1) should be considered in cases where new, pivotal evidence is generated, for switching from prescription to non-prescription status. Other points of concern refer to how environmental risks for medicines are to be assessed. “Decisions to minimise the environmental impact should always lead to proportional risk mitigation measures and never interfere with clinical priorities and benefit/ risk assessments that ensure EU citizens get access to the healthcare products they need”, wrote AESGP.

Improvement to the Commission’s proposal would also be needed with regard to the adoption of electronic Product Information, where a phased and harmonised approach to digitalisation is suggested. A better definition of real-world evidence/data would also be needed. As for shortages, mitigation measures should be proportionate and aimed at the critical medicines that do not have alternatives and have concentrated supply chains. AESGP supports the extension of the proposed approach to Risk Management Plans exemption also to medicinal products of well-established use, as for generics and biosimilars.

We appreciate the proposals aimed at streamlining and digitalising regulatory procedures, yet we are concerned that other provisions will undermine R&D, innovation, and EU competitiveness. These will be especially detrimental to the small and mid-sized innovative companies that Eucope represents. The proposal introduces more risk and unpredictability into the system while reducing incentives for innovation and investment, which will negatively impact patient access”, wrote the association in its comments to the proposal of reform.

The Commission’s revision includes troubling proposals, such as the introduction of (High) Unmet Medical Need, which risk reducing the EU’s global competitiveness in life sciences, thereby limiting the development and availability of innovative therapies”, said Eucope Secretary General Alexander Natz.


HERA reports on stockpiling of antimicrobials

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By Giuliana Miglierini

The European Health Emergency Preparedness and Response Authority (HERA) has published the two final reports, prepared by McKinsey Solutions for the European Commission, describing respectively the results obtained during the first and second phases of the antimicrobial resistance (AMR) feasibility study on stockpiling.

Antibiotic resistance represents a major threat for human health, as many active substances are losing efficacy towards many bacterial species. The first report (deliverables D1–D5) focuses on the mapping exercise run during the project and aimed to assessing the current situation, identifying vulnerabilities, and reviewing the stockpiling systems currently available in the EU and at the global level.

The second report (deliverables D6-D7) discusses the vulnerabilities identified in the previous phase and the potential tools and solutions to address them, including the assessment of available options for stockpiling of antimicrobials at EU level.

Mapping of the current situation

According to the first report, 32 classes of antibiotics were identified as critical with respect to the need to ensure continued access to patients in order to offer sufficient therapeutic and prophylactic options against systemic bacterial infections.

The analysis proceeded further to identify narrower sets of antibiotics most useful to treat infections due to common pathogens with acquired antibiotic resistance: a first subset of 20 substances was indicated as specially relevant as first- or last-line/reserve therapies against AMR pathogens, and from this a shorter sublist of 13 was identified as last-line/reserve therapies for severe and potentially lethal infections.

The report did not identified any critical market withdrawal of antibiotic substances from the EU market, even though some criticalities may occur in some member states. Alternatives with better efficacy and/or safety profiles are still available on the market for the six substances identified as fully withdrawn.

According to the report, stockpiling at the EU level might not have a direct impact on the mitigation of market-driven trends. Improved monitoring of potentially critical future withdrawals would be needed to enable early detection of shortages and establishment of counteractions.

Innovation in the field of new antibiotics is still largely insufficient, with only six substances currently in phase 3 clinical development. These might prove useful especially as the ultimate reserve line of therapy after exhaustion of the currently available therapeutic options. The report suggests that, upon reaching approval, these innovative substances could be considered for future stockpiling or incentives to facilitate launch in the EU.

The analysis of supply chain vulnerabilities aimed to identify higher priority antibiotics as possible candidates for stockpiling. The report highlights that the analysis was “significantly limited by a lack of outside-in transparency”. Potential single points of failure and/or past disruptions in most supply chains were identified for the 32 critical antimicrobial classes, but the lack of capacity data made the in-depth analysis particularly difficult.

Six representative sets of antibiotic substances were assessed, for five of which less than 25% of API manufacturing occurs in the EU. Similar trends have been also observed for the remaining 26 classes. The supply of critical intermediates (i.e., 6-APA and 7-ACA) appears particularly worrying and may potentially lead to a future shortage of that specific antibiotic/class in the case of a shock. HERA report warns against the possible risks related to potential vulnerability to trade disruptions and unforeseen geopolitical shocks, which may lead to a significant shortage in case of failure of just a single manufacturing site, independent of its location.

The feasibility study also mapped the already existing or planned stockpiling systems, so to use this information to better design the new, EU-level stockpiling system. Four different levels were identified, ranging from the EU’s and member states’ systems to multilateral and/or international NGO stockpiles, stockpiles/inventories in the commercial value chain, and extra-EU national stockpiles.

At the EU and EFTA national level, 13 countries reported a national stockpile that includes antimicrobials, even if greatly differing as for the chosen model. The rescEU system was identified at the EU level as the most relevant mechanism potentially useful to complement and/or integrate with a publicly managed physical stockpile of antibiotics.

The Stop TB Partnership’s Global Drug Facility (GDF) was identified as one of the international models of interest, together with the US Strategic National Stockpile (SNS). The GDF includes more than 2,000 partners and acts as the largest purchaser and supplier of medicines to treat tuberculosis in the public sector globally. The suggestion is for HERA and the European Commission to collaborate with the GDF in case of a TB-related demand spike. The SNS may represent a significant example of how to address many of the criticalities highlighted by the report.

How to better address stockpiling of antibiotics

The second report builds on the above-mentioned observations to go deeper in analysing from different perspectives and targets the possible approaches to the stockpiling of antibiotics. The indication is for HERA to consider using existing initiatives (e.g., rescEU, the EU’s Joint Procurement Agreement and the Emergency Response Coordination Centre) and to work closely with EU member states and other EU agencies (i.e., EMA and the ECDC).

An important warning was also made: stockpiling is just “a short-term mechanism. It does not alter the fundamental market environment. It can only represent one part of any answer to the challenges faced by health agencies including HERA, whether AMR-related or otherwise”.

A sudden and unpredictable surge in demand and an interruption to supply are the two archetypes analysed to better identify how to address stockpiling.

More than 30 potential demand scenarios were considered, leading to the identification of one high priority stockpiling candidate (higher demand for anti-mycobacterial medicines due to a surge of imported tuberculosis cases) and other three important, but not yet prioritised scenarios. These include stockpiling against the accidental or deliberate release of a bacterial pathogen, treating bacterial super-infections due to a viral pandemic, and the potential rapid spread of an AMR pathogen in the current European context.

Stockpiling for supply chain disruptions was also assessed, leading to the conclusion that alternative products are available as substitutes in the great majority of cases. A point of attention is represented by cross-class substitution, that might provoke different side effects for different groups of patients and could represent a potential factor for the promotion of AMR. More complex treatment procedures (e.g., i.m. vs oral administration), higher costs for healthcare systems and organisational issues for providers should also be considered.

Virtual stockpiling to be managed through the new European Shortages Monitoring Platform (ESMP) or the existing European Medicines Verification System (EMVS) would increase transparency of the system. A mandate or incentives to support private sector physical stockpiling was considered as the most feasible option available. Efforts should be made by the EU Commission to better characterise the relationships between the economic sustainability of limited generics productions (e.g. oral formulations for paediatric use of narrow-spectrum genericised penicillins) and the risk of shortages.

Five lines of possible action

The second report identifies five possible lines for future action aimed to strengthen the antibiotic supply chain and improve the stockpiling feasibility. At first instance, it would be important to improve transparency and reporting, so to better enable the availability of targeted preparedness and response measures.

This might include the harmonisation and extension of mandatory reporting of medicine shortages across the EU, the possibility for HERA to access regulatory data from agencies and information from marketing authorisation holders on supply chain setup and inventories in the case of a healthcare emergency situation, the implementation of an opt-out mechanism from stockpiling obligations at final product level, and the introduction of a general extension of reporting requirements for the supply chain of antibiotic products sold in the EU.

The second line of possible action addresses how to lower wastage in existing private and public inventories and stockpiles. Available options include regulatory measures and limited financial support for drug stability studies or for packaging options able to maintain product quality over longer periods of time.

Facilitation and regulatory support for mutual recognition of national level approvals for antibiotics might help to improve the flexibility of existing inventories and stockpiles, so as to better mitigate the shortages occurring in some member states.

Other two complementary approaches have been identified as potentially useful to improve the supply chain resilience of the EU antibiotics market. On one hand, diversified and in-market antibiotic manufacturing capacities and capabilities could be supported by targeted incentives and investments. On the other, the maintenance of reserve/convertible manufacturing capacity for hard-to-make substances might be also supported, so to better face the need to rapidly compensate the increased requests from patients should disruptions occur.


EMA/EFSA joint report on human dietary exposure to residues of veterinary medicines, pesticides and feed additives

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By Giuliana Miglierini

The presence of residues of veterinary medicines, feed additives and pesticides in food of animal origin may pose exposure risks for human health. The topic has been historically approached under different perspectives according to the specific reference legislative framework and the respective authority involved in regulating and monitoring the products. The European Medicines Agency (EMA) and the European Food Safety Authority (EFSA) are among the main regulators involved in setting and verifying the legally binding maximum residue limits (MRLs) for chemical substances, together with the European Chemicals Agency (ECHA).

EMA and EFSA received in 2020 a mandate by the European Commission to work at the development of a harmonised approach to the assessment of dietary exposure to residues of veterinary medicines in food of animal origin. The comparison of the current situation run by the two agencies included only exposure assessment methods used in the regulatory areas, which are all based on traditional deterministic approaches. The resulting recommendations have recently been published in the form of a joint report.

EMA/EFSA experts focused on key concepts and features in order to provide a general agreement on the basic “building blocks” of a recommendable harmonised methodology, leaving the setting up of more detailed methodological aspects targeted to the different sectorial applications to a further phase of discussion. The document shall now be assessed by the European Commission and, if adopted, may request the implementation of specific action targeted to the different sectors to reach a better harmonisation. The Technical Report to be submitted to the Commission may also contain other elements to be considered.

Meanwhile, on 9 February 2023 the Commission implementing Regulation (EU) 2022/1255 designating antimicrobials or groups of antimicrobials reserved for treatment of certain infections in humans entered into force. The regulation lists a wide range of antibiotic, antiviral and antiprotozoal active substances. Those use is from now on excluded to treat animals, so to preserve their efficacy in humans. The measure is part of the broader approach against antimicrobial resistance, and it aims to promote a more prudent and responsible use of antimicrobial medicinal products in animals, including very strict rules on their veterinary prescription for prophylactic and metaphylactic use.

The main issues examined by the EMA/EFSA report

Sectorial legislations in the field of medicinal products (managed by EMA), food (EFSA) and chemicals (ECHA) may greatly differ from one another in the approach and methodologies chosen to define exposure limits and to run risk assessments referred to residues of veterinary medicinal products, feed additives, pesticides and biocides. This lack in harmonisation may lead to significantly different outcomes in the assessment of the same active substance, especially when it is characterised by a dual use for applications in different sectors.

There are several pieces of legislation in place aimed to guarantee a high level of protection of both human and animal health and the environment [Commission Regulation (EU) 2018/7829, Regulation (EC) No 1107/200910 and Commission Regulation (EC) No 429/2008], as well as sectorial legislations in the pharmaceutical, food, and feed additives fields that may diverge at the level of data requirements, purpose of the required studies, methodologies for exposure assessment, consumption models, etc.

In general terms, exposure studies are usually run using radiolabeling to trace the fate of a substance and to characterise its metabolites and their concentration in edible tissues/food commodities from target animals. The “residue of concern” (RoC) considered in the dietary exposure assessment is most commonly estimated assuming that metabolites have the same pharmacological/ toxicological potential as the parent compound. The difficulty of measuring the concentration of all compounds in residue monitoring often leads to the selection of a marker residue to be traced.

Health Based Guidance Values (HBGVs, or Reference Values) corresponds to the concentration of a chemical that may present hazards for the human, animal or environmental health; they are listed in the EFSA Open Food Tox Database, as well as in similar WHO and US-EPA databases.

HBGV, as well as acceptable daily intake (ADI) in case of chronic risk and the acute reference dose (ARfD) in case of acute risk, can be used in association with the estimated dietary exposure to the RoC to evaluate the risk of exposure.

The report initially discusses the different approaches and models currently in use by EMA, EFSA, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Joint Meeting on Pesticide Residues (JMPR). Reference is made to the alternative definitions for the establishment of residue limits related to veterinary medicinal products charactering the different sectorial legislation, as well as to methods to assess the related hazard.

The Theoretical Maximum Daily Intake model (TMDI, or diet-based approach), for example, is used by EMA to estimate the risk from life-long exposure to residues in food commodities from animals treated with veterinary medicinal products. This model has been already abandoned by JECFA and EFSA, that switched respectively to the Feed Additives Consumer Exposure (FACE) and Pesticide Residue Intake Model (PRIMo 4), as better suited to estimate age-dependent exposure scenarios based on individual food consumption data. The report also discusses the Global Estimated Chronic Dietary Exposure (GECDE) model, and the International Estimated Daily Intakes (IEDI) model. This last one is based on the WHO GEMS Food Cluster diets, estimating average per capita consumption figures based on international trade and production statistics of foods.

A further level of complexity in the assessment has to be considered for substances with dual uses, such as veterinary medicines and pesticides. In such instances, it is important to note that maximum residue limits/levels may vary for the same substance in the same animal commodity, as their concentration may differ in different tissues and/or organs (i.e., muscle, fat, liver, kidney, eggs, or milk). This may result in uncertainties at the level of the enforcement of the appropriate level and residue definition by different authorities.

The recommendations for future harmonization

The analysis and evaluation of the performance of the many available methods led EMA and EFSA to conclude that the observed differences in exposure assessment could be primarily attributed to the type and use of consumption and occurrence data. Other possible elements impacting on the obtained result may include the chosen calculation model and exposure model, the exposure to residues from multiple uses, and the use of commodity definitions and combined exposure from multiple species. Different timelines in the implementation of scientific innovation may have also contributed to the observed divergences.

The final goal of the exercise was to obtain a most realistic exposure assessment possible based on the available methodologies. The so identified “preferred methodology” focuses on data sources and models, includes also alternative proposals on a number of items, and it might represent the “blueprint” for a future harmonised methodology. EMA and EFSA’s recommendations pay particular attention to exposure assessment as the first step of a risk assessment; as for risk characterisation, no specific recommendations have been developed during this round of discussions.


European Council’s conclusions on the European Innovation Agenda and research infrastructures

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by Giuliana Miglierini

The European socio-economic framework is undergoing a profound transformative moment, as a result of the new vision impressed by the von der Leyen Commission, with its goals in the field of the Digital and Green transitions. The subsequent crisis caused by the Covid pandemic and the following war at the boundaries of the European Union deeply impacted the already fragile economy, asking for new measures to sustain its competitiveness and ability to innovate.

A major goal of the Commission’s Agenda is to reposition the EU as a global leader in innovation. The European Council endorsed this vision at the beginning of December 2022, by adopting the Conclusions on the New European Innovation Agenda.

The recent crises have shown the need for the EU to support an open strategic autonomy in order to curb the dependencies and vulnerabilities that affect our industry. We have to strengthen the EU’s own capacity in strategic areas. This will not be possible without ambitious investments in innovation”, said Vladimír Balaš, Czech Minister for Education, Youth and Sport, commenting the document.

The European Council also adopted its new Conclusions on research infrastructures (RIs), which complement and complete the framework to support innovation and set the basis for the full development of the European Research Area (ERA).

According to the European Commission, almost two thirds of the EU’s growth is driven by innovation. Despite this, the EU still positions behind other countries as for Gross domestic product expenditure on R&D activities (2.18%, vs 4.52% of South Korea, 3.28% of Japan and 2.82% of the US. Only China slightly follows at 2.14%). The same trend applies also to business enterprise investments in R&D (EU 1.45%, vs 3.63% of South Korea, 2.6% Japan, 2.05% of the US, and 1.66% of China).

The new Innovation Agenda

The Conclusions on the New European Innovation Agenda are the result of a work started in November 2021, when the Council’s Recommendation on a Pact for Research and Innovation (R&I) in Europe highlighted the importance of synergies with sectorial policies and industrial policy, as well as the coordination of R&I policies and programmes to support the development of breakthrough and incremental innovations across the Union. The New European Innovation Agenda was announced by the Commission in July 2022 and is intended to fully exploit the potential of deep tech innovations. In September 2022, the Czech Presidency of the Council started the drafting of the conclusions, and the final text adopted by the Competitiveness Council (Research) at its meeting of 2 December 2022.

All types of innovation play a critical role in driving EU’s competitiveness, states the document, with a particular emphasis on research-driven innovation, deemed able of shaping and creating new markets. Incremental and breakthrough innovation are both essential to maximise the societal and economic value of the resulting outcomes. Investing in higher education and R&I is thus essential to achieve these goals, and to position the EU as a global R&I leader. Social sciences and humanities should also be part of the comprehensive approach to innovation described by the Conclusions.

The diversification of supplies and the mitigation measures to tackle strategic dependencies on external suppliers are critical issues to be faced to compete in the complex global geopolitical scenario. An open approach to international R&I cooperation is still the goal of the European institutions, requiring shared fundamental values and principles with other countries and a balanced and reciprocal approach.

At the regulatory level, flexibility, fit-for-purpose, forward-looking and innovation-friendly remain the preferred keywords to characterise the new framework. The development of breakthrough, deep-tech and disruptive innovations should be supported by standardisation and accreditation, and regulatory adaptation and experimentation.

The Council also supports the role of private R&I investments and strategic use of intellectual assets as a fundamental part of the undergoing transition, as well as further policy reforms at Union, national and regional levels to better encourage the full development and implementation of new technologies, including testing and demonstration facilities.

The European Innovation Council (EIC) Fund has been confirmed as the tool to support investments in innovation. Among others, the Conclusions ask the Commission to implement the EIC’s Scale Up 100 action and to facilitate access to capital for innovative start-ups and SMEs through the InvestEU Programme.

Conclusions on Research Infrastructures

The second document approved in December 2022 updates the vision of the European RI ecosystem, with a particular focus on the system of integrated research infrastructures. Access to RIs is deemed fundamental to support innovation by private, large and medium-small companies. It can take different forms, i.e. proprietary access to RIs, contractual research, joint R&I, training and industrial, supply of top-class products and services to RIs. Research infrastructures are also important to sustain regional development and support the availability of a wide range of skills and relating jobs.

A central part of document is represented by the call to proceed with the implementation of the ERA Policy Agenda for the period 2022–2024 and, in particular, ERA Action 8 (“Strengthen sustainability, accessibility and resilience of RIs in the ERA”). To this instance, a major activity should aim to involve RIs in producing, collecting, processing, storing and providing quality certified scientific data in accordance with the FAIR (Findable, Accessible, Interoperable and Reusable) principles. This action is considered essential to facilitate the sharing and use of data across a broad range of disciplines as well as at the international level.

To improve the RIs’ framework, the invitation of the Council is for the European Strategy Forum on Research Infrastructures (ESFRI) to run a comparative study aimed to identify best practices and elaborate recommendations to national and regional RI stakeholders by the end of 2023. A common approach for the staff of the RIs, especially in the case of a European Research Infrastructure Consortium (ERIC), is also envisaged.

Research infrastructures can’t operate without the support of Technology Infrastructures (TIs); a mapping exercises of the last ones is considered essential in order to proceed with the implementation of the TI concept within the ERA Policy Agenda. Members states and the Commission should also work to better identify the role of RIs in the implementation of Horizon Europe (i.e. European Partnerships and Missions, industrial technology roadmaps, etc.). RIs may also contribute to designing new services based on their different missions and should be supported by long-term investments by member states with the support of the Commission. To this instance, the analysis of possible types of financial support throughout RIs’ life cycle, with identification of good practices and synergies of various funding resources, should be accomplished by ESFRI.

The Council also invited the Commission to present an initiative on a revised European Charter for Access to Research Infrastructures by the end of 2023. A better coordination between ESFRI and the European Open Science Cloud (EOSC) Steering Board would also be needed.


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.


EIC: challenges for the governance and opportunities for innovation

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by Giuliana Miglierini

The European Innovation Council (EIC) was launched in March 2021 by the EU Commission to support the growth of highly innovative startup companies. Since then, the programme experienced some difficulties to become fully operative, as delays occurred with companies requesting grant-only or grant-first support and with the decision-making procedures for companies requesting blended finance or equity-only investments.

According to the Commission, this situation is a result of the restructuring of the EIC Fund to better reflect Horizon Europe legislation and the outcomes of the pilot phase. Negotiations are also ongoing with an external fund manager of the EIC Fund and are expected to close by the end of June. Internal discussions in the European Commission and IT problems are among the possible causes of the delays, reported Politico. A situation that is highly impacting on the selected companies, that are hampered from proceeding with the timely development of their business.

The difficult governance of the EIC prompted the European Parliament to start an investigation, led by Horizon Europe’s rapporteur Christian Ehler, to better clarify the issues undermining the EIC functioning (see more on ScienceBusiness). Mr. Ehler asked the stakeholders to provide inputs by 14 June; the final outcomes of the investigation will be summarised in a non-legislative report on the implementation of the EIC.

The idea behind the report is to get the debate about the future of the EIC out in the open and provide the Parliament’s perspective on it. As co-legislator we have a duty to ensure the Commission implements the legislation we approved,” said Christian Ehler.

The EIC Accelerator

Available investments for startups and SMEs under the EIC Accelerator programme total €2.5 million for grants and €0.5 to €15 million equity investments through the EIC Fund. Higher investments are possible to support the development of technologies of strategic European interest.

A fast assessment procedure was introduced in 2021 to submit new projects at any time. A tailored business coaching support is available to successful candidates to draft the full applications, which are then evaluated at regular cut-off dates approximately every three months. The Commission announced it is finalising its decision-making procedure for the grant and equity components to companies selected for blended finance during the 2021 cut-offs. This is expected to allow the signature of contracts for the grant component of blended finance in a couple of days after the closure of the decision-making procedure, followed by the payment of a pre-financing of the grant one week later. A due diligence is needed to support the investment decision by the EIC Fund for the equity component, that will thus occur few weeks or months later.

The current status of the EIC Accelerator

According to the European Commission, 65 companies were selected for funding under the EIC Accelerator programme for the June 2021 cut-off, following the evaluation of their full application. Of these, 29 companies requested grant-only or grant-first support and 31 requested blended finance, including a grant component and equity investment. Contracts for six grant-only or grant-first companies were still to be signed as of 13 May 2022. The grant component is expected to close by early June 2022, while for the equity investment component and equity-only closure of the investment agreement is expected after June.

Some other 99 companies were selected for support in the October 2021 cut-off. Only one contract of the overall 34 companies that requested grant-only or grant-first support has been signed. Signature of the grant component for companies that selected blended finance is planned in July 2022, followed by the equity component and equity-only projects from the summer up to the end of the year.

The third cut-off round of March 2022 saw the selection of some other 74 companies, over a total of more than 1000 applications. Selected companies will each receive grants and/or equity investments up to €17.5 million. The next cut-offs for full applications is 15 June and 7 October.

Deep-tech training needed

A report published in April 2022 by the EIC Pilot Expert Group suggests the creation of two new deep-tech training programmes to better support the development of human entrepreneurial talent while fostering technological solutions. “We argue that EIC can’t succeed without including in its mandate the objective of proactively realising the entrepreneurial talent of Europe’s brilliant scientists”, write the members of the Expert Group in the foreword of the document.

The EIC Trailblazer Programme and the Pioneer Programme are the tools identified to reach this challenging goal. Both of the programmes should be implemented in a phased manner using pilot projects to allow for experimentation and learning, according to the recommendations set forth in the report. A main expected outcome is the creation of a new generation of deep-tech entrepreneurs, the EIC Innovators, able to better evaluate how their technologies are fitting into the world for commercialisation and impact.

The EIC Trailblazer Programme is targeted to support talented PhD candidates and postdocs that are part of projects funded by the EIC Pathfinder and EIC Transition. These EIC Trailblazer Fellows may receive a deep tech training programme, aimed to work as an internal accelerator and an elite programme targeting proto-entrepreneurs. A special prize and/or grant may also be considered to recognise scientific and entrepreneurial talents.

The Pioneer programme would allow for deep-tech add-on modules sponsored by the EIC to complement existing programmes delivered at the local level, in member states and potentially EU associated countries. Beneficiaries would include talented scientists that one day may apply for EIC funding, the “proto-EIC Innovators”.

Comments from research-intensive universities

The Guild of European research-intensive universities published a statement to contribute to MEP Christian Ehler’s initiative of a report on the implementation of the EIC. A better recognition of the role of universities’ Technology transfer offices (TTOs) as key actors in enabling researchers to develop their results for commercial and societal purposes is the key message of the Guild. To this instance, duplication of activities of the TTOs in terms of project management and support services should be avoided. Concerns are also highlighted with reference to the standard Intellectual Property (IP) provisions in the EIC Pathfinder and Transition schemes, as they might negatively affect the functioning of already well-performing TTOs without strengthening the capacities of weaker TTOs.

A positive experience is also acknowledged as for the EIC Transition scheme, that supports universities and their spin-offs with appropriate financial support for proof-of-concept projects. The Guild asks for the extension of this funding scheme to support an higher number of innovative projects.

An example of funded project

Swedish company Bico (formerly Cellink) is an example of EIC-funded project which saw a very rapid growth of its business, achieving $ 1 billion in market valuation in the first five years of activity. Founded in 2016, the company is now leader in the bioink sector and is developing new bio-printing technologies to be used for 3D printing of organs and tissues, so to overcome the lack of donors, reduce shortages and improve drug development.

Bioprinting is only one of the technologies included in Bico’s portfolio; gene therapy, gene editing, CRISPR, diagnostics are also investigated. The company built up from the first universal bioink created by Professor Paul Gatenholm (Chalmers University), a special biomaterial that enables human cells to grow outside the body and perform all the vital functions.



IVD regulation in force: new MDCG guidelines and criticalities for innovation in diagnostics

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by Giuliana Miglierini

The new regulation on in vitro diagnostic medical devices (IVDR, Regulation (EU) 2017/746) entered into force on 26 May 2022. The new rules define a completely renewed framework for the development, validation and use of these important tools supporting the diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of a disease, in line with technological advances and progress in medical science. “Diagnostic medical devices are key for lifesaving and innovative healthcare solutions. Today we are marking a big step forward for the patients and the diagnostics industry in the EU. The COVID-19 pandemic has underlined the importance of accurate and safe diagnostics, and having stronger rules in place is a key element in ensuring this is the case for EU patients.”, said Stella Kyriakides, Commissioner for Health and Food Safety

The European Commission also published a Q&A document to facilitate the comprehension of the new framework.

The main contents of the IVDR

The risk-based approach for the classification and development of in vitro diagnostics is at the core of the IVDR. There are four different classes of IVDs: class A (low individual risk and low public health risk), class B (moderate individual risk and/or low public health risk), class C (high individual risk and/or moderate public health risk) and class D (high individual risk and high public health risk). The assessment of the quality, safety and performance of IVDs by independent notified bodies shall be based on more detailed and stringent rules. Higher-risk categories will also be subject to further assessment by newly created scientific bodies acting under the auspices of the European Commission, such as the expert panels and the network of EU reference laboratories. Twelve expert panels have been established up to now.

Each single IVD will be associated to a Unique Device Identifier (UDI), so to facilitate its traceability along the entire life cycle. The identifier will also serve to locate the relevant information about a diagnostic marketed in the EU within the European database of medical devices (EUDAMED), where also a summary of safety and performance will be publicly available for medium- and high-risk devices. The database will also contain information about all economic operators and provide a repository for the certificates issued by notified bodies.

The new regulation strengthened the framework for post-marketing surveillance of IVDs, asking for a closer coordination of the vigilance activities by all member countries. The IVDR also introduced reinforced rules on clinical evidence and performance evaluation, including an EU-wide coordinated procedure for authorising multi-centre performance studies, and a specific regime for devices manufactured and used in the same health institution (in-house devices).

Difficulties in the timely implementation of the (EU) 2017/746 regulation may still be possible due to the lack of a sufficient number of notified bodies, as only seven have been designated up to now, established in only four countries (Germany, France, the Netherlands and Slovakia), while eleven other applications were pending in May 2022. To solve this issue, Regulation (EU) 2022/112 was adopted. A transition period up to May 2025 applies to devices that require a notified body certificate already under the previous Directive (around 8%, vs about 80% according to the IVDR); other classes of IVDs benefit of different transition periods (May 2025 for class D, May 2026 for class C and May 2027 for class B and A sterile).

Q&As on the interface with the Clinical Trial regulation and UDI

The Medical Devices Coordination Group (MDCG) published a Q&A document (MDCG 2022-10) to provide guidance on the interface between Regulation (EU) 536/2014 on clinical trials for medicinal products for human use (CTR) and the IVDR.

The guideline addresses the requirements for assays used in clinical trials, that may include IVDs carrying a CE mark for the intended purpose, IVDs developed in-house and devices for performance studies. Only the devices falling on the definition of an IVD with regards to their intended purpose are subject to the IVD legislation. The guideline also provides suggestions on assays likely to be considered IVDs, as they are used for medical management decisions of trial subjects within the trial.

Another Q&A guideline (MDCG 2022-7) provides clarifications on how to apply the Unique Device Identification system to both medical devices and in vitro diagnostics.

Topics covered by the document include the need for a new UDI-DI assignment in case the number of items in a device package changes or for single-use reprocessed devices, the requirement for economic operators to maintain a registry of all UDIs of the devices which they have supplied or with which they have been supplied, or the requirement of a new UDI-DI for substance-based medical devices, in case of formula quantity changes or additional claims.

The MDCG also addressed the assignment and use of the Basic UDI-DI and the determination of the ‘grouping’ for design or manufacturing characteristics, including the case of devices comprising a patient and a physician facing module, and the contents of the Declaration of Conformity (DoC). Labelling is also addressed, as well as rules for systems and procedure packs (SPPs) and configurable devices, as well as those applying to retail point of sale, promotional packs and marketing related samples.

The impact of the IVDR on innovation

The issues linked to the IVDR implementation and their impact on innovation and diagnostic laboratories, including the development and use of in-house devices, have been analysed by the BioMed Alliance In Vitro Diagnostics Task Force, and published in HemaSphere.

The Task Force identified two main challenges to be faced by the academic diagnostic sector. The first one impacts on the possibility to use in-house IVDs, based on the demonstration that no equivalent CE-IVD kit is present on the market or when the specific needs cannot be met at the appropriate level of performance by an equivalent CE-IVD. The strict exemptions applying to in-house IVDs (e.g. prohibition of transferring to other legal entities, compliance with EN ISO 15189 and justification of use, etc.) may impact also on the potential for innovation in the diagnostic sector.

The second challenge refers to the not so clearly defined boundaries between CE marked-IVDs, modified CE-IVDs, Research Use Only (RUO) tests, and in-house IVDs. The Task Force recalls the immediate applicability of the General Safety and Performance Requirements specified in Annex I of the IVDR, as they have not been included in the approved amendment of the implementation timeline.

Furthermore, only tests meeting economic viability may in the future be transferred from the academia to the industry, while rare or complex tests would probably remain excluded. According to the paper, the cost of diagnostics shall likely increase, and the academa should carefully consider how to support further research into rare or complex diagnostics in order to ensure their availability to patients.

Following the results of a survey among medical societies on current diagnostic practices, several suggestions are made to better support the implementation of the IVDR, namely by mean of the availability of diagnostic equivalents of the European Reference Networks for rare diseases and a concerted action involving all stakeholders. A joint biomarker-to-test pipeline between the IVD industry and research/academic labs would also be useful to facilitate the initial development and local application of innovative diagnostics within healthcare institutions or diagnostic reference networks with specific expertise, to then transfer them to manufacturers above a certain production volume.