The EU Commission proposal of the new pharmaceutical legislation

May 5, 2023

AESGP, antimicrobial medicines, approval time, CHMP, comparative clinical trials, Council Recommendation, daptive clinical trials, data protection, Directive, earlier warnings, early scientific advice, EFPIA; Medicines for Europe, electronic product information, EMA Committees, environmental risk assessment, EUCOPE, EuropaBio, European Commission, European Council, European Parliament, exclusivity protection, generic and biosimilar medicines, health data, innovative medicines, list of critical medicines, market protection, marketing authorisation renewal, medical needs, medicines shortages, new indications, paediatric medicines, patient representatives, patient-centricity, PRAC, prevention plans, price negotiations, rare diseases, real world evidence, regulation, regulatory flexibility, regulatory procedures, regulatory protection, regulatory sandboxes, repurposing, revision of the European pharmaceutical legislation, rolling review, single European market for medicines, temporary emergency marketing authorisations, Transferable data exclusivity voucher, transparency on public funding for R&D, unmet medical needs

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.

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

January 6, 2023

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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.

Approval of the Data Governance Act, and EMA’s consultation on the protection of personal data in the CTIS

June 24, 2022

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by Giuliana Miglierini

The Data Governance Act (DGA) was approved and adopted in May 2022 by the European Council, following the positive position of the EU Parliament; the new legislation will entry into force after being signed by the presidents of the Parliament and of the Council and twenty days after the publication in the Official Journal of the European Union. The new rules governing data collection and sharing will start to apply 15 months after the entry into force of the new regulation.

The protection of personal data is also central to the new transparency requirements established by the Clinical Trials Regulation (CTR). To support pharmaceutical companies dealing with personal data within the Clinical Trials Information System (CTIS), the drafting of a dedicated guideline is ongoing. The European Medicines Agency has published a document to support the public consultation which will remain open until 8 September 2022.

The Data Governance Act

The new DGA regulation is part of the European data strategy and aims to promote the availability of data within a trustworthy environment, with the final goal to improve their use for research and the creation of innovative services and products.

Central to the DGA are some categories of public-sector data that are subject to property rights (i.e. trade secrets, personal data and data protected by intellectual property rights), which were not covered by the previous Open Data Directive (2019). Under the new rules, the reuse of such data shall be permitted provided that the public-sector bodies allowing it are technically equipped to ensure the preservation of privacy and confidentiality.

The DGA will also parallel the General Data Protection Regulation (GDPR) in providing appropriate safeguards against the unlawful international transfer of or governmental access to non-personal data (as the GDPR does for the personal ones). Secondary legislation may be issued by the Commission, for example, to ensure specific non-EU countries provide appropriate safeguards for the use of non-personal data transferred from the EU, on the basis of the existence of local equivalent measures of a similar protection level to that existing in the EU.

The reuse of public-sector data shall be justified with respect to the provision of a service of general interest; exclusive arrangements are needed, with a duration of 12 months for new contracts and 30 months for the existing ones. The access to data will operate through a searchable electronic register of public-sector data to be established by the European Commission and available via national single information points. Model contractual clauses may be adopted by the Commission in order to support public-sector bodies and re-users with the transfer of nonpersonal data covered by the DGA to third countries.

Data intermediation services

Data intermediation services are the core of the new business model resulting from the Data Governance Act; they will be listed in a register to improve transparency and trust. The final target is to enable a secure environment for the sharing of data.

Digital platforms shall represent the reference point for voluntary data-sharing between companies; they should fulfil all data-sharing obligations at the European and national level. Individuals shall maintain full control over their personal data; service providers should support them in exercising their rights according to the GDPR. New tools may be introduced to facilitate sharing on the basis of data holder’s consent, i.e. personal data spaces or data wallets. Service providers won’t be able to share data for purposes other than the allowed ones, and cannot benefit from selling data, even though they can charge for the transactions the carry out.

Data altruism is another key concept of the DGA regulation, making possible to voluntary share its own data for the common good, for example in the field of medical research. Data altruism will apply to both individuals and companies; the access to data should be possible upon registration of the interested entities in a national register of recognised data altruism organisations. A specific logo will support the easy identification of both compliant providers of data intermediation services and data altruism organisations.

The new European Data Innovation Board (EDIB) will be in charge of assisting the EU Commission on issues relative to the interoperability of data intermediation services and the development of guidelines on the creation of data spaces.

Data protection in the regulatory field

EMA’s draft guideline provides a description of the Clinical Trials Information System, its components and functionalities, as well as the rules for the publication of clinical trials information submitted to the CTIS (chapter 2). The protection of both personal data and commercially confidential information (CCI) submitted to the CTIS is then discussed (chapters 3 and 4), together with the protection of personal data and CCI in inspection reports (chapter 5).

The CTR established the CTIS as the single entry point for the submission of data and documents relating to clinical trials; the corresponding EU Database contains such data and documents, and the two are jointly referred to as the EU Portal and Database (EUPD).

The EUPD is the first component of the CTIS, representing the Clinical Trial module providing secure domains accessible to regulatory authorities and sponsors along the entire life cycle of the medicinal product and a public website where to find public information. The second component of the CTIS is represented by the EudraVigilance (EV) safety module, consisting of the Repository of Annual Safety Reports (ASRs) and the Clinical Trial Module (EVCTM) for Individual Case Safety Reports (ICSRs) of suspected unexpected serious adverse reactions (SUSARs) related to Investigational Medicinal Products. The optimisation of regulatory data flow also involve the use of data contained in the Extended EudraVigilance Medicinal Product Dictionary (XEVMPD), in the Organisation Management Service (OMS), and in the Identity Access Management (IAM).

The CTR regulation establishes the rules preventing the access to data stored in the EU Database on the basis of confidentiality information. Is this the case, for example, of personal data falling under Regulation (EU) 2018/17255 governing the protection of natural persons and their personal data. Commercially confidential information may also fall under this provision, upon consideration of the status of the marketing authorisation and unless there is an overriding public interest in disclosure. This means no data from the clinical trial application dossier can be made public before the decision on the clinical trial has been taken.

All personal data (such as the ones of trial participants) in documents submitted to the CTIS should follow the general principles on anonymisation and pseudonymisation of personal data. The draft guideline provides examples of the public information that should be made available with respect to a certain clinical trial. This should include as a minimum the main characteristics of the trial, the conclusion on Part I of the assessment report for the authorisation, the decision on the authorisation of a clinical trial, the substantial modification of a clinical trial, and the clinical trial results including reasons for temporary halt and early termination.

A dedicated module of the CTIS is meant for inspectors to manage all information relative to GCP inspections conducted under the CTR, including the uploading of the final report. To this instance, the guideline indicates no personal data should be included in the version of the inspection report due for publication.

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