(1)

The Union pharmaceutical legislation for centrally authorised medicinal products, laid down in, inter alia, Regulations (EC) No 141/2000 (3), (EC) No 726/2004 (4) and (EC) No 1901/2006 (5) of the European Parliament and of the Council, has enabled the authorisation of high-quality, safe and efficacious medicinal products in the Union, contributing to a high level of public health and the smooth functioning of the internal market for those products.

(2)

The ‘Pharmaceutical Strategy for Europe’ adopted by the Commission in its communication of 25 November 2020 marks a turning point, with the addition of further key objectives. It aims to create an attractive environment for research, development and production of medicinal products in the Union, together with a modern framework that makes innovative and established medicinal products available to patients and healthcare systems at affordable prices. It also aims to strengthen the fight against shortages of medicinal products, ensure security of supply and address environmental concerns.

(3)

Ensuring that patients receive the medicinal products they need, when they need them, regardless of where they live in the Union, is a central objective of the Commission’s approach as set out in its communication of 22 May 2024 entitled ‘The European Health Union: acting together for people’s health’. Ensuring the competitiveness of the European pharmaceutical industry, whilst providing better availability of medicinal products and more equal and timely access for patients, is a key objective of the Union pharmaceutical reform, as proposed by the Commission in April 2023.

(4)

Commission communication of 24 October 2023 entitled ‘Addressing medicine shortages in the EU’ outlined key measures aimed at addressing critical shortages of medicinal products and strengthening security of supply in the Union in anticipation of the measures provided for in a revised pharmaceutical regulation. Among other things, that communication envisaged a first informal Union list of critical medicinal products and the launch of a European voluntary solidarity mechanism for medicinal products allowing Member States to request support from another Member State and redistribution of available stocks in the event of shortage.

(5)

Addressing unequal patient access to medicinal products has become a key priority of the Pharmaceutical Strategy for Europe as has been highlighted by the Council and the European Parliament. Member States and the European Parliament have called for revised mechanisms and incentives for development of medicinal products tailored to the level of unmet medical need, while ensuring a transparent process, patient access to medicinal products, and availability as well as affordability of medicinal products in all Member States.

(6)

Previous amendments to the Union pharmaceutical legislation have addressed access to medicinal products by providing for accelerated assessment of marketing authorisation applications or by allowing conditional marketing authorisation for medicinal products to meet unmet medical needs. While these measures accelerated the authorisation of innovative and promising therapies in some areas, the medicinal products do not always reach the patient and patients in the Union still have different levels of access to medicinal products. In addition, many unaddressed public health priorities remain.

(7)

The COVID-19 pandemic further underlined critical issues, which require a reform of the Union pharmaceutical legislation to strengthen its resilience, while improving the availability of medicinal products and ensuring that it contributes to public health needs and serves the people under all circumstances.

(8)

For the sake of legal clarity and simplification, and having regard to the need to reform the Union pharmaceutical legislation, the legal provisions applicable to centrally authorised medicinal products should be integrated into a new Regulation.

(9)

Veterinary medicinal products are governed by Regulation (EU) 2019/6 of the European Parliament and of the Council (6). Those medicinal products fall outside the scope of this Regulation, except for certain provisions on the governance and general tasks of the European Medicines Agency (the ‘Agency’) set out in this Regulation that still apply to them. The Agency’s specific tasks concerning veterinary medicinal products are laid down in Regulation (EU) 2019/6 and Regulation (EC) No 470/2009 of the European Parliament and of the Council (7).

(10)

Without prejudice to the provisions laid down in Regulation (EU) 2019/6, which remain applicable for veterinary medicinal products, in order to create greater legal certainty, this Regulation should set certain conditions for placing on the market medicinal products authorised by the Union, confer on the Agency powers to monitor the distribution of medicinal products authorised by the Union, define the responsibilities regarding the transparency rules for the Agency’s work and, in the event of failure to observe this Regulation and the conditions contained in the marketing authorisations granted under the procedures it establishes, specify the sanctions and the procedures for implementing them.

(11)

It is necessary to provide for the coordinated implementation of Union procedures for the marketing authorisation of medicinal products, and of Member States procedures for the marketing authorisation which have already been harmonised to a considerable degree by Directive (EU) 2026/… of the European Parliament and of the Council (8) (+).

(12)

The scope of this Regulation with regard to centrally authorised medicinal products needs to be adapted to the realities of the market and technological development as well as to the need to ensure a centralised evaluation of certain categories of medicinal products. In the light of the Commission’s report of 31 August 2021, addressed to the European Parliament and the Council, on the experience acquired with the procedures for authorising and supervising medicinal products for human use, it has proved necessary to improve the functioning of the marketing authorisation procedures for the placing of medicinal products on the internal market and to amend certain administrative aspects of the Agency. In addition, the regulatory framework should be adapted to the current market conditions and economic reality, while continuing to safeguard a high level of protection of public health and the environment. It emerges from the report that certain operating procedures need to be corrected and adapted in order to take account of scientific and technological development. It also emerges from the report that the previously established general principles which govern the centralised marketing authorisation procedure (‘centralised procedure’) should be maintained.

(13)

As regards the scope of this Regulation, the authorisation of antimicrobials at Union level is in the interest of patients’ health and therefore it should be made possible to authorise them through the centralised procedure.

(14)

Medicinal products for rare diseases and for children should be subject to the same provisions as any other medicinal product concerning their quality, safety and efficacy, for example as regards the marketing authorisation procedures and the pharmacovigilance, quality and environmental risk assessment requirements. However, specific requirements also apply to them. Such requirements, which are currently laid down in separate legislative acts, should be integrated into this Regulation in order to ensure the clarity and coherence of all the measures applicable to such medicinal products.

(15)

With a view to maintaining a high level of scientific evaluation for new medicinal products and medicinal products that will serve the entire Union population, the centralised procedure should be mandatory for high-technological medicinal products, particularly those resulting from biotechnological processes, and for advanced therapy medicinal products, priority antimicrobials, orphan medicinal products, medicinal products authorised in accordance with paediatric use marketing authorisation and any medicinal product containing a new active substance. In addition, the mandatory scope of the centralised procedure should be aligned with that provided for in Regulation (EC) No 726/2004. Accordingly, it should continue to apply to medicinal products containing a new active substance authorised between 20 May 2004 and the date of application of this Regulation, for the indications listed in Annex I to this Regulation.

(16)

For medicinal products for human use, optional access to the centralised procedure should also be provided for where a single procedure offers added value for patients. The centralised procedure should remain optional for medicinal products that do not fall within categories subject to centralised marketing authorisation but are nonetheless therapeutically innovative. It is appropriate to extend access to that procedure to medicinal products that, while not necessarily innovative, could still provide benefits to society or to patients, including paediatric patients, especially if they are authorised at Union level from the outset, such as certain medicinal products which can be dispensed without a medical prescription. This option could be extended to generic medicinal products and biosimilar medicinal products authorised by the Union, provided that this does not undermine harmonisation achieved when the reference medicinal product was evaluated nor the results of that evaluation. At the same time, to ensure wide availability of generic medicinal products, it is possible for those medicinal products to be authorised by the competent authorities of the Member States, even if they are based on a centrally authorised reference medicinal product.

(17)

The Court of Justice of the European Union (hereafter ‘the Court’) has on numerous occasions held that the health and life of humans rank foremost among the assets and interests protected by the Treaties. According to the Charter of Fundamental Rights of the European Union (the ‘Charter’), a high level of human health protection is to be ensured in the definition and implementation of all the Union’s policies and activities. The centralised procedure ensures a high standard of scientific evaluation and delivers significant benefits to the Union’s patient population, particularly regarding innovative medicinal products that can improve prevention, diagnosis and treatment of diseases and patients’ lives. In addition to its objective of guaranteeing a high level of protection of public health at Union level, the centralised procedure also brings greater clarity and efficiency to the Union’s authorisation system. This allows the marketing authorisation applicant (the ‘applicant’) of such medicinal products to benefit from easier and harmonised access to the internal market. However, these innovative medicinal products are often unevenly available across the Union. This results in different levels of patient access depending on the Member State in which patients live. While fully respecting fundamental rights and without prejudice to the provisions of the Treaties, including provisions on the free movement of goods and common rules on competition, it is essential that marketing authorisation holders who obtain a centralised marketing authorisation for such medicinal products make every effort to place them on the market in all Member States. In light of the fact that medicinal products are key for a broad and good therapeutic offer to patients in the Union, this is necessary to maintain a high level of public health protection across the Union, remove obstacles within the internal market and to strengthen Union-wide access to these products. Marketing authorisation holders should, in addition to complying with national legislation and procedures aiming at placing on the market and supplying medicinal products at national level, also make their best efforts in complying with the specific requirements on placing on the market and supplying a medicinal product in a Member State provided for by Directive (EU) 2026/… (+) that allow Member States to signal directly to companies their interest to have supply of a specific new medicinal product. Accordingly, a marketing authorisation holder for a medicinal product authorised through the centralised procedure which is subject to regulatory protection or intellectual property rights, should ensure that the medicinal product is placed on the market and supplied in accordance with the needs of patient populations across all Member States. This obligation, however, is neither to compromise the financial viability of the company nor to be considered breached where external factors beyond the company’s control make supply in all Member States impossible.

(18)

The establishment of the Agency by means of Council Regulation (EEC) No 2309/93 (9), which was repealed by Regulation (EC) No 726/2004, has made it possible to reinforce the scientific evaluation and monitoring of medicinal products in the Union, in particular through its scientific bodies and committees for which competent authorities of the Member States provide experts and expertise, ensuring a high quality and independent assessment. As this Regulation serves to replace Regulation (EC) No 726/2004, the Agency, previously established under Regulation (EC) No 726/2004, should continue to function under this Regulation.

(19)

Experience with the functioning of the regulatory system has shown that the existing Agency multi-scientific committee structure often creates complexity in the scientific assessment process among committees, duplication of work and non-optimised use of expertise and resources. In addition, the Agency and the competent authorities of the Member States are confronted with challenges related to limited capacity and appropriate expertise to deal with increasing number of procedures related to existing medicinal products and assessment of new ones, in particular cutting edge innovative and complex medicinal products.

(20)

Scientific committees, such as the Committee for Advanced Therapies, have been instrumental to ensure expertise and capacity building in an emerging technological field. However, after more than 15 years, advanced therapy medicinal products are now more common. The integration of their assessment in the work of the Committee for Medicinal Products for Human Use will facilitate the scientific evaluation of medicinal products within the same therapeutic class, regardless of the technology on which they are based.

(21)

To optimise the functioning and efficiency of the regulatory system, the structure of the Agency’s scientific committees is simplified and reduced to two main committees for medicinal products for human use, namely the Committee for Medicinal Products for Human Use and Pharmacovigilance Risk Assessment Committee.

(22)

The simplification of procedures should not have an impact on standards or the quality of scientific evaluation of the medicinal products to guarantee the quality, safety and efficacy of medicinal products. It should also allow for the reduction of the scientific evaluation period from 210 days to 180 days.

(23)

The Agency’s scientific committees should be supported, in relation to their evaluation duties, by working parties, whilst retaining complete responsibility for the scientific opinions issued by them. Those working parties should be open to experts from the scientific world appointed for that purpose.

(24)

The Agency and its committees should, where necessary, establish the appropriate working parties to ensure the appropriate expertise for the evaluation of medicinal products, including an Environmental Risk Assessment working party. That working party should have the scientific expertise necessary to characterise and assess the environmental risks, and the mitigation measures for such risks, related to the use and disposal of medicinal products.

(25)

The expertise of the Committee for Advanced Therapies, the Committee for Orphan Medicinal Products, the Paediatric Committee and Committee for Herbal Medicinal Products is retained through working groups, working parties, advisory groups, and a pool of experts who are organised based on different areas of expertise and who are giving input to the Committee for Medicinal Products for Human Use and the Pharmacovigilance Risk Assessment Committee. This structure gives the possibility for the Committee for Medicinal Products for Human Use and the Pharmacovigilance Risk Assessment Committee to call upon additional scientific experts to provide specific input and advice on specific aspects raised during the evaluation. In addition, patients and healthcare professionals can be part of the pool of experts based on their expertise. The Committee for Medicinal Products for Human Use and the Pharmacovigilance Risk Assessment Committee consist of experts from all Member States while working parties and expert groups consist in majority of experts appointed by the Member States, based on their expertise, and, if necessary, of external experts. The model of rapporteurs remains unchanged. The efficiency gain, involvement of appropriate scientific expertise and broad geographic representation of experts in the scientific committees, working parties and working groups will be ensured as part of the strategy for the organisational management and internal control systems. Representation of patients and health-care professionals, with expertise in a wide range of areas, including rare and paediatric diseases, is assured at the Committee for Medicinal Products for Human Use and the Pharmacovigilance Risk Assessment Committee, in addition to the dedicated working groups representing patients and health-care professionals. Information regarding the composition and work of the committees, working parties and working groups, should be publicly available.

(26)

It is crucial not only that the expertise of experts be preserved within working groups, working parties and a pool of experts, but also that the relevant expertise be expanded to cover emerging technologies, incorporate expertise from a broader range of Member States and enable the Agency to continue fulfilling its obligations at the highest scientific level. It is also essential for experts to be able to share knowledge, expand their skills through training programmes, such as those offered by the EU Network Training Centre, and engage in on-the-job learning activities, including through shadowing rapporteurs, mentoring, and participating in discussions on topics of interest in working parties, European scientific expert groups, and other relevant fora.

(27)

The Agency’s scientific committees field of activity should be enlarged and their operating methods and composition modernised. Therefore it is important to ensure patient and healthcare professional representation in the Committee for Medicinal Products for Human Use as it is the main evaluation committee of the Agency.

(28)

The Committee for Medicinal Products for Human Use should be exclusively responsible for preparing the Agency’s opinions on all questions concerning medicinal products for human use.

(29)

The patients and healthcare professionals representatives, for both the Committee for Medicinal Products for Human Use and the Pharmacovigilance Risk Assessment Committee, should be selected by the Commission, based on a public call for expressions of interest. Healthcare professionals can be represented by doctors and pharmacists. The appointment of such representatives should ensure there is a well-balanced representation of medical specialties and diseases amongst appointed members and alternates, and there are robust rules on the prevention of conflicts of interest including financial or other interests in the pharmaceutical or medical devices industry which could affect their impartiality.

(30)

The structure and functioning of the Agency’s various bodies should be designed in such a way as to ensure the continuous renewal of scientific expertise, foster cooperation between Union and national bodies and ensure the adequate involvement of civil society, as well as to be able to accommodate a future enlargement of the Union. The Agency’s various bodies should establish and develop appropriate contacts with the parties concerned, in particular with representatives of patients, consumers and healthcare professionals.

(31)

The Agency’s primary task should be to provide Member States and Union institutions with the best possible scientific opinions, enabling them to exercise the powers of authorisation and supervision of medicinal products conferred on them by Union legal acts in this field. Marketing authorisation should be granted by the Commission after completion of a single scientific evaluation procedure, conducted by the Agency, applying the highest possible standards, addressing the quality, safety and efficacy of high-technology medicinal products.

(32)

When examining the marketing authorisation application of the medicinal product, the Agency should draw up the European public assessment report (EPAR) on the quality, safety, efficacy, and the environmental risk assessment of the medicinal product and state the reasons for its opinion. The Agency should make publicly available a summary of the EPAR and a summary of the environmental risk assessment, after the deletion of any information of a commercially confidential nature and written in a manner that is understandable to the public.

(33)

To ensure close cooperation between the Agency and the experts operating in Member States, the composition of the Management Board should be such as to guarantee that the competent authorities of the Member States are closely involved in the overall management of the system for authorising medicinal products in the Union.

(34)

The independence and impartiality of the members of the Management Board, the committees, rapporteurs and experts who participate in meetings or working groups of the Agency is crucial to avoid any conflict of interest and to preserve the scientific integrity of the work and activities of the Agency. In implementing this objective, the Agency faces the challenge of balancing the need for specific expert input within tight time -limits with the necessity of safeguarding the credibility of its decisions from being compromised by conflicts of interest. In certain fields, such as rare diseases, special populations, niche therapeutic indications and highly innovative technologies, the pool of experts is limited, and many are involved in clinical research on medicinal products. In situations where specific expertise is required and can be provided only by individuals with competing interests, which would normally disqualify or limit their involvement in the Agency’s activities as a member or expert, it might still be in the interest of public health to allow such individuals to provide observations before a scientific evaluation is finalised, while excluding them from direct involvement in discussions or decision-making.

(35)

The Agency’s budget should be transparent and composed of fees and charges paid by the private sector and contributions from the Union budget to implement Union policies as well as contributions paid from third countries, and comply, where applicable, with Regulation (EU) 2024/568 of the European Parliament and of the Council (10). Although the majority of its funding comes from fees, the Agency is a public authority. It is of utmost importance to safeguard Agency’s integrity and impartiality in order to maintain public trust in its work and the Union regulatory framework.

(36)

It is important that Member States ensure adequate funding of competent authorities to carry out their tasks under this Regulation and under Directive (EU) 2026/… (+). In addition, in line with the Joint Statement of the European Parliament, the Council and the Commission on decentralised agencies of 19 July 2012, Member States ensure that adequate resources are assigned by the competent authorities of the Member States for the purposes of their contributions to the work of the Agency, taking into account the cost-based remuneration they receive from the Agency.

(37)

The staff of the Agency, including the Executive Director and the Deputy Executive Director of the Agency, as officials or other servants of the Union, are bound by the principles of independence, impartiality, integrity, as well as by the obligations provided for in the Staff Regulations of Officials of the European Union and the Conditions of Employment of Other Servants of the Union laid down in Council Regulation (EEC, Euratom, ECSC) No 259/68 (11) (‘the Staff Regulations’ and ‘Conditions of Employment of Other Servants’) and the rules agreed upon by the Union’s institutions. These obligations should continue after leaving the service such as engaging in lobbying or advocacy vis-à-vis staff of their former institution for their business, clients or employers on matters for which they were responsible. The Staff Regulations also lay down rules for those intending to engage in an occupational activity, whether gainful or not, after leaving the service and provides for the possibility for the Agency, having regard to the interests of the service, either forbid them from undertaking it or give its approval subject to any conditions it thinks fit.

(38)

Scientific advice for future applicants seeking a marketing authorisation should be provided more generally and in greater depth and should be adapted to the specificities of the medicinal product concerned. Similarly, structures allowing the development of advice for companies, in particular micro, small and medium-sized enterprises (‘SMEs’) within the meaning of Commission Recommendation 2003/361/EC (12), and for not-for-profit entities, should be put in place. The Agency should also promote open and public exchanges about the latest scientific developments and updates of scientific guidelines.

(39)

In order to allow for scientific advice for future applicants that is more informative and an exchange of information between different bodies, scientific advice provided by the Agency should sometimes take place in parallel to scientific advice provided by other bodies. This should be the case for the joint scientific consultation carried out by the Member State Coordination Group on Health Technology Assessment established by Regulation (EU) 2021/2282 of the European Parliament and of the Council (13) and for the consultation of the expert panels, in cases of medicinal products involving a medical device, as provided for in Regulation (EU) 2017/745 of the European Parliament and of the Council (14). Where parallel scientific advice consultation mechanisms are established under other relevant Union legal acts, a similar mechanism should apply.

(40)

Promising medicinal products that have the potential to significantly address patients’ unmet medical needs and are expected to be of major public health interest, particularly regarding their level of therapeutical innovation, or are priority antimicrobials or are likely to target a neglected tropical disease, should benefit from early and enhanced scientific support. Such support will ultimately help patients benefit from new therapies as early as possible.

(41)

It is important to recognise that unmet medical needs also exist in the area of mental health, and that promising medicinal products to address such unmet medical needs should also benefit from early and enhanced scientific support.

(42)

The Agency should deliver on request scientific recommendations on whether a product under development, which could potentially fall under the mandatory scope of the centralised procedure, meets the scientific criteria to be a medicinal product. Such an advisory mechanism would address, as early as possible, questions related to borderline cases with other areas, such as substances of human origin, cosmetics or medical devices, which could arise as science develops. To ensure that recommendations given by the Agency take into account the views of equivalent advisory mechanisms in other legal frameworks, the Agency should consult the relevant advisory or regulatory bodies.

(43)

Pharmaceutical research plays a decisive role in the continuing improvement in public health and in ensuring the Union’s competitiveness. Medicinal products, in particular those that are the result of long, costly research will not continue to be developed in the Union unless they are covered by favourable rules that provide for sufficient protection to encourage such research. While such rules can contribute to the attractiveness of the internal market, they are however agnostic to the medicinal products’ geographical origin and medicinal products from third countries authorised in the Union are equally eligible to receive Union incentives.

(44)

To promote innovation and the development of new medicinal products by SMEs and to reduce the cost of the placing on the market of medicinal products for human use authorised via the centralised procedure, these undertakings should benefit from a support scheme from the Agency.

(45)

The support scheme should be composed of regulatory, procedural and administrative support, and of a reduction, deferral or waiver of fees. The scheme should cover the various steps involved in pre-authorisation procedures, such as scientific advice, the submission of the marketing authorisation application, and post-authorisation procedures.

(46)

Not-for-profit entities, such as universities, public bodies, research centres or not-for-profit organisations, represent an important source of research in the area of unmet medical needs, research in different subpopulations, repurposing and treatment optimisation and should also benefit from this support scheme. Whereas it should be possible to take account of the particular situation of these entities on an individual basis, such support can best be achieved by means of a dedicated support scheme, including administrative support and through the reduction, deferral and waiver of fees.

(47)

To increase transparency of scientific assessments and all other activities, a European medicines web-portal should be created and maintained by the Agency.

(48)

The Union Register of Medicinal Products lists all medicinal products for human use as well as orphan medicinal products that have been granted a marketing authorisation by the Commission through the centralised procedure. The information provided in the Union Register can be used to search for pertinent information on the medicinal product in question, including the active substance, and any post-authorisation requirements as well as applicable prolongations to regulatory protection periods.

(49)

To allow for more informative advice on clinical trial applications and therefore a more integrated development advice in view of future data requirements for marketing authorisation applications, the Agency can engage in consultation with representatives from Member States having clinical trial expertise. Nevertheless, decisions on clinical trial applications should remain within the competence of the Member States, in accordance with Regulation (EU) No 536/2014 of the European Parliament and of the Council (15).

(50)

To allow for a more informative decision making and for exchange of information and pooling of knowledge on general issues of scientific or technical nature related to the tasks of the Agency regarding medicinal products for human use, in particular to scientific guidelines on unmet medical needs and the design of clinical trials, or other studies and the generation of evidence along the life cycle of medicinal product, the Agency should be able to have recourse to a consultation process of authorities or bodies active along the life cycle of medicinal products. These authorities or bodies could be, as appropriate, representatives from Heads of Medicines Agencies, the Clinical Trial Coordination and Advisory Group, the substances of human origin (SoHO) Coordination Board, the Coordination Group on Health Technology Assessment, the Medical Devices Coordination Group, medical devices competent authorities of Member States, competent authorities of Member States for pricing and reimbursement of medicinal products, national insurance funds or healthcare payers. The Agency should also be able to extend the consultation mechanism to consumers, patients, healthcare professionals, industry, associations representing payers, or other stakeholders, as relevant.

(51)

It is also necessary to reinforce the role of the Agency’s scientific committees in such a way as to enable it to participate actively in international scientific dialogue and to develop certain activities that will be necessary, in particular regarding international scientific harmonisation and technical cooperation with the World Health Organization (‘WHO’).

(52)

In the context of cooperation with international organisations to support global public health, it is important to leverage the scientific assessment performed by the Union and to promote reliance by third-country regulatory authorities based on the use of certificates of medicinal products for authorised medicinal products in the Union. An applicant should be able to request independently or as part of an application under the centralised procedure a scientific opinion from the Agency for the use of the medicinal product for markets outside the Union. The Agency should cooperate with the WHO and relevant third-country regulatory authorities and bodies to issue such scientific opinions.

(53)

The Agency should be able to cooperate with competent authorities of third countries in the context of performing its tasks. Such regulatory cooperation should be consistent with the broader economic relationship of the Union with the third country concerned, taking account of the relevant international agreements between the Union and that third country.

(54)

The Union is required, pursuant to Article 208 of the Treaty on the Functioning of the European Union (TFEU), to take account of the objectives of development cooperation in the policies that it implements which are likely to have an impact on low- and middle-income countries. Union pharmaceutical legislation has a role to play in the realisation of global public health objectives by promoting the development of efficacious, safe, accessible, and affordable innovations for antimicrobial resistance, poverty-related, emerging and re-emerging health threats, and neglected diseases, and other conditions of global public health interest. For example, as part of its Priority Medicines scheme, the Agency will offer dedicated support to medicinal product developments in the area of neglected tropical diseases. The Commission needs to continue encouraging research, development and innovation in areas of major global health interest, in line with its international commitments.

(55)

In the interest of public health, marketing authorisation decisions under the centralised procedure should be taken on the basis of the scientific criteria of quality, safety and efficacy of the medicinal product concerned, to the exclusion of economic and other considerations. However, Member States should be able, exceptionally and temporarily, to prohibit the use in their territory of certain medicinal products. Member States should provide justification for such prohibition of use to the Commission and the Agency.

(56)

The quality, safety and efficacy principles of Directive (EU) 2026/… (+) should apply to medicinal products authorised by the Union under the centralised procedure. The benefit-risk balance of all medicinal products should be assessed when they are placed on the market, and at any other time the competent authority deems appropriate.

(57)

To avoid unnecessary administrative and financial burden both for the pharmaceutical industry and the competent authorities of the Member States or the Agency, certain streamlining measures should be introduced. Marketing authorisation applications, like any other application submitted to the Agency, should follow the ‘digital by default’ principle and hence be sent to the Agency in electronic form. Electronic applications for marketing authorisations and for variations to the terms of the marketing authorisation should be made possible.

(58)

Applications should be examined on the basis of the file submitted by the applicant in accordance with the provisions of Directive (EU) 2026/… (+) on different types of applications. At the same time, the Agency and its relevant committees should be able to take into account any information that is in their possession. Applicants should be requested to generally submit raw data, in particular with regard to the clinical trials conducted by the applicant in order to ensure a full scientific evaluation of the quality, safety and efficacy of the medicinal product. However, the obligation to submit raw data should not be construed as obliging the Agency and the relevant committees to examine or make use of all such data during their scientific assessment. They should retain the discretion to determine in which cases such data are relevant and necessary for the purpose of examining the application.

(59)

To optimise the use of resources for both applicants and competent authorities of the Member States or the Agency assessing such applications, a single assessment of an active substance master file should be introduced. The outcome of the single assessment should be issued through a certificate. To avoid duplication of assessment, the use of an active substance master file certificate should be mandatory for subsequent applications for marketing authorisations for medicinal products for human use containing that active substance from an active substance master file certification holder.

(60)

In the context of the development and authorisation of medicinal products, it is crucial that particular attention be given to the composition of clinical trials in order to ensure comprehensive clinical data and, where appropriate, gender-based equity.

(61)

Directive 2010/63/EU of the European Parliament and of the Council (16) lays down provisions on the protection of animals used for scientific purposes based on the principle of replacement, reduction and refinement. Any study involving the use of live animals, which provides essential information on the quality, safety and efficacy of a medicinal product, should take into account that principle of replacement, reduction and refinement, where it concerns the care and use of live animals for scientific purposes, and should be optimised in order to provide the most satisfactory results whilst using the minimum number of animals. The procedures of such testing should be only used where necessary and be designed to avoid causing pain, suffering, distress or lasting harm to animals and should follow the available guidelines of the Agency and of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. In particular, the applicant and the marketing authorisation holder should take into account the principle of replacement, reduction and refinement laid down in Directive 2010/63/EU, giving priority to new approach methodologies in place of animal testing. These can include: in vitro models, such as microphysiological systems including organ-on-chips, (2D and 3D-) cell culture models, organoids and human stem cells-based models; in silico tools, in chemico technologies and any combination thereof or read-across models. Ultimately, efforts should be made to fully replace procedures on live animals for scientific purposes.

(62)

This Regulation contributes to the implementation of the One Health Approach, stressing the well-established interconnectedness between human, animal and ecosystem health, and the need to include those three dimensions when addressing public health threats. Environmental stress and degradation, including biodiversity loss, contribute to the transmission of diseases between, and the disease burden of, humans and animals. In addition, pollution from active pharmaceutical ingredients negatively affects the quality of waters and ecosystems, causes antimicrobial resistance to increase rapidly, posing risks to public health globally.

(63)

Procedures are to be in place to facilitate joint animal testing, wherever possible, in order to avoid unnecessary testing using live animals covered by Directive 2010/63/EU. Applicants and marketing authorisation holders should make all efforts to reuse animal study results and make the results obtained from animal studies publicly available. In line with Directive (EU) 2026/… (+), abridged applications are to refer to the relevant studies conducted for the reference medicinal product.

(64)

The summary of product characteristics and the package leaflet should reflect the scientific evaluation of the Agency and be part of its scientific opinion. The opinion could recommend certain conditions that should be part of the marketing authorisation, for example on the safe and efficacious use of the medicinal product or on post-authorisation obligations that have to be complied with by the marketing authorisation holder. Those conditions could include the requirement to conduct post-authorisation safety or efficacy studies or other studies that are considered necessary to optimise the treatment, for example where the dose scheme proposed by the applicant, whilst acceptable and justifying a favourable benefit-risk balance, could be further optimised after the authorisation has been granted. Where the applicant disagrees with parts of the opinion, the applicant should be able to submit a request for its re-examination.

(65)

Due to the need to reduce overall approval times for medicinal products, the time between the opinion of the Committee for Medicinal Products for Human Use and the final decision on the application for a marketing authorisation should in principle be no longer than 46 days.

(66)

On the basis of the opinion of the Agency, the Commission should adopt a decision on the application for a marketing authorisation by means of implementing acts. In justified cases, the Commission should be able to refer back the opinion for further examination or deviate in its decision from the opinion of the Agency. Taking into account the need to make medicinal products swiftly available to patients, it should be acknowledged that the chairperson of the Standing Committee on Medicinal Products for Human Use will use the available mechanisms under Regulation (EU) No 182/2011 of the European Parliament and of the Council (17) and in particular the possibility to obtain the committee’s opinion by written procedure and within expeditious time limits which, in principle, will not exceed 10 calendar days.

(67)

As a general rule, a marketing authorisation should be granted for an unlimited time. However, one renewal may be decided only on justified grounds related to the safety of the medicinal product.

(68)

There is a need to ensure that the ethical requirements of Regulation (EU) No 536/2014 apply to medicinal products authorised by the Union. In particular, with respect to clinical trials conducted outside the Union on medicinal products to be authorised within the Union, at the time of the examination of the application for authorisation, it should be verified that those trials were conducted in accordance with the principles of good clinical practice and the ethical requirements that are equivalent to those set out in Regulation (EU) No 536/2014 as regards the rights and safety of the subject and the reliability and robustness of the data generated in the clinical trial.

(69)

Environmental risks can arise from medicinal products consisting of, or containing, genetically modified organisms (GMOs). It is thus necessary to subject such medicinal products to an environmental risk-assessment procedure similar to the procedure under Directive 2001/18/EC of the European Parliament and of the Council (18), to be conducted in parallel with the evaluation, under a single Union procedure, of the quality, safety and efficacy of the medicinal product concerned. The environmental risk-assessment should be conducted in accordance with the requirements laid down in this Regulation and in Directive (EU) 2026/… (+) which are based on the principles set out in Directive 2001/18/EC but taking into account the specificities of medicinal products.

(70)

Directive (EU) 2026/… (+) permits Member States to temporarily allow the use and supply of unauthorised medicinal products for public health reasons or individual patient needs and that includes medicinal products to be authorised under this Regulation. It is also necessary, that Member States are allowed under this Regulation to make a medicinal product available for compassionate use prior to its marketing authorisation. In those exceptional and urgent situations, where there is a lack of a suitable authorised medicinal product, the need to protect public health or the health of individual patients must prevail over other considerations, in particular the need to obtain a marketing authorisation and consequently, to have available complete information about the risks posed by the medicinal product, including any risks to the environment from medicinal products consisting of, or containing, GMOs. To avoid delays in making these products available or uncertainties as regards their status in certain Member States, it is appropriate, in those exceptional and urgent situations, that for a medicinal product consisting of, or containing, GMOs, an environmental risk assessment or consent in accordance with Directive 2001/18/EC or Directive 2009/41/EC of the European Parliament and of the Council (19) should not be a prerequisite. Nevertheless, in those cases, Member States should implement appropriate measures in line with the precautionary principle to minimise foreseeable negative environmental impacts resulting from the intended or unintended release of the medicinal products consisting of, or containing, GMOs into the environment.

(71)

For medicinal products, the period for protection of data relating to non-clinical tests and clinical trials should be the same as that provided for in Directive (EU) 2026/… (+).

(72)

In order to meet, in particular, the legitimate expectations of patients and to take account of the increasingly rapid progress of science and therapies, accelerated assessment procedures should be set up, reserved for medicinal products of major therapeutic interest, and procedures for obtaining conditional marketing authorisations subject to certain regularly reviewable conditions.

(73)

Compassionate use programmes allow for an early access to medicinal products. Existing provisions should be reinforced to ensure that a common approach is followed, whenever possible, regarding the criteria and conditions for the compassionate use of new medicinal products under national law. Moreover, it is important to allow for data on such use to be collected to inform decisions regarding the benefit-risk balance of the medicinal products concerned.

(74)

It should be recognised that unmet medical needs also exist in the area of mental health. Promising medicinal products to address serious mental health conditions should therefore also be considered for compassionate use.

(75)

There is the possibility under certain circumstances for marketing authorisations to be granted, subject to specific obligations or conditions, on a conditional basis or under exceptional circumstances. The legislation should allow under similar circumstances for medicinal products with a standard marketing authorisation for new indications to be authorised on a conditional basis or under exceptional circumstances. The medicinal products authorised on a conditional basis or under exceptional circumstances should in principle satisfy the requirements for a standard marketing authorisation, with the exception of the specific derogations or conditions outlined in the relevant conditional or exceptional marketing authorisation, and should be subject to specific review of the fulfilment of the imposed specific conditions or obligations. The grounds for refusal of a marketing authorisation should apply mutatis mutandis for such cases.

(76)

Before a medicinal product for human use is authorised for placing on the market of one or more Member States, it generally has to undergo extensive studies to ensure that it is of high quality, safe and effective for use in the target population. However, in the case of certain categories of medicinal products for human use, in order to meet unmet medical needs of patients and in the interest of public health, it might be necessary to grant marketing authorisation on the basis of less complete data than is normally the case. Such marketing authorisation should be granted subject to specific obligations. The categories of medicinal products for human use concerned should be the medicinal products that aim at the prevention, diagnosis or treatment of seriously debilitating or life-threatening diseases, or that are intended to be used in emergency situations in response to public health threats.

(77)

In principle, it should not be possible for more than one marketing authorisation to be granted to an applicant for a medicinal product. Duplicate marketing authorisations should be granted only in exceptional circumstances. When those exceptional circumstances are no longer present, in particular as regards the protection by a patent or a supplementary protection certificate in one or more Member States, any potentially negative effects on markets from the existence of duplicate marketing authorisations should be minimised through a withdrawal of the initial or the duplicate marketing authorisation.

(78)

Regulatory decision-making on the development, authorisation and supervision of medicinal products can be supported by access and analysis of health data, including real-world data, where appropriate, i.e. health data generated outside of clinical studies, and data generated via in silico methods, such as computational modelling and simulation, digital molecular representation and mechanistic modelling, digital twin technology and artificial intelligence (AI). The Agency should be able to use such data, including via the Data Analysis and Real World Interrogation Network and the European Health Data Space interoperable infrastructure. Through the use of those possibilities, the Agency can take advantage of all the potential of supercomputing, AI and big-data science to fulfil its mandate, without compromising privacy rights. The Agency should put in place sufficient, effective and specific technical and organisational measures to safeguard the fundamental rights and interests of data subjects in accordance with Union law. It is appropriate for the Agency to cooperate with the competent authorities of the Member States, where necessary, with a view to achieving that objective.

(79)

The handling of health data requires a high level of protection against cyber attacks. It is necessary for the Agency to be equipped with a high level of security controls and processes against cyber attacks to ensure that the Agency operates normally at all times. To that end, the Agency should establish a plan to prevent, detect, mitigate and respond to cyber attacks so that its operations are secure at all times, while preventing any illegal access to documentation held by the Agency.

(80)

Due to the sensitive nature of health data, the Agency should safeguard its processing operations and ensure that they respect the data protection principles of lawfulness, fairness and transparency, purpose limitation, data minimisation, accuracy, storage limitation, integrity and confidentiality. Where the processing of personal data is necessary for the purposes of this Regulation, such processing should be done in accordance with Union law on the protection of personal data. Any processing of personal data under this Regulation should take place in accordance with Regulations (EU) 2016/679 (20) and (EU) 2018/1725 (21) of the European Parliament and of the Council.

(81)

Access to individual patient data from clinical studies in structured format allowing for statistical analyses is valuable to assist regulators in understanding the submitted evidence and to inform regulatory decision-making on the benefit-risk balance of a medicinal product. The introduction of such possibility in the legislation is important to further enable data-driven benefit-risk assessments at all stages of the life cycle of a medicinal product. This Regulation therefore empowers the Agency to receive and use such data as part of the assessment of initial and post-authorisation applications.

(82)

In a situation of public health emergency, it is of major interest for the Union that safe and efficacious medicinal products can be developed and made available within the Union as soon as possible. Agile, fast and streamlined processes are of the essence. A range of measures already exists at Union level to facilitate, support and speed up the development of and granting marketing authorisations for treatments and vaccines during a public health emergency.

(83)

It is also considered appropriate for the Commission to have the possibility to grant temporary emergency marketing authorisations to address public health emergencies. Temporary emergency marketing authorisations can be granted provided that, having regard to the circumstances of the public health emergency, the benefit of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent to the fact that additional comprehensive quality, non-clinical and clinical data might still be required. A temporary emergency marketing authorisation should be valid only during the public health emergency. The Commission should be given the possibility to vary, suspend or revoke such marketing authorisations in order to protect public health or when the marketing authorisation holder has not complied with the conditions and obligations laid down in the temporary emergency marketing authorisation.

(84)

It is appropriate to have in place transparency measures and standards regarding the Agency’s regulatory activities in relation to medicinal products, in particular those that are granted a temporary emergency marketing authorisation. Those measures should include the timely publication of all relevant information on centrally approved medicinal products.

(85)

In the event of a risk to public health, the marketing authorisation holder or the competent authorities of the Member States or the Agency should be able to implement urgent safety or efficacy restrictions on their own initiative to ensure a swift adaption of the marketing authorisation to maintain the safe and efficacious use of the medicinal product by healthcare professionals and patients. If a review is launched by a competent authority regarding the same safety or efficacy concern as one which has been covered by urgent restrictions, any written observations by the marketing authorisation holder should be considered in that review to avoid duplication of assessment.

(86)

The terms of a marketing authorisation for a medicinal product for human use can be varied. While the core elements of a variation to the marketing authorisation are laid down in this Regulation, the Commission should be empowered by means of delegated acts to complement those core elements by laying down further necessary elements, to adapt the system to technical and scientific progress, and to employ digitalisation measures to ensure that unnecessary administrative burden is avoided for marketing authorisation holders and competent authorities of the Member States or the Agency.

(87)

Competent authorities of the Member States or the Agency should have the power to evaluate additional evidence that could affect the benefit-risk balance of medicinal products, beyond the evidence provided by marketing authorisation holders. Where justified, competent authorities of the Member States or the Agency should be able to recommend that the marketing authorisation holder vary the terms of its marketing authorisation.

(88)

For generic medicinal products and biosimilar medicinal products, as a general rule, risk management plans should not be developed and submitted, also considering that the reference medicinal product has such a plan. However, in specific cases, a risk management plan for generic medicinal products and biosimilar medicinal products should be developed and submitted to the competent authorities of the Member States or the Agency.

(89)

It is appropriate to entrust the Commission, in close cooperation with the Agency and after consultations with the Member States, with the task of coordinating the execution of the various supervisory responsibilities vested in the Member States, and in particular with the tasks of providing information on medicinal products and of checking the observance of good manufacturing, laboratory and clinical practices.

(90)

Without prejudice to the powers of the competent authorities of Member States and without undermining their national inspection resources, the Agency should be provided with the targeted inspection capacity to contribute to the strengthening of the supervision of the manufacturing of the medicinal products worldwide, in the interest of the Union. This could be the case in situations where, to ensure faster access to medicinal products, challenges with inspection capacities at national level have to be addressed in a timely manner or where a response to a public health emergency or a major event requires immediate action. Therefore, the Agency should be empowered and given the capacity to support Member States with regard to carrying out inspections in third countries. In particular, where the competent authorities of the Member States request support in carrying out their tasks under Directive (EU) 2026/… (+), the Agency should be able to participate in inspections. Where the competent authority of a Member State cannot carry out an inspection, the Agency should facilitate the delegation of the inspection to another competent authority of a Member State. As a last resort, where no other competent authority of a Member State is able to accept the delegation to carry out an inspection, the competent authority concerned should be able to request the Agency to carry out the inspection.

(91)

To ensure consistency in supervision of inspected activities and enforcement of good manufacturing and distribution practices in the Union, harmonised inspection standards should be ensured through the establishment of a joint audit programme (‘JAP’) within the Agency. This JAP will also further harmonise the interpretation of good manufacturing and distribution practices on the basis of Union legislative requirements. As regards the implementation of the JAP by the competent authorities of the Member States or the Agency, this Regulation takes into account the specific constitutional and administrative structures of each Member State pursuant to Article 4(2) of the Treaty on the European Union (TEU), while ensuring the effectiveness of such implementation, in accordance with Article 4(3) TEU. Moreover, it will support further mutual recognition of inspection outcomes between Member States and with strategic partners. Within the JAP, the competent authorities of the Member States or the Agency are subject to regular audits conducted by other Member States to maintain an equivalent and harmonised quality system and to ensure an appropriate implementation of relevant good manufacturing and distribution practices in national law and their equivalence with those of other Member States.

(92)

The inspection working groups, which provide input and recommendations on all matters relating, directly or indirectly, to good clinical practice, good manufacturing practice, good distribution practice and good pharmacovigilance practice, irrespective of the marketing authorisation procedure through different reporting lines, should be established within the Agency. In particular, the working group in charge of good manufacturing and good distribution practices should be responsible for the establishment, development and overall supervision of the JAP.

(93)

The Union should have the means to carry out a scientific assessment of a medicinal product authorised in accordance with the decentralised marketing authorisation procedures. Moreover, with a view to ensuring the effective harmonisation of administrative decisions taken by Member States with regard to a medicinal product authorised in accordance with decentralised marketing authorisation procedures, it is necessary to endow the Union with the means to resolve disagreements between Member States concerning the quality, safety and efficacy of medicinal products in accordance with the referral procedure.

(94)

The development of antimicrobial resistance is a growing concern. However, antimicrobial research and development is being hampered by the low commercial value of the antimicrobial medicinal product market. It is therefore necessary to maintain the efficacy of existing antimicrobials for as long as possible and to consider a number of new measures to promote the development of priority antimicrobials that are effective against antimicrobial resistance and to support companies, often SMEs, and not-for-profit entities which choose to invest in this area. It is equally necessary to support research and development of novel antimicrobials including through the establishment of subscription models. Such models delink the volume of antimicrobial sales from the reward received, in particular through voluntary joint procurement and can help overcome such market failures. Such measures should facilitate the development of alternative treatments, such as bacteriophages, which can be effective against multi-drug resistant bacteria and can be used as an alternative treatment or together with antibiotics.

(95)

Reluctance to invest in the development of antimicrobials exists in part because the development of antimicrobials is costly and many developers, often SMEs, cannot afford to proceed to the next stage of development. Additionally, when an antimicrobial is developed, there is a limited market for it by virtue of the inherent need to use antimicrobials prudently, which typically limits the sales of such products. Therefore, it is necessary to consider further Union level action to support the development of antimicrobials and address existing market failures. Accordingly, a voluntary subscription model for the joint procurement of antimicrobials should be developed to ensure that a market exists for developers that delinks volumes sold from payment received.

(96)

To be considered a ‘priority antimicrobial’, a medicinal product should represent a real advancement against antimicrobial resistance and therefore its developer should provide non-clinical and clinical data that underpin a significant clinical benefit with respect to antimicrobial resistance. When assessing the conditions for antimicrobials, the Agency should take into account the prioritisation of pathogens as regards the risk of antimicrobial resistance set out in the ‘WHO Bacterial Priority Pathogens List: Bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance’ (‘WHO bacterial priority pathogens list’), specifically those listed in the ‘critical group’ or in the ‘high group’. Where there is an equivalent list of priority pathogens established at Union level, it would be appropriate for the Agency to give precedence to that Union list.

(97)

The creation of a transferable data exclusivity voucher (‘data exclusivity voucher’) as an incentive rewarding the development of priority antimicrobials through an additional year of regulatory data protection has the capacity to provide the needed financial support to developers of priority antimicrobials. However, in order to ensure that the financial reward which is ultimately borne by health systems is mostly absorbed by the developer of the priority antimicrobial and not the buyer of the data exclusivity voucher, the number of available data exclusivity vouchers on the market should be kept to a minimum. It is therefore necessary to establish strict conditions of granting, transfer and use of the data exclusivity voucher and to further give the possibility to the Commission to revoke the data exclusivity voucher under certain circumstances.

(98)

A data exclusivity voucher should only be available to those antimicrobials that bring a significant clinical benefit with respect to antimicrobial resistance, and which have the characteristics described in this Regulation. It is also necessary to ensure that an undertaking which receives this incentive is in turn capable to supply the antimicrobial to patients across the Union in sufficient quantities and to provide information on all funding received for research related to its development in order to provide a full account of the direct financial support given to those antimicrobials.

(99)

To ensure a high level of transparency and complete information on the economic effect of a data exclusivity voucher, in particular as regards the risk of overcompensation of investment, a developer of a priority antimicrobial is required to provide in a declaration information on all direct financial support received for research related to the development of the priority antimicrobial. The declaration should include direct financial support received from any source worldwide.

(100)

It should be possible for the transfer of a data exclusivity voucher for a priority antimicrobial to be conducted by sale. It should not be possible for such a voucher to be transferred more than once. The value of the transaction, which can be monetary or otherwise agreed between the buyer and the seller, should be made public so as to inform regulators and the public. The identity of the holder of a data exclusivity voucher that has been granted and not yet used should be publicly known at all times so as to ensure a maximum level of transparency and trust.

(101)

The provisions related to data exclusivity vouchers should be applicable for a specified period from the entry into force of this Regulation or until a maximum number of those vouchers are granted by the Commission in order to limit the total cost of the measure to Member State health systems. The limited application of the measure will also provide the possibility to assess the effect of the measure in addressing the market failure in the development of new antimicrobials tackling antimicrobial resistance and assess the cost on national health systems. That assessment will provide the knowledge necessary to decide whether to extend the application of the measure. On the basis of that assessment, the Commission should, where appropriate, submit a proposal to the European Parliament and to the Council to extend the period of application of the provisions on data exclusivity vouchers for priority antimicrobials and the total number of those vouchers.

(102)

Through the Priority Medicines (PRIME) scheme, the Agency has gained experience of the provision of early scientific and regulatory support to developers of certain medicinal products that, based on preliminary evidence, are likely to address an unmet medical need and are considered promising at an early stage of development. It is appropriate to recognise this early support mechanism for medicinal products that have the potential to significantly address patients’ unmet medical needs and are expected to be of major interest from the point of view of public health, in particular as regards therapeutic innovation, or are antimicrobials addressing antimicrobial resistance or target a neglected tropical disease when they fulfil the criteria for the scheme. The Agency, in consultation with the Member States and the Commission, should establish selection criteria for promising medicinal products.

(103)

The Agency, in consultation with the Member States and the Commission, should set the scientific selection criteria for medicinal products that receive pre-authorisation support with priority to be given to the most promising developments in therapies. In the case of medicinal products for unmet medical needs, based on the scientific selection criteria set by the Agency, any interested developer can submit preliminary evidence to demonstrate that the medicinal product has the potential to address an identified unmet medical need and be of major public health interest particularly regarding its therapeutic innovation.

(104)

In the preparation of scientific advice and in duly justified cases, the Agency should also be able to consult authorities established in other relevant Union legal acts or other public bodies established in the Union, as applicable. These could include experts in clinical trials, medical devices, substances of human origin or any other as required for the provision of the scientific advice in question.

(105)

Some conditions occur so infrequently that the cost of developing and bringing to the market a medicinal product to diagnose, prevent or treat the condition cannot be recovered by the expected sales of the medicinal product. However, patients suffering from such rare conditions should be entitled to the same quality of treatment as other patients. It is therefore necessary to stimulate the research, development and placing on the market of appropriate medicinal products by the pharmaceutical industry.

(106)

Regulation (EC) No 141/2000 has proved to be successful in boosting developments of orphan medicinal products in the Union, although more progress is needed, as a majority of rare diseases are still without an authorised treatment. Action at Union level therefore remains preferable to uncoordinated measures by the Member States, which could result in distortions of competition and barriers to intra-Union trade.

(107)

The open and transparent centralised procedure for the designation of potential medicinal products as orphan medicinal products established by Regulation (EC) No 141/2000 should be maintained. To increase legal clarity and simplification, the specific legal provisions applicable to those medicinal products should be integrated in this Regulation.

(108)

Objective criteria for the orphan designation based on the prevalence of the life-threatening or chronically debilitating condition for which prevention, diagnosis, or treatment is sought and the existence of no satisfactory method of prevention, diagnosis or treatment of the condition in question that has been authorised in the Union should be maintained. A prevalence of not more than five affected persons per 10 000 is generally regarded as appropriate for orphan designation. The orphan designation criterion on the basis of return on investment has been abolished, since it has never been used.

(109)

The criterion for orphan designation based on prevalence of a disease might not be appropriate to identify rare diseases in all cases. For example, for conditions which have a short duration and high mortality, measuring the number of people that acquired the disease during a specific time period would better reflect if it is rare within the meaning of this Regulation than measuring the number of people who are ‘affected by it’ in a specific moment of time.

(110)

With the aim to better identify only those diseases which are rare, the Commission should be empowered to supplement the designation criteria by a delegated act if they are not appropriate for certain conditions due to scientific reasons and on the recommendation of the Agency. In addition, the designation criteria require implementing acts to be adopted by the Commission.

(111)

If a satisfactory method of prevention, diagnosis or treatment of the condition in question has already been authorised in the Union, the orphan medicinal product will have to be of significant benefit to those affected by that condition. In this context, a medicinal product authorised in one Member State is generally deemed as being authorised in the Union. It is not necessary for it to have Union authorisation or to be authorised in all Member States to be considered a satisfactory method. In addition, commonly used methods of prevention, diagnosis, or treatment that are not subject to a marketing authorisation can be considered to be satisfactory if there is scientific evidence of their safety and efficacy. In certain cases, medicinal products prepared for an individual patient in a pharmacy according to a medical prescription, or according to the prescriptions of a pharmacopoeia and intended to be supplied directly to patients served by the pharmacy, may be considered to be satisfactory treatment if they are well known and safe and this is a general practice for the relevant patient population in the Union.

(112)

The competence to designate a medicinal product as an orphan medicinal product, in the form of a decision, is accorded to the Agency. This is expected to facilitate and expedite the designation procedure, while ensuring high level of scientific expertise.

(113)

In order to incite faster authorisation of designated orphan medicinal products, the validity of orphan designation has been set at seven years, with the possibility of extension by the Agency under certain specified conditions. The orphan designation can be withdrawn at the request of the orphan medicinal product sponsor, who provides a reasoned justification for the withdrawal request. The Agency should make the reasoned justification for the withdrawal request publicly available, when that justification is provided by the orphan medicinal product sponsor.

(114)

The Agency is responsible for designation of an orphan medicinal product as well as for the setting up and management of a register of designated orphan medicinal products. That register should be publicly available. The minimum data which should be included in the register have been specified in this Regulation and the Commission is empowered to amend or supplement those minimum data by a delegated act.

(115)

Sponsors of orphan medicinal products designated under this Regulation should be entitled to the full benefit of incentives granted by the Union or by the Member States to support the research and development of medicinal products for the prevention, diagnosis or treatment of orphan conditions, including rare diseases.

(116)

Patients suffering from rare diseases deserve medicinal products of the same quality, safety and efficacy as other patients. Designated orphan medicinal products should therefore be submitted to the normal evaluation process carried out by the Committee of Medicinal Products for Human Use for the applicant to obtain a marketing authorisation for those indications which meet the criteria for orphan designation, while a separate marketing authorisation can be granted for indications not meeting the criteria of an orphan medicinal product. Those marketing authorisations should be considered as belonging to the same global marketing authorisation.

(117)

A vast percentage of rare diseases remains without treatment with research and development clustered in the areas where profit is better assured. Therefore, there is a need to target those areas where research is mostly needed and where investments are most risky.

(118)

Orphan medicinal products are considered to be breakthrough orphan medicinal products if they prevent, diagnose or treat conditions where no other method of prevention, diagnosis or treatment exists and they result in a clinically relevant reduction in disease morbidity or mortality for the relevant patient population.

(119)

Experience since the adoption of Regulation (EC) No 141/2000 shows that the strongest incentive for industry to invest in the development and making available of orphan medicinal products is where there is a prospect of obtaining market exclusivity for a certain number of years during which part of the investment might be recovered. In addition to the periods of market exclusivity, orphan medicinal products will benefit from the periods of regulatory data and market protection set out in Directive (EU) 2026/… (+), as well as from one additional year of regulatory data protection provided for in this Regulation by using a data exclusivity voucher. However, where an orphan medicinal product obtains an additional therapeutic indication, it should only benefit from the prolongation of market exclusivity in accordance with this Regulation.

(120)

In order to incentivise research and development of breakthrough orphan medicinal products, to ensure market predictability and to ensure a fair distribution of incentives, a modulation of market exclusivity has been introduced. Breakthrough orphan medicinal products benefit from the longest market exclusivity, while market exclusivity for well-established-use orphan medicinal products, requiring less investment, is the shortest. In order to ensure increased predictability for developers, the possibility to review the eligibility criteria for market exclusivity six years after the marketing authorisation has been abolished.

(121)

To maximise the potential benefit of clinical research, continued exploration of new therapeutic indications for orphan medicinal products should be encouraged. To reward research into and development of new therapeutic indications, an additional period of one year of market exclusivity is provided for a new therapeutic indication (with a maximum of two indications).

(122)

This Regulation aims to avoid unjustified benefits being derived from market exclusivity and to improve the accessibility of medicinal products by ensuring faster entry on the market of generic medicinal products, biosimilar medicinal products and similar medicinal products. It also clarifies the concurrence of market exclusivity with regulatory data protection periods and sets out situations in which a similar medicinal product can be granted a marketing authorisation despite ongoing market exclusivity.

(123)

The EU Health Strategy developed by the Commission has identified rare diseases as a priority for action with the aim to improve patient access to diagnosis, information and care. Programmes for Union action in this field build on a supportive policy framework at Union level that encourages national plans and collaborative efforts among Member States. Under Directive 2011/24/EU of the European Parliament and of the Council (22), the Commission has supported the continued development of European Reference Networks connecting healthcare providers across the Union to share expertise and provide consultations for patients suffering from rare diseases. Funding is provided through programmes like Horizon Europe to support research on rare diseases. Moreover, efforts are made to enhance patient registries and data collection to support research and improve knowledge on rare diseases. Additionally, the European Health Data Space is set to have a transformative impact on research, particularly for rare diseases. It will draw on the work of the European Platform on Rare Diseases Registration, to address the issue of fragmentation of patient data across the Union. In 2024 the Commission launched a new 7-year research partnership, the European Rare Diseases Research Alliance for better prevention, better diagnosis, and better treatment of rare diseases. With these comprehensive set of actions, the Union aims to improve diagnosis, treatment, and quality of life and to better meet the unmet needs of people living with rare diseases and their carers.

(124)

Before a medicinal product for human use is placed on the market in one or more Member States, it has to have undergone extensive studies, including non-clinical tests and clinical trials, to ensure that it is safe, of high quality and effective for use in the target population. It is important that such studies are undertaken also in the paediatric population in order to ensure that medicinal products are appropriately authorised for use in the paediatric population, and to improve the information available on the use of medicinal products in the various paediatric population. It is also important that medicinal products be presented in dosages and formulations that are suitable for children.

(125)

Therefore, the development of medicinal products that could potentially be used for the paediatric population should become an integral part of the development of medicinal products, integrated into the development programme for adults. Thus, paediatric investigation plans should be submitted early during medicinal product development, in time for studies to be conducted in the paediatric population, where appropriate, before marketing authorisation applications are submitted.

(126)

As the development of medicinal products is a dynamic process dependent on the result of ongoing studies, in certain cases, for example when limited information on the medicinal products are available because the medicinal products are tested for the first time in the paediatric population, a specific procedure allowing to progressively build up a paediatric investigation plan should be put in place.

(127)

During public health emergencies, in order not to delay a prompt authorisation of a medicinal product intended for the prevention or treatment of a condition related to the public health emergency, there should be a possibility to temporarily waive the requirements concerning paediatric studies to be submitted at the moment of marketing authorisation.

(128)

In order to not endanger the health of children and to avoid exposing them to unnecessary clinical trials, the obligation to agree and conduct studies in children should be waived when the medicinal product is likely to be ineffective or unsafe in part or all of the paediatric population, the specific medicinal product does not represent a significant therapeutic benefit over existing methods of prevention, diagnosis or treatment for children or the disease for which the medicinal product is intended occurs only in the adult population. Nevertheless, if on the basis of existing scientific evidence, the medicinal product due to its mechanism of action is relevant for a different disease or condition in children in the same therapeutic area, the obligation should be maintained.

(129)

To ensure that research in the paediatric population is only conducted to meet their therapeutic needs, the Agency should agree and make public lists of waivers for specific medicinal products or for classes or part of classes of medicinal products. As knowledge of science and medicine evolves over time, provision should be made for the lists of waivers to be amended. However, if a waiver is revoked, the requirement for a paediatric investigation plan should not apply for a given period in order to allow time for such a plan to be agreed and for studies in the paediatric population to be initiated before an application for marketing authorisation is submitted.

(130)

With a view to ensuring that research is conducted only when safe and ethical and that the requirement for study data in the paediatric population does not block or delay the authorisation of medicinal products for other populations, the Agency should be able to defer, on scientific or technical grounds or on the basis of considerations related to public health, the initiation or completion of some or all of the measures contained in a paediatric investigation plan for a limited period. Such deferral should be extended only in duly justified cases.

(131)

The possibility to modify an agreed paediatric investigation plan should be provided for in cases where the applicant encounters such difficulties with its implementation as to render the plan unworkable or no longer appropriate.

(132)

The Agency, after consultation of the Commission and of interested parties, should draw up the details of the content of an application for agreement of a paediatric investigation plan, for its modification, for waivers and for deferral requests.

(133)

Where it is intended to develop medicinal products for use only in children, simplified details of the paediatric investigation plan should be sufficient.

(134)

To ensure that the data supporting the marketing authorisation concerning the use of a medicinal product in children to be authorised under this Regulation have been correctly developed, the Committee for Medicinal Products for Human Use should check compliance with the agreed paediatric investigation plan and any waivers and deferrals at the validation step for marketing authorisation applications.

(135)

Scientific advice, free of charge, should be provided by the Agency as an incentive to sponsors developing medicinal products for the paediatric population.

(136)

To provide healthcare professionals and patients with information on the safe and efficacious use of medicinal products in the paediatric population, the results of the studies conducted in compliance with an agreed paediatric investigation plan, independently from the fact that they support or not the use of the medicinal product in children, should be included in the summary of product characteristics and, if appropriate, in the package leaflet.

(137)

To sustain the development of novel, paediatric only indications from authorised medicinal products no longer covered by intellectual property rights, it is necessary to establish a specific type of marketing authorisation, the paediatric use marketing authorisation. A paediatric use marketing authorisation should be granted through existing marketing authorisation procedures but should apply specifically for medicinal products developed exclusively for use in the paediatric population. It should be possible for the name of the medicinal product that has been granted a paediatric use marketing authorisation to retain the existing name of the corresponding medicinal product authorised for adults, in order to capitalise on existing brand recognition, while benefiting from the regulatory protection associated with a new marketing authorisation.

(138)

An application for a paediatric use marketing authorisation should include the submission of data concerning use of the medicinal product in the paediatric population, collected in accordance with an agreed paediatric investigation plan. Such data could be derived from the published literature or from new studies. An application for a paediatric use marketing authorisation should also be able to refer to data contained in the dossier of a medicinal product which is or has been authorised in the Union. This is intended to provide an additional incentive to encourage SMEs, including companies manufacturing generic medicinal products, to develop off-patent medicinal products for the paediatric population.

(139)

Some paediatric investigation plans might be discontinued for various reasons despite possible positive results for the treatment of children obtained from the studies already conducted. The information of such discontinuations and their reasons should be collected by the Agency and made public in order to inform eventual third parties who might be interested in continuing those studies.

(140)

To increase the transparency on clinical trials conducted in children in third countries and referred to in a paediatric investigation plan or conducted from a marketing authorisation holder independently from a paediatric investigation plan, information on these clinical trials should be included in the European clinical trial database (‘EU database’) created pursuant to Regulation (EU) No 536/2014.

(141)

The summary of the results of all the paediatric clinical trials included in the EU database created by Regulation (EU) No 536/2014 should be made publicly available within six months of the end of the clinical trials unless this is not possible for justified scientific reasons.

(142)

To discuss priority in medicinal product development, in particular in areas of unmet medical need for children and to coordinate studies relating to paediatric medicinal products, the Agency should set up a European network for paediatric research composed of patient representatives, academics, medicinal products developers, investigators and research centres based in the Union or in the European Economic Area.

(143)

Union funding should be provided to cover all aspects of the work of the Agency resulting from paediatric related activities, such as the assessment of paediatric investigation plans, fee waivers for scientific advice, and information and transparency measures, including the database of paediatric studies and the European network for paediatric research.

(144)

It is necessary to take measures for the supervision of medicinal products authorised by the Union, and in particular for the intensive supervision of undesirable effects of these medicinal products, and the collection of real-world data within the framework of Union pharmacovigilance activities, so as to ensure the rapid withdrawal from the market of any medicinal product presenting a negative benefit-risk balance under normal conditions of use.

(145)

The main tasks of the Agency in the area of pharmacovigilance laid down in Regulation (EC) No 726/2004 should be maintained. They include the management of the Union pharmacovigilance database and data-processing network (the ‘Eudravigilance database’), the coordination of safety announcements by the Member States and the provision to the public of information regarding safety issues. The Eudravigilance database should be the single point of receipt of pharmacovigilance information. Member States should therefore not impose any additional reporting requirements on marketing authorisation holders. The database should be fully and permanently accessible to the Member States, the Agency and the Commission, and accessible to an appropriate extent to marketing authorisation holders and the public.

(146)

Member States and marketing authorisation holders should operate a pharmacovigilance system to collect information that is useful for the monitoring of medicinal products, including information on suspected adverse reactions arising from use of a medicinal product within the terms of the marketing authorisation as well as from use outside the terms of the marketing authorisation, including off-label use, overdose, misuse, abuse and medication errors by patients and healthcare professionals. Mistakes in the prescribing, dispensing, storing, preparation and administration of medicinal products are common types of medication errors. Suspected adverse reactions should be recorded and reported by Member States and marketing authorisations holders to the Eudravigilance database for the monitoring of safety of medicinal products. The reports should be part of the continuous evaluation of the benefit-risk balance of the medicinal products. Summaries of data relevant to the benefit-risk balance should be included in periodic safety update reports. Marketing authorisation holders should also record and report information on adverse reactions occurring in the context of post-authorisation studies, including post authorisation studies in specific populations such as children, for evaluation of the benefit-risk balance.

(147)

Where the Commission considers that there are reasons to believe that a medicinal product could present a potential serious risk to human health, a scientific evaluation of the medicinal product should be undertaken by the Agency, leading to a decision whether to maintain, vary, suspend or revoke the marketing authorisation, and taken on the basis of an overall evaluation of the benefit-risk balance. It should also be possible for the Commission to act on a centralised marketing authorisation where the conditions attached to it are not complied with.

(148)

It is recognised that improved access to information contributes to public awareness and increases public trust, gives the public the opportunity to express its observations and enables authorities to take due account of those observations. The general public should therefore have access to information in the Union Register of Medicinal Products, the Eudravigilance database and the Union database referred to in Article 191(15) of Directive (EU) 2026/… (+), after the deletion of any commercially confidential information by the competent authority, unless there is an overriding public interest in disclosure, in accordance with Regulation (EC) No 1049/2001 of the European Parliament and of the Council (23). Regulation (EC) No 1049/2001 gives the fullest possible effect to the right of public access to documents and lays down the general principles and limits on such access. The Agency should therefore give the widest possible access to the documents while carefully balancing the right to information with existing data protection requirements. Certain public and private interests, such as personal data and commercially confidential information, should be protected by way of exception in accordance with Regulation (EC) No 1049/2001.

(149)

To enhance the efficiency of market surveillance, the Agency should be responsible for coordinating Member States’ pharmacovigilance activities. A number of provisions are required to put in place stringent and efficient pharmacovigilance procedures, to allow the competent authority of the Member State to take provisional emergency measures, including the introduction of amendments to the marketing authorisation and, finally, to permit a reassessment to be made at any time of the benefit-risk balance of a medicinal product.

(150)

Scientific and technological progresses in data analytics and data infrastructure are essential for the development, authorisation and supervision of medicinal products. The digital transformation has affected regulatory decision-making, making it more data-driven and multiplying the possibilities to access evidence and real-world data, across the life cycle of a medicinal product. This Regulation recognises the Agency’s experience and capacity to access and analyse data submitted independently from the applicant or marketing authorisation holder. On this basis, the Agency should take the initiative to recommend the marketing authorisation holder to vary the summary of product characteristics in cases where new safety or efficacy data have an impact on the benefit-risk balance of a medicinal product, without excluding other actions that the competent authority might take.

(151)

The Union and Member States have developed an evidence-based scientific evaluation process that allows competent authorities of the Member States to determine the relative effectiveness of new or existing medicinal products. This process focuses specifically on the added value of a medicinal product in comparison with other new or existing medicinal products and health technologies. However, such process should not be conducted in the context of a marketing authorisation for which it is agreed that the fundamental criteria of quality, safety and efficacy should be retained. It is useful in this respect to allow the Agency for the possibility of gathering information on the methods used by the Member States to determine the therapeutic benefit obtained by each new medicinal product.

(152)

In the area of medicinal products, a high level of protection of health of, inter alia, citizens and consumers, as well as legal certainty and a level playing field and fair competition, always need to be ensured and existing levels of protection need to be respected.

(153)

Regulatory sandboxes can provide a structured context for experimentation under a controlled framework, to enable where appropriate in a real-world environment the testing of innovative technologies, products, services or approaches – at the moment especially in the context of digitalisation or the use of AI and machine learning in the life cycle of medicinal products from drug discovery, through the development to the administration of medicinal products – for a limited time and in a limited part of a sector or area under regulatory supervision ensuring that appropriate safeguards are in place. In particular, SMEs and startups should have the possibility to participate in regulatory sandboxes to which they can, as relevant contribute with their knowhow and experience.

(154)

Implementing powers should be conferred on the Commission to establish a regulatory sandbox, based on the recommendation of the Agency, when the development and authorisation of an innovative medicinal product or innovative category of medicinal products cannot be achieved under the requirements applicable to medicinal products, due to methods related to those innovative medicinal products or innovative categories of medicinal products or their inherent scientific or technical characteristics. A regulatory sandbox facilitates the development, validation and testing of the innovative element of the medicinal products or categories of medicinal products under the supervision of the Agency and national regulators while allowing, where necessary and justified, the adaptation of the regulatory requirements for those medicinal products or categories of medicinal products. However, such adaptation should ensure that the principles of quality, safety and efficacy of medicinal products laid down in Union legislation are respected. Regulatory sandboxes can also benefit patients’ access to groundbreaking new therapies without compromising the standards of quality, safety and efficacy. The outcome of regulatory sandboxes should guide the Commission in assessing if an adapted framework for the medicinal products in question is appropriate and should be pursued.

(155)

The establishment of a regulatory sandbox by means of a Commission implementing Decision, following a recommendation of the Agency, should be based on a detailed and comprehensive plan outlining the particularities of the sandbox as well as describing the products to be covered. A regulatory sandbox should be limited in duration and could be terminated at any time based on public health considerations. The learnings stemming from a regulatory sandbox are capable of informing future changes to the legal framework to fully integrate the particular innovative aspects into the medicinal product regulation. Where appropriate, adapted frameworks could be developed by the Commission on the basis of the results of a regulatory sandbox. Marketing authorisations under a sandbox should ensure that the principles of quality, safety and efficacy under this Regulation and Directive (EU) 2026/… (+) are respected. The regulatory sandbox should not affect the supervisory and corrective powers of the competent authorities of the Member States or the Agency and the liability of the participants, such as clinical trial sponsors, marketing authorisation holders, applicants, or any entities involved in the lifecycle of the medicinal product.

(156)

Shortages of medicinal products represent a growing threat to public health, with potential serious risks to the smooth functioning of the internal market, as well as the health of patients in the Union and impacts on their right to access appropriate medical treatment, including longer delays or interruptions in care or therapy, longer periods of hospitalisation, increased risks of exposure to falsified medicinal products, medication errors, adverse events following the substitution of unavailable medicinal products with alternative ones, significant psychological distress for patients and increased costs for healthcare systems. The root causes of shortages are multifactorial, with challenges identified along the entire pharmaceutical value chain, and can range from quality to manufacturing problems. In particular, shortages of medicinal products can result from supply chain disruptions and vulnerabilities affecting the supply of key ingredients and components. Member States, depending on their situation, have addressed this in different ways. Due to a lack of coordination of measures taken at national level, these efforts have resulted in a fragmented response jeopardising the availability of medicinal products across the Union. Increased coordination is therefore required at Union level.

(157)

More often than in the past, Member States experience critical shortages of various medicinal products, including certain antimicrobials, endangering the health of patients and risking the development of antimicrobial resistance. Those critical shortages of antimicrobials are the result of a multiplicity of factors, including changing infection patterns, which strongly increases demand. On the supply side, the long lead times needed to boost production make it difficult to respond quickly. This experience underlines the need for a dedicated effort from all actors to address the issue of critical shortages.

(158)

To achieve a better security of supply for medicinal products in the internal market and to contribute thereby to a high level of public health protection, it is appropriate to approximate the rules on reporting of supply disruptions and monitoring of expected or actual shortages of medicinal products, including the procedures and the respective roles and obligations of concerned entities in this Regulation. It is important to ensure continued supply of medicinal products, which is often taken for granted in the Union. This is especially true for the most critical medicinal products which are essential to ensure the continuity of care, the provision of quality healthcare and guarantee a high level of public health protection within the Union.

(159)

A Member State should be able to decide to exempt a marketing authorisation holder from complying with certain obligations under Chapter X where the medicinal product is authorised by that Member State based on public health grounds.

(160)

Without prejudice to this Regulation, Member States remain the sole responsible for their own national security. They are responsible for defending their essential state functions, including ensuring their territorial integrity and safeguarding national security. In particular, under Article 346 TFEU, no Member State is obliged to supply information the disclosure of which it considers contrary to the essential interests of its security. For this reason, Member States should be able to exempt marketing authorisation holders and other relevant actors from some of the obligations applicable to them only when the medicinal products are manufactured for military and defence purposes and insofar as the application of such requirements imply a risk to national security and defence. For medicinal products that are supplied for military and defence purposes but also to cover the needs of patients, such exemptions should only target the specific batches that are supplied for military and defence purposes. Furthermore, Member States should be able to also exempt national authorities from communicating information where such a requirement would imply a risk to national security and defence.

(161)

To prevent or mitigate future shortages of medicinal products, marketing authorisation holders should notify the concerned competent authorities of the Member States and, where applicable, the Agency of any future withdrawal of a marketing authorisation, permanent market cessation or temporary suspension of the marketing of a medicinal product and any supply disruption exceeding two weeks. Supply disruptions should be notified as soon as the marketing authorisation holder becomes aware of the situation, and at the latest six months in advance of the interruption, unless there are duly justified exceptional circumstances, to allow competent authorities of the Member States or the Agency to engage with relevant stakeholders and take the necessary mitigation measures. Furthermore, shortage prevention plans are key tools for the prevention of shortages given that they require marketing authorisation holders to identify risks in their supply chains and take the necessary mitigation measures to avoid shortages. Therefore, marketing authorisation holders should have shortage prevention plans in place for medicinal products subject to medical prescription and, where applicable, additional medicinal products identified by the Commission, taking into account recommendations from the Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG), to prevent or mitigate shortages. The Agency should provide guidance to marketing authorisation holders on approaches to streamline the implementation of those plans. A documented risk assessment of supply chain risks should be required for other medicinal products. The Commission should be able to request the information of the shortage prevention plans of medical countermeasures in the context of crisis preparedness.

(162)

To ensure continuity of supply and availability of medicinal products identified as critical at national level and other specific medicinal products on the market of any Member State where the medicinal product is authorised, rules for the transfer of the marketing authorisation or for the offer of a letter of access prior to the withdrawal of the marketing authorisation or the permanent market cessation, respectively, in Member States where the marketing authorisation is valid, should be laid down. Such transfer should not be considered to be a variation. Rules on wholesale distribution of medicinal products, marketed as a result of a marketing authorisation, whose data have been shared via a letter of access, do not affect the contractual arrangements between the marketing authorisation holders or wholesalers concerned.

(163)

The competent authorities of the Member States should monitor shortages of medicinal products that are authorised through both national and centralised procedures, based on notifications of marketing authorisation holders. The Agency should monitor shortages of centrally authorised medicinal products, also based on notifications of marketing authorisation holders. When critical shortages of Union concern are identified, both competent authorities of the Member States and the Agency should work in a coordinated manner to manage those critical shortages, whether the medicinal product concerned by the critical shortage is covered by a centralised marketing authorisation or a national marketing authorisation and communicate the necessary information to patients, consumers and healthcare professionals. Marketing authorisation holders and other relevant entities should provide the relevant information to inform the monitoring. Wholesale distributors and other entities, including natural and legal persons, such as patient organisations or health-care professionals, should also be able to report a shortage of a given medicinal product marketed in the Member State concerned to the competent authority. The Agency, with the support of MSSG already established within the Agency pursuant to Regulation (EU) 2022/123 of the European Parliament and of the Council (24), should establish and, where necessary, update a list of critical shortages of Union concern. The Agency, in coordination with the competent authority of the Member State concerned should ensure monitoring of those shortages.

(164)

Parallel trade of medicinal products concerns medicinal products traded from one Member State to another Member State. Parallel trade facilitates the free movement of medicinal products due to the fact that the medicinal products are authorised in more Member States on the basis of the Union legislation. This situation is different from export, where the harmonised system of authorising and making medicinal products available on the market does not exist. While the Court has ruled that parallel trade fosters the free movement of medicinal products and is therefore beneficial to the internal market, it has also recognised the need to ensure that a Member State has reliable supplies for essential medical purposes, in particular a supply of medicinal products to the public that is reliable and of good quality. Therefore, it should be possible for a Member State to require, for certain medicinal products, wholesale distributors to inform it whenever such a product leaves the Member State in question to be distributed in another Member State. On the basis of that information and other information at its disposal, including shortage prevention plans, the Member State should be able to take measures to prevent or mitigate shortages and should notify them to the Agency. Those measures should also be appropriate and proportionate to such objectives and take into account that the principle of the free movement of goods is restricted only for the purpose of safeguarding public health, thus respecting the case law of the Court and the Treaties, in particular the provisions on free movement of goods and competition. The information requirements laid down in this Regulation do not affect existing obligations under Union law for the notification of technical regulations and technical barriers to the internal market, including those laid down in Directive (EU) 2015/1535 of the European Parliament and of the Council (25). It is important to recognise that parallel import can contribute to the objective of access to medicinal products, especially in smaller or vulnerable markets.

(165)

A voluntary mechanism can foster solidarity between Member States in the context of critical shortages that require urgent collective action. The voluntary solidarity mechanism for medicinal products can be activated as a last resort mechanism and should aim to support Member States experiencing critical shortages that cannot be resolved at national level despite exhaustive short-term measures. Activation of that Mechanism should be contingent upon specific conditions, including the lack of therapeutic alternatives and insufficient quantities to cover critical indications and an imminent risk of stockout which underline the urgency of the situation. The Agency should facilitate communication and coordinate support responses, thereby also offering assistance in liaising with marketing authorisation holders when necessary. The MSSG should be responsible for establishing procedural rules to ensure the efficient operationalisation of that Mechanism.

(166)

Competent authorities of the Member States should identify, on the basis of a common Union methodology, medicinal products they consider to be critical at national level. The resulting list of critical medicinal products identified by Member States (‘Union long list’) should be adopted and published by the Commission. The MSSG should also propose a Union list of critical medicinal products authorised in accordance with Directive (EU) 2026/… (+) or in accordance with this Regulation to ensure monitoring of the supply of those products, to be adopted by the Commission. The MSSG, supported by the Agency, should undertake the vulnerability evaluation of critical medicinal products on the Union list of critical medicinal products following a defined prioritisation. The Commission should gradually, taking into account the outcome of the vulnerability evaluation, specify the critical medicinal product for which a vulnerability is established. Among those medicinal products the Commission should also specify those critical medicinal products, including their active substances, which are vulnerable due to a high level of dependency on a single or limited number of countries outside the Union. The MSSG should be able to provide recommendations on measures to be taken by marketing authorisation holders, the Member States, the Commission and other entities to resolve any critical shortage or to ensure the security of supply of those critical medicinal products to the market. Where appropriate, those security of supply measures should also comprise the use of regulatory flexibilities such as on packaging and labelling requirements. However, such flexibility should not undermine the quality, safety, and efficacy standards.

(167)

Monitoring and prevention activities, together with targeted actions at national level, have at times proven to be insufficient to prevent disruption of supply within the Union of critical medicinal products. Experience has shown that difficulties in the supply chain have led to uncoordinated approaches at company and governmental level, such as imposing contingency stocks requirements on actors in the supply chain, which led to restrictions in the internal market. Such restrictions are also likely to result in a suboptimal level of availability of critical medicinal products, due to the fact that a fragmented approach is jeopardising the availability throughout the Union. It is necessary to ensure that tools for a Union approach are available to address such situations which are likely to lead to such restrictions, in specific circumstances, to ensure the free movement of medicinal products by safeguarding security of a safe and stable supply of them at Union level. The Commission should therefore be able to draw up recommendations on national measures, after having duly identified a serious risk of disruptions, to improve security of supply within the Union.

(168)

To ensure the enforcement of certain obligations relating to the marketing authorisation for medicinal products for human use granted in accordance with this Regulation, the Commission should be able to impose financial penalties. When assessing the responsibility for failures to comply with those obligations and imposing such penalties, it is important that means exist to address the fact that marketing authorisation holders could be part of a wider economic entity. Otherwise, there is a clear and identifiable risk that the responsibility for a failure to comply with those obligations could be evaded, which might have an impact on the ability to impose effective, proportional and dissuasive penalties. The penalties imposed should be effective, proportionate and dissuasive, having regard to the circumstances of the specific case. For the purpose of ensuring legal certainty in the conduct of the infringement procedure, it is necessary to set maximum amounts for penalties. Those maximum amounts should not be linked to the turnover of a particular medicinal product but the economic entity involved.

(169)

To supplement or amend certain non-essential elements of this Regulation, the power to adopt acts in accordance with Article 290 TFEU should be delegated to the Commission in respect of determining the situations in which post-authorisation efficacy studies could be required; specifying the categories of medicinal products to which a marketing authorisation subject to specific obligations could be granted and specifying the procedures and requirements for granting such a marketing authorisation and for its renewal; specifying exemptions to variation and the categories in which variations should be classified and establishing procedures for the examination of applications for variations to the terms of marketing authorisations as well as specifying conditions and procedures for cooperation with third countries and international organisations for examination of applications for such variations; establishing procedures for the examination of applications for the transfer of marketing authorisations; laying down the procedure and rules for the imposition of fines or periodic penalty payments for a failure to comply with the obligations under this Regulation as well as the conditions and methods for their collection. The Commission should be empowered to adopt supplementary measures laying down the situations in which post-authorisation efficacy studies could be required. It is of particular importance that the Commission carries out appropriate consultations during its preparatory work, including at expert level, and that those consultations be conducted in accordance with the principles laid down in the Interinstitutional Agreement between the European Parliament, the Council of the European Union and the European Commission of 13 April 2016 on Better Law-Making (26). In particular, to ensure equal participation in the preparation of delegated acts, the European Parliament and the Council receive all documents at the same time as Member States’ experts, and their experts systematically have access to meetings of Commission expert groups dealing with the preparation of delegated acts.

(170)

In order to ensure uniform conditions for the implementation of this Regulation in relation to marketing authorisations for medicinal products for human use, implementing powers should be conferred on the Commission. The implementing powers related to the granting of centralised marketing authorisations and for suspending, revoking or withdrawing those authorisations, for granting data exclusivity vouchers, establishing and modifying regulatory sandboxes and adopting decisions on the regulatory status of medicinal products should be exercised in accordance with Regulation (EU) No 182/2011.

(171)

Article 91 of Regulation (EU) No 536/2014 currently stipulates, amongst others, that it applies without prejudice to Directives 2001/18/EC and 2009/41/EC.

(172)

Experience shows that, in clinical trials with investigational medicinal products consisting of, or containing, GMOs, the procedure to achieve compliance with the requirements of Directives 2001/18/EC and 2009/41/EC as regards the environmental risk assessment and consent by the competent authority of a Member State is complex and can take a significant amount of time.

(173)

The complexity of that procedure increases greatly in the case of multi-centre clinical trials conducted in several Member States, as sponsors of clinical trials need to submit multiple requests for authorisation to multiple competent authorities in different Member States in parallel. In addition, national requirements and procedures for the environmental risk assessment (ERA) and written consent by competent authorities under GMO legislation vary greatly from one Member State to another as some Member States apply Directive 2001/18/EC, others apply Directive 2009/41/EC and there are Member States that apply either Directive 2009/41/EC or 2001/18/EC depending on the specific circumstances of a clinical trial. It is therefore not possible to determine a priori the national procedure that is to be followed.

(174)

Consequently, it is particularly difficult to conduct multi-centre clinical trials with investigational medicinal products that consist of, or contain, GMOs involving several Member States.

(175)

One of the objectives of Regulation (EU) No 536/2014 is that there will be a single coordinated and harmonised assessment of the clinical trial application between the involved Member States, with one country leading the coordination of the assessment (the ‘reporting Member State’).

(176)

It is therefore appropriate to envisage a centralised assessment of the ERA involving experts from the competent authorities of the Member States and where relevant the Environmental Risk Assessment working party.

(177)

Article 5 of Directive 2001/18/EC provides that the authorisation procedures for the deliberate release into the environment of GMOs for any other purpose than for placing on the market and related provisions in Articles 6 to 11 do not apply to medicinal substances and compounds for human use if such release is authorised by Union legal acts that meet the requirements listed in that Article.

(178)

The requirement for the holding of authorisation of manufacturing and import of investigational medicinal products in the Union in accordance with Article 61(2), point (a), of Regulation (EU) No 536/2014 should be extended to investigational medicinal products consisting of, or containing, GMOs in Directive 2009/41/EC.

(179)

It is thus judicious, in order to ensure an efficient functioning of Regulation (EU) No 536/2014, to define a specific authorisation procedure for the deliberate release of medicinal substances and compounds for human use consisting of, or containing, GMOs that meet requirements of Article 5 of Directive 2001/18/EC and taking into account the specific characteristics of medicinal substances and compounds.

(180)

Detailed rules concerning financial penalties for failure to comply with certain obligations laid down in this Regulation are specified in Commission Regulation (EC) No 658/2007 (27). Those rules should be maintained, but it is appropriate to consolidate them by moving their core elements and the list specifying those obligations into this Regulation, while maintaining a delegation of powers that allows the Commission to supplement this Regulation by laying down procedures for imposing such financial penalties. It is appropriate, in order to provide for legal certainty, to clarify that Commission Regulation (EC) No 2141/96 (28) remains in force and continues to apply unless and until repealed. For the same reason, it should be clarified that Commission Regulations (EC) No 2049/2005 (29), (EC) No 507/2006 (30), (EC) No 658/2007 and (EC) No 1234/2008 (31) remain in force and continue to apply unless and until repealed.

(181)

This Regulation is based on the double legal basis of Article 114 and Article 168(4), point (c), TFEU. It aims at achieving an internal market as regards medicinal products for human use, based on a high level of protection of health. At the same time, this Regulation sets high standards of quality and safety for medicinal products in order to meet common safety concerns as regards those products. Both objectives are being pursued simultaneously. Those two objectives are inseparably linked and one is not secondary to another. Regarding Article 114 TFEU, this Regulation establishes a European Medicines Agency and provides specific provision with regard to the central authorisation of medicinal products, therefore ensuring the functioning of the internal market and the free movement of medicinal products. Regarding Article 168(4), point (c), TFEU, this Regulation sets high standards of quality and safety for medicinal products.

(182)

Since provisions on the centralised procedure for the authorisation and supervision of medicinal products for human use, including orphan medicinal products and paediatric medicinal products, and on the European Medicines Agency, are integrated into this Regulation, it is necessary to repeal Regulations (EC) No 141/2000, (EC) No 726/2004 and (EC) No 1901/2006.

(183)

This Regulation respects the fundamental rights and observes the principles recognised by the Charter and in particular human dignity, the integrity of the person, the rights of the child, respect for private and family life, the protection of personal data and the freedom of art and science. Similarly this regulation integrates a high level of protection of the environment.

(184)

Since the objective of this Regulation, namely to ensure the authorisation of high quality medicinal products, including for paediatric patients and patients suffering from rare diseases throughout the Union, cannot be sufficiently achieved by the Member States but can rather, by reason of the scale of the action needed, be better achieved at Union level, the Union may adopt measures, in accordance with the principle of subsidiarity as set out in Article 5 of the Treaty on European Union. In accordance with the principle of proportionality, as set out in that Article, this Regulation does not go beyond what is necessary in order to achieve that objective.

(185)

The European Data Protection Supervisor was consulted in accordance with Article 42(1) of Regulation (EU) 2018/1725 and delivered an opinion on 19 June 2023 (32),