Overwegingen bij COM(2023)193 - Procedures van de Unie voor het verlenen van vergunningen en het toezicht met betrekking tot geneesmiddelen voor menselijk gebruik en tot vaststelling van regels voor het Europees Geneesmiddelenbureau - Hoofdinhoud
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| dossier | COM(2023)193 - Procedures van de Unie voor het verlenen van vergunningen en het toezicht met betrekking tot geneesmiddelen voor menselijk ... |
|---|---|
| document | COM(2023)193  |
| datum | 26 april 2023 |
(2)The Pharmaceutical Strategy for Europe marks a turning point with the addition of further key objectives and by creating a modern framework that makes innovative and established medicinal products available to patients and healthcare systems at affordable prices, while ensuring security of supply and addressing environmental concerns.
(3)Addressing unequal patient access of 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 have called for revised mechanisms and incentives for development of medicinal products tailored to the level of unmet medical need, while ensuring patient access and availability of medicinal products in all Member States.
(4)Previous amendments to the Union pharmaceutical legislation have addressed access to medicinal products by providing for accelerated assessment for marketing authorisation applications or by allowing conditional marketing authorisation for medicinal products for unmet medical need. While these measures accelerated the authorisation of innovative and promising therapies, these medicinal products do not always reach the patient and patients in the Union still have different levels of access to medicines.
(5)The COVID-19 pandemic has spotlighted critical issues which require a reform of the Union pharmaceuticals framework to strengthen its resilience and to ensure that it serves the people under all circumstances.
(6)For the sake of clarity, it is necessary to replace Regulation (EC) No 726/2004 of the European Parliament and of the Council 38 with a new Regulation.
(7)Veterinary medicinal products are governed by Regulation (EU) No 2019/6 of the European Parliament and of the Council 39 . These medicinal products are outside the scope of this Regulation, even if certain provisions regarding the governance and general tasks of the Agency set out in this Regulation apply to these medicinal products. The specific tasks of the Agency in respect to veterinary medicinal products are laid down in Regulation 2019/6 and Regulation 470/2009 of the European Parliament and of the Council 40 .
(8)The scope of centrally authorised medicinal products has been adapted to the realities of the market and technological development as well as the need to ensure a centralised assessment for certain categories of medicinal products. In the light of the Commission's report 41 on the experience gained, it has proved necessary to improve the operation of the marketing authorisation procedures for the placing of medicinal products on the Union market and to amend certain administrative aspects of the European Medicines 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. The conclusions of that report call for corrections to some of the operating procedures and require adaptations to take account of scientific and technological development. It also emerges from the report that the general principles previously established which govern the centralised marketing authorisation procedure ('centralised procedure’) should be maintained.
(9)As to the scope of this Regulation, the authorisation of antimicrobials is, in principle, in the interest of patients' health at Union level and therefore it should be made possible to authorise them at Union level.
(10)With a view to maintain 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, priority antimicrobials, orphan medicinal products, paediatric use medicinal products and any medicinal product that includes an active substances not authorised before the last important change to the scope of the centralised procedure in 2004.
(11)As regards medicinal products for human use, optional access to the centralised procedure should also be foreseen in cases where use of a single procedure produces added value for the patient. The centralised procedure should remain optional for medicinal products which, although not belonging to the categories of products to be authorised by the Union, are nevertheless therapeutically innovative. It is also appropriate to allow access to this procedure for medicinal products which, although not innovative, may be of benefit to society or to patients, including paediatric patients, if they are authorised from the outset at Union level, such as certain medicinal products which can be supplied without a medical prescription. This option may be extended to generic and biosimilar medicinal products authorised by the Union, provided that this in no way undermines either the harmonisation achieved when the reference medicinal product was evaluated or the results of that evaluation. At the same time, to ensure wide availability of generic medicinal products, those medicinal products may be authorised in any case by the competent authorities of the Member States, even if they are based on a centrally authorised reference medicinal product.
(12)The structure and operation of the various bodies making up the Agency should be designed in such a way as to take into account the need to constantly renew scientific expertise, the need for cooperation between Union and national bodies, the need for adequate involvement of civil society, and the future enlargement of the Union. The various bodies of the Agency should establish and develop appropriate contacts with the parties concerned, in particular with representatives of patients and healthcare professionals.
(13)The chief task of the Agency should be to provide Union institutions and Member States with the best possible scientific opinions to enable them to exercise the powers of authorisation and supervision of medicinal products conferred on them by Union legal acts in the field of medicinal products. Marketing authorisation should be granted by the Commission only after a single scientific evaluation procedure addressing the quality, safety and efficacy of high-technology medicinal products has been conducted by the Agency, applying the highest possible standards.
(14)To ensure close cooperation between the Agency and scientists 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 Union system for authorising medicinal products.
(15)The Agency's budget should be composed of fees and charges paid by the private sector and contributions from the Union budget to implement Union policies and contributions paid from third countries.
(16)Exclusive responsibility for preparing the Agency's opinions on all questions concerning medicinal products for human use should be vested in the Committee for Medicinal Products for Human Use.
(17)The creation of the Agency through Council Regulation (EEC) No 2309/93 42 which was replaced 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. This Regulation does not establish a new Agency. The Agency mentioned in this Regulation is the Agency established by Regulation (EC) No 726/2004.
(18)The field of activity of the scientific committees should be enlarged and their operating methods and composition modernised. In this regard it is important to ensure patient and healthcare professional representation in the Committee for Human Medicinal Products as it is the main evaluation committee of the Agency for medicinal products for human use.
(19)Scientific advice for future applicants seeking a marketing authorisation should be provided more generally and in greater depth. Similarly, structures allowing the development of advice for companies, in particular small and medium-sized enterprises (‘SMEs’), should be put in place.
(20)Promising medicinal products that have the potential to significantly address patients’ unmet medical needs should benefit from early and enhanced scientific support. Such support will ultimately help patients benefit from new therapies as early as possible.
(21)In order to allow for advice 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 foreseen in Regulation (EU) 2021/2282 of the European Parliament and of the Council 43 and, in cases of medicinal products involving a medical device, the consultation of the expert panels as described in Article 106 of Regulation (EU) No 2017/745 of the European Parliament and of the Council 44 . Where parallel scientific advice consultation mechanisms are established under other relevant Union legal acts, a similar mechanism should apply.
(22)It is also necessary to reinforce the role of the scientific committees in such a way as to enable the Agency 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.
(23)Furthermore, 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, it is necessary to define the responsibilities regarding the transparency rules for the Agency's work, to set certain conditions for the marketing of medicinal products authorised by the Union, to confer on the Agency powers to monitor the distribution of medicinal products authorised by the Union, to carry out inspections together with the Member States in third countries, and to specify the sanctions and the procedures for implementing them in the event of failure to observe the provisions of this Regulation and the conditions contained in the marketing authorisations granted under the procedures it establishes.
(24)In particular, the Agency should be empowered and given the capacity to carry out inspections, where this is in the interest of the Union and where the competent authorities of the Member States request support in carrying out their tasks under revised Directive 2001/83/EC of the European Parliament and of the Council 45 . The interest of the Union may concern situations where, to ensure faster access to medicinal products, challenges with inspections 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. Providing the Agency with appropriate inspection capacity will also, in the interest of the Union, facilitate the dissemination of best practices, know-how, and improve the oversight of manufacturing of medicinal products worldwide. Following the request from a competent authority of the Member State, the Agency, at its own discretion, can accept to either provide support to the inspections of sites located in the Union or to carry out inspections of sites located in third countries.
(25)In certain cases, shortcomings in Member States’ system of supervision and related enforcement activities could risk to substantially hinder the achievement of the objectives of this Regulation and those of revised Directive 2001/83/EC which could even lead to the emergence of risks to public health. To address these challenges, harmonised inspection standards should be ensured through the establishment of a joint audit programme within the Agency. This joint audit programme will also further harmonise the interpretation of good manufacturing and distribution practices on the basis of Union legislative requirements. Moreover, it will support further mutual recognition of inspection outcomes between Member States and with strategic partners. Within the joint audit programme, the competent authorities 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 into national laws and equivalence with other EEA inspectorates.
(26)An inspection working group, which provides input and recommendations on all matters relating, directly or indirectly, to good manufacturing practice and good distribution practice irrespective of the marketing authorisation procedure through different reporting lines, should be established within the Agency. In particular, that working group should be responsible for the establishment, development and overall supervision of the joint audit programme.
(27)To promote innovation and the development of new medicinal products by SMEs within the meaning of Commission Recommendation 2003/361/EC 46 , 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.
(28)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.
(29)Legal entities that are not engaged in an economic activity such as universities, public bodies, research centres or not-for-profit organisations, represent an important source of innovation 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.
(30)The Agency should be empowered to give 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 may 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.
(31)To increase transparency of scientific assessments and all other activities, a European medicines web-portal should be created and maintained by the Agency.
(32)Experience with the functioning of the regulatory system has shown that the existing European Medicines 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.
(33)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, the Committee for Medicinal Products for Human Use (CHMP) and Pharmacovigilance Risk Assessment Committee (PRAC).
(34)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.
(35)The Agency’s scientific committees should be able to delegate some of their evaluation duties to working parties which should be open to experts from the scientific world and appointed for this purpose, whilst retaining complete responsibility for the scientific opinions issued by them.
(36)The expertise of the Committee for Advanced Therapies (CAT), the Committee for Orphan Medicinal Products (COMP), the Paediatric Committee (PDCO) and Committee for Herbal Medicinal Products (HMPC) is retained through working groups, working parties and a pool of experts who are organised based on different domains and who are giving input to the CHMP and PRAC. The CHMP and PRAC consists of experts from all Member States while working parties consist in majority of experts appointed by the Member States, based on their expertise, and of external experts. The model of rapporteurs remains unchanged. Representation of patients and health care professionals, with expertise in all areas, including rare and paediatric diseases, is increased at the CHMP and PRAC, in addition to the dedicated working groups representing patients and health care professionals.
(37)Scientific committees like the CAT 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 full integration of their assessment in the work of the CHMP will facilitate the assessment of medicinal products within the same therapeutic class, independent of the technology on which they are based. It will also ensure that all biological medicinal products are assessed by the same committee.
(38)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 with 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 47 .
(39)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 could be, as appropriate, representatives from Heads of Medicines Agencies, the Clinical Trial Coordination and Advisory Group, the SoHO Coordination Board, the Coordination Group on Health Technology Assessment, Medical Devices Coordination Group, medical devices national competent authorities, national competent authorities for pricing and reimbursement of medicines, 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.
(40)Member States should ensure adequate funding of competent authorities to carry out their tasks under this Regulation and under [revised Directive 2001/83/EC]. In addition, in line with the Joint Statement of the European Parliament, the Council of the EU and the European Commission on decentralised agencies 48 , Member States should ensure adequate resources are assigned by the competent authorities of the Member States for the purpose of their contributions to the work of the Agency, taking into account the cost-based remuneration they receive from the Agency.
(41)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 may 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 World Health Organization and relevant third country regulatory authorities and bodies to issue such scientific opinions.
(42)The Agency may cooperate with competent authorities of third countries in the context of performing its tasks. Such regulatory cooperation should be coherent 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.
(43)In the interest of public health, marketing authorisation decisions under the centralised procedure should be taken on the basis of the objective 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, to prohibit the use in their territory of medicinal products for human use.
(44)The quality, safety and efficacy criteria of [revised Directive 2001/83/EC] should apply to medicinal products authorised by the Union under the centralised procedure. The benefit-risk balance of all medicinal products will be assessed when they are placed on the market, and at any other time the competent authority deems appropriate.
(45)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. Applications should be assessed based on the file submitted by the applicant in accordance with the different legal basis provided by [revised Directive 2001/83/EC]. At the same time, the Agency and the relevant committees may take into account any information that is in its possession. Applicants shall be requested to generally submit raw data, in particular with regard to the clinical trials performed by the applicant in order to ensure a full assessment of the quality, safety and efficacy of the medicinal product.
(46)Directive 2010/63/EU of the European Parliament and of the Council on the protection of animals used for scientific purposes 49 lays down provisions on the protection of animals used for scientific purposes based on the principles 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 those principles of replacement, reduction and refinement, where they concern 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 designed to avoid causing pain, suffering, distress or lasting harm to animals and should follow the available Agency and the International Committee for Harmonisation (ICH) guidelines. In particular, the marketing authorisation applicant and the marketing authorisation holder should take into account the principles laid down in Directive 2010/63/EU, including, where possible, use of new approach methodologies in place of animal testing. These can include but are not limited to: 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 or read-across models.
(47)Procedures should be in place to facilitate joint animal testing, wherever possible, in order to avoid unnecessary duplication of testing using live animals covered by Directive 2010/63/EU. Marketing authorisation applicants and marketing authorisation holders should make all efforts to reuse animal study results and make the results obtained from animal studies publicly available. For abridged applications marketing authorisation applicants should refer to the relevant studies conducted for the reference medicinal product.
(48)The summary of product characteristics and the package leaflet should reflect the assessment of the Agency and be part of its scientific opinion. The opinion may 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 may 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 proposed dose scheme by the applicant, whilst acceptable and justifying a positive benefit-risk balance, could be further optimised post-authorisation. Where the applicant disagrees with parts of the opinion, the applicant may request its re-examination.
(49)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 (CHMP) and the final decision on the application for a marketing authorisation should in principle be no longer than 46 days.
(50)On the basis of the opinion of the Agency the Commission should adopt a decision on the application by means of implementing acts. In justified cases, the Commission may return 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) 182/2011 of the European Parliament and of the Council 50 and notably the possibility to obtain the committee’s opinion by written procedure and within expeditious deadlines which, in principle, will not exceed 10 calendar days.
(51)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.
(52)There is a need to provide for the ethical requirements of Regulation (EU) No 536/2014 to apply to medicinal products authorised by the Union. In particular, with respect to clinical trials conducted outside the Union on medicinal products destined to be authorised within the Union, at the time of the evaluation of the application for authorisation, it should be verified that these trials were conducted in accordance with the principles equivalent to these of 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.
(53)Environmental risks may arise from medicinal products containing or consisting of genetically modified organisms. 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 51 , 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 set out in this Regulation and in [revised Directive 2001/83/EC] which are based on the principles set out in Directive 2001/18/EC but taking into account the specificities of medicinal products.
(54)[revised Directive 2001/83/EC] 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 containing or consisting of genetically modified organisms (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 containing or consisting of 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 52 should not be a prerequisite. Nevertheless, in these cases, Member States should implement appropriate measures to minimise foreseeable negative environmental impacts resulting from the intended or unintended release of the medicinal products containing or consisting of GMOs into the environment.
(55)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 [revised Directive 2001/83/EC].
(56)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.
(57)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 Member States' legislation. Moreover, it is important to allow for data on such uses to be collected to inform decisions regarding the benefit-risk balance of the medicinal products concerned.
(58)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 shall be subject to specific review of the fulfilment of the imposed specific conditions or obligations. It is also understood that the grounds for refusal of a marketing authorisation shall apply mutatis mutandis for such cases.
(59)In principle, only one marketing authorisation may be granted to an applicant for a medicinal product. Duplicate marketing authorisations should only be granted in exceptional circumstances. When those exceptional circumstances are no longer present, notably 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.
(60)Regulatory decision-making on the development, authorisation and supervision of medicinal products may be supported by access and analysis of health data, including real world data, where appropriate, i.e. health data generated outside of clinical studies. The Agency should be able to use such data, including via the Data Analysis and Real World Interrogation Network (DARWIN) and the European Health Data Space interoperable infrastructure. Through these capabilities the Agency may take advantage of all the potential of supercomputing, artificial intelligence and big data science to fulfil its mandate, without compromising privacy rights. Where necessary the Agency may cooperate with the competent authorities of the Member States towards this objective.
(61)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.
(62)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 Regulation (EU) 2016/679 53 and Regulation (EU) 2018/1725 54 of the European Parliament and of the Council.
(63)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 foster data-driven benefit-risk assessments at all stages of the life cycle of a medicinal product. This Regulation therefore empowers the Agency to request such data as part of the assessment of initial and post-authorisation applications.
(64)For generic 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 and biosimilar medicinal products should be developed and submitted to the competent authorities.
(65)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 may 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.
(66)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, including for priority antimicrobials and repurposed medicinal products when they fulfil the criteria for the scheme, and allow the Agency, in consultation with the Member States and the Commission, to establish selection criteria for promising medicinal products.
(67)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 provide a major therapeutic advancement with respect to the identified unmet medical need.
(68)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 safe, of high quality 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 may 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, including orphan medicinal products, that aim at the treatment, prevention or medical diagnosis of seriously debilitating or life-threatening diseases, or that are intended to be used in emergency situations in response to public health threats.
(69)The Union should have the means to carry out a scientific assessment of the medicinal products presented 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 medicinal products presented 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.
(70)In the event of a risk to public health, the marketing authorisation holder or the competent authorities should be able to make 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 on the same safety or efficacy concern addressed by urgent restrictions initiated by a competent authority, any written observations by the marketing authorisation holder should be considered in that review to avoid duplication of assessment.
(71)The terms of a marketing authorisation for a medicinal product for human use may be varied. While the core elements of a variation are laid down in this Regulation, the Commission should be empowered to complement these 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.
(72)To avoid unnecessary administrative and financial burden both for the pharmaceutical industry and the competent authorities, certain streamlining measures should be introduced. Electronic applications for marketing authorisations and for variations to the terms of the marketing authorisation should be made possible.
(73)To optimise the use of resources for both applicants for marketing authorisations and competent authorities assessing such applications, a single assessment of an active substance master file should be introduced. The outcome of the 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 or marketing authorisations for medicinal products for human use containing that active substance from an active substance master file certification holder. The Commission should be empowered to establish the procedure for the single assessment of an active substance master file. To further optimise the use of resources, the Commission should be empowered to extend the certification scheme to additional quality master files, e.g. in case of novel excipients, adjuvants, radiopharmaceutical precursors and active substance intermediates, when the intermediate is a chemical active substance by itself or used in conjugation with a biological substance.
(74)To avoid unnecessary administrative and financial burdens for applicants, marketing authorisation holders and competent authorities, certain streamlining measures should be introduced. Electronic application for marketing authorisation and for variations to the terms of the marketing authorisation should be introduced. For generic and biosimilar medicinal products, except in specific cases, risk management plans do not need to be developed and submitted to the competent authorities.
(75)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.
(76)It is considered appropriate to also have the possibility for the Commission to grant temporary emergency marketing authorisations to address public health emergencies. Temporary emergency marketing authorisations may 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, clinical data may 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 set out in the temporary emergency marketing authorisation.
(77)The development of antimicrobial resistance is a growing concern and the pipeline of effective antimicrobials is obstructed due to a market failure; it is therefore necessary to consider new measures to promote the development of priority antimicrobials that are effective against antimicrobial resistance and to support undertakings, often SMEs, which choose to invest in this area.
(78)To be considered a ‘priority antimicrobial’, a medicinal product should represent a real advancement against antimicrobial resistance and should therefore bring forward non-clinical and clinical data that underpin a significant clinical benefit with respect to antimicrobial resistance. When assessing the conditions for antibiotics, the Agency shall take into account the prioritisation of pathogens as regards the risk of antimicrobial resistance provided for in the ‘WHO priority pathogens list for R&D of new antibiotics’, specifically those listed as priority 1 (critical) or priority 2 (high) or in case there is an equivalent list of priority pathogens adopted at Union level, the Agency should take such Union list into account as a priority.
(79)The creation of a voucher 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 voucher, the number of available 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 voucher and to further give the possibility to the Commission to revoke the voucher under certain circumstances.
(80)A transferable data exclusivity voucher should only be available to those antimicrobial products 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 medicinal product 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 the medicinal product.
(81)To ensure a high level of transparency and complete information on the economic effect of the transferable data exclusivity voucher, notably as regards the risk of overcompensation of investment, a developer of a priority antimicrobial is required to provide 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.
(82)A transfer of a voucher for a priority antimicrobial may be conducted by sale. The value of the transaction which may be monetary or otherwise agreed between the buyer and the seller, shall be made public so as to inform regulators and the public. The identity of the holder of a 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.
(83)The provisions related to transferable data exclusivity vouchers shall be applicable for a specified period from the entry into force of this Regulation or until a maximum number of 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 addressing antimicrobial resistance and assess the cost on national health systems. Such assessment will provide the necessary knowledge to decide whether to extend the application of the measure.
(84)The period of application of the provisions on transferable exclusivity vouchers for priority antimicrobials and the total number of vouchers may be extended by the Parliament and the Council upon proposal by the Commission on the basis of the experience acquired.
(85)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 benefit-risk assessment. The Commission may also act on a centralised marketing authorisation where the conditions attached to it are not complied with.
(86)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 for what concerns the marketing authorisation procedures, the pharmacovigilance and quality requirements. However, specific requirements also apply to them. Such requirements, which are currently defined in separate legislations, should be integrated in this Regulation in order to ensure clarity and coherency of all the measures applicable to these medicinal products.
(87)Some orphan 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 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 medications by the pharmaceutical industry.
(88)Regulation (EC) No 141/2000 of the European Parliament and of the Council 55 has proved to be successful in boosting developments of orphan medicinal products in the Union; therefore an action at Union level remains preferable to uncoordinated measures by the Member States which may result in distortions of competition and barriers to intra-Union trade.
(89)The open and transparent Union 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 these medicinal products should be integrated in this Regulation.
(90)Objective criteria for the orphan designation based on the prevalence of the life-threatening or chronically debilitating condition for which diagnosis, prevention or treatment is sought and the existence of no satisfactory method of diagnosis, prevention 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 the appropriate threshold. The orphan designation criterion on the basis of return on investment has been abolished, since it has never been used.
(91)The criterion for orphan designation based on prevalence of a disease may, however, 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. With the aim to better identify only those diseases which are rare, the Commission should be empowered to set up specific designation criteria for certain conditions if the one provided for are not appropriate due to scientific reasons and on the basis of a recommendation of the Agency.
(92)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 measures to be adopted by the Commission.
(93)If a satisfactory method of diagnosis, prevention 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 as a satisfactory method. In addition, commonly used methods of diagnosis, prevention or treatment that are not subject to a marketing authorisation may be considered satisfactory if there is scientific evidence of their efficacy and safety. 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 as satisfactory treatment if they are well known and safe and this is a general practice for the relevant patient population in the Union.
(94)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.
(95)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 may be withdrawn at the request of the orphan medicine sponsor.
(96)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 and the minimum data which should be included in the register have been specified in this Regulation with the empowerment for the Commission to amend or supplement this data by a delegated act.
(97)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 diagnosis, prevention or treatment of such conditions, including rare diseases.
(98)Patients suffering from orphan conditions deserve medicinal products of the same quality, safety and efficacy as other patients; 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 an marketing authorisation for orphan medicinal product, while a separate marketing authorisation may be granted for indications not fulfilling the criteria of an orphan medicinal product.
(99)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.
(100)Orphan medicinal products addressing a high unmet medical need prevent, diagnose or treat conditions where either no other method of prevention, diagnosis or treatment exists or, if such method already exists, they would bring exceptional therapeutic advancement. In both cases, the criterion of meaningful reduction in disease morbidity or mortality for the relevant patient population should ensure that only most effective medicinal products are covered. The Agency should draw up scientific guidelines on the category of ‘orphan medicinal products addressing a high unmet medical need’.
(101)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 protection set out in [revised Directive 2001/83/EC], including the prolongations of regulatory data protection. However, where an orphan medicinal product obtains an additional therapeutic indication it will benefit only from the prolongation of market exclusivity.(102)In order to incentivise research and development of orphan medicinal products addressing high unmet needs, to ensure market predictability and to ensure a fair distribution of incentives, a modulation of market exclusivity has been introduced; orphan medicinal products addressing high unmet medical needs 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 after six years after the marketing authorisation has been abolished.
(103)In order to encourage faster and wider access also to orphan medicinal products, an additional period of one year of market exclusivity is granted to orphan medicinal products for a Union market launch, with the exception of well-established use medicinal products.
(104)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).
(105)This Regulation includes several provisions aimed to avoid not-justified benefits being derived from the market exclusivity and to improve accessibility of medicinal products by ensuring faster entry of generics and biosimilars, and similar medicinal products on the market. It also clarifies the concurrence of market exclusivity with data protection and defines situations when a similar medicinal product may be granted a marketing authorisation, despite the ongoing market exclusivity.
(106)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 on 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 are presented in dosages and formulations adequate for the use in children.
(107)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.
(108)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.
(109)During public health emergencies, in order not to delay a prompt authorisation of a medicinal product intended for the treatment or the prevention 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.
(110)In order to not endanger the health of children and avoid to expose them to unnecessary clinical trials, the obligation to agree and conduct paediatric 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 treatments for children or the disease for which the medicinal product is intended occurs only in adult populations. Nevertheless, in the last case, if on the basis of existing scientific evidence, the medicinal product due to its molecular mechanism of action is expected to be effective against a different disease in children, the obligation should be maintained.
(111)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 medicinal products and 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, that requirement should not apply for a given period in order to allow time for at least a paediatric investigation plan to be agreed and studies in the paediatric population to be initiated before an application for marketing authorisation is submitted.
(112)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 may defer the initiation or completion of some or all of the measures contained in a paediatric investigation plan for a limited period of time. Such deferral should be extended only in duly justified cases.
(113)The possibility to modify an agreed paediatric investigation plan should be foreseen when the applicant encounters such difficulties with its implementation as to render the plan unworkable or no longer appropriate.
(114)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.
(115)For medicinal products intended to be developed for use only in children which would be developed independently from the current provisions, simplified details of the paediatric investigation plan should be required.
(116)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.
(117)Free scientific advice should be provided by the Agency as an incentive to sponsors developing medicinal products for the paediatric population.
(118)To provide healthcare professionals and patients with information on the safe and effective use of medicinal products in the paediatric population, the results of the studies conducted in accordance with a 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.
(119)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 brand 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.
(120)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. These data may 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 generic companies, to develop off-patent medicinal products for the paediatric population.
(121)Some paediatric investigation plans may be discontinued due to 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 may be interested in continuing the above-mentioned studies.
(122)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 created by Regulation (EU) No 536/2014.
(123)The summary of the results of all the paediatric clinical trials included in the European clinical trial database created by Regulation (EU) No 536/2014 should be made publicly available within 6 months after the end of the clinical trials unless this is not possible for justified scientific reasons.
(124)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 composed of patient representatives, academics, medicines developers, investigators and research centres based in the Union or in the European Economic Area.
(125)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 network.
(126)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 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.
(127)The main tasks of the Agency in the area of pharmacovigilance laid down in Regulation (EC) No 726/2004 should be maintained. This includes 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.
(128)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 risk-benefit balance of a medicinal product.
(129)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, 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 marketing authorisation applicant or marketing authorisation holder. On this basis, the Agency should take initiative to update the summary of product characteristics in case new efficacy or safety data has an impact on the benefit-risk balance of a medicinal product.
(130)It is also 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.
(131)It is necessary to provide for the coordinated implementation of Union procedures for the marketing authorisation of medicinal products, and of the marketing authorisation procedures of Member States which have already been harmonised to a considerable degree by [revised Directive 2001/83/EC].
(132)The Union and Member States have developed a scientific evidence-based process that allows competent authorities 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 health technologies However, this evaluation should not be conducted in the context of the marketing authorisation, for which it is agreed that the fundamental criteria should be retained. It is useful in this respect to allow 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.
(133)Regulatory sandboxes can provide the opportunity for advancing regulation through proactive regulatory learning, enabling regulators to gain better regulatory knowledge and to find the best means to regulate innovations based on real-world evidence, especially at a very early stage of development of a medicinal product, which can be particularly important in the face of high uncertainty and disruptive challenges, as well as when preparing new policies. Regulatory sandboxes provide a structured context for experimentation, 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 artificial intelligence and machine learning in the life cycle of medicinal products from drug discovery, 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 its conclusions of 23 December 2020 the Council has encouraged the Commission to consider the use of regulatory sandboxes on a case-by-case basis when drafting and reviewing legislation.
(134)In the area of medicinal products, a high level of protection of inter alia citizens, consumers, health, as well as legal certainty, a level playing field and fair competition always need to be ensured and existing levels of protection need to be respected.
(135)The establishment of a regulatory sandbox should be based on a Commission Decision following a recommendation of the Agency. Such decision should be based on a detailed 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 may be terminated at any time based on public health considerations. The learning stemming from a regulatory sandbox should inform future changes to the legal framework to fully integrate the particular innovative aspects into the medicinal product regulation. Where appropriate, adapted frameworks may be developed by the Commission on the basis of the results of a regulatory sandbox.
(136)Shortages of medicinal products represent a growing threat to public health, with potential serious risks to the health of patients in the Union and impacts on the right of patients to access appropriate medical treatment. The root causes of shortages are multifactorial, with challenges identified along the entire pharmaceutical value chain, from quality and manufacturing problems. In particular, shortages of medicinal products can result from supply chain disruptions and vulnerabilities affecting the supply of key ingredients and components. Therefore, all marketing authorisation holders should have shortage prevention plans in place, to prevent shortages. The Agency should provide guidance to marketing authorisation holders on approaches to streamline the implementation of those plans.
(137)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 monitoring and reporting of actual or potential 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 across Europe. 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 in Europe.
(138)The national competent authorities should be empowered to monitor shortages of medicinal products that are authorised through both national and centralised procedures, based on notifications of marketing authorisation holders. The Agency should be empowered to monitor shortages of medicinal products that are authorised through the centralised procedure, also based on notifications of marketing authorisation holders. When critical shortages are identified, both national competent authorities 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. Marketing authorisation holders and other relevant entities must provide the relevant information to inform the monitoring. Wholesale distributors and other persons or legal entities, including patient organisations or health care professionals, may also report a shortage of a given medicinal product marketed in the Member State concerned to the competent authority. The Executive Steering Group on Shortages and Safety of Medicinal Products (‘the Medicines Shortages Steering Group’ (MSSG)) already established within the Agency pursuant to Regulation (EU) 2022/123 of the European Parliament and of the Council 56 , should adopt a list of critical shortages of medicinal products and ensure monitoring of those shortages by the Agency. The MSSG should also adopt a list of critical medicinal products authorised in accordance with [revised Directive 2001/83/EC] or this Regulation to ensure monitoring of the supply of those products. The MSSG may 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. Implementing acts can be adopted by the Commission to ensure that appropriate measures, including the establishment or maintenance of contingency stocks, are taken by marketing authorisation holders, wholesale distributors or other relevant entities.
(139)To ensure continuity of supply and availability of critical medicinal products to the market, rules on the transfer of the marketing authorisation prior to the permanent marketing cessation should be laid down. Such transfer should not be considered to be a variation.
(140)It is recognised that improved access to information contributes to public awareness, 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 manufacturing and wholesale distribution database, after the deletion of any commercially confidential information by the competent authority. Regulation (EC) No 1049/2001 of the European Parliament and of the Council 57 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 for 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.
(141)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 purposes 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.
(142)To supplement or amend certain non-essential elements of this Regulation, the power to adopt acts in accordance with Article 290 of the Treaty on the Functioning of the European Union (‘TFEU’) should be delegated to the Commission in respect of determining the situations in which post-authorisation efficacy studies may 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 may 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 58 . 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.
(143)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 vouchers, establishing and modifying regulatory sandboxes and decisions on the regulatory status of medicinal products should be exercised in accordance with Regulation (EU) 182/2011.
(144)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.
(145)Experience shows that, in clinical trials with investigational medicinal products containing or consisting of 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.
(146)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.
(147)Consequently, it is particularly difficult to conduct multi-centre clinical trials with investigational medicinal products that contain or consist of GMOs involving several Member States.
(148)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).
(149)It is therefore appropriate to envisage a centralised assessment of the ERA involving experts from the national competent authorities.
(150)Article 5 of Directive 2001/18/EC provides that the authorisation procedures for the deliberate release into the environment of GMOs and their related rules described in its Articles 6 to 11 do not apply for medicinal substances and compounds for human use if authorised by Union legal acts that fulfil the criteria listed in that Article.
(151)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 containing or consisting of GMOs in Directive 2009/41/EC.
(152)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 containing or consisting of GMOs fulfilling the requirements of Article 5 of Directive 2001/18/EC and taking into account the specific characteristics of medicinal substances and compounds.
(153)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 59 . 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 60 remains in force and continues to apply unless and until repealed. For the same reason, it should be clarified that Regulations (EC) No 2049/2005 61 , No 507/2006 62 , No 658/2007 and (EC) No 1234/2008 63 remain in force and continue to apply unless and until repealed.
(154)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, taking as a base 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 these products. Both objectives are being pursued simultaneously. These 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.
(155)This Regulation respects the fundamental rights and observes the principles recognised in particular by the Charter of Fundamental Rights of the European Union and notably 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.
(156)The objective of this Regulation is to ensure the authorisation of high quality medicinal products, including for paediatric patients and patients suffering from rare diseases throughout the Union. Where this objective cannot be sufficiently achieved by the Member States but can rather, by reason of its scale, 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.