Changes from plenary report to adopted text

Added(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.

RemovedArticle 48 – paragraph 1 – subparagraph 3: The opinion of the Agency shall be made publicly available and the competent authorities of the Member States and the marketing authorisation holder shall be informed.

Added(132a) To better facilitate patient’ access to innovative medicinal products, it is appropriate to establish common rules for the testing and authorisation of innovative medicinal products and innovative technologies related to such products for which, due to their exceptional nature or characteristics, the Union regulatory framework for medicinal products is not expected to be adapted. [Am. 71]

RemovedArticle 48 – paragraph 3: deleted

Added(132b) On duly justified grounds, regulatory sandboxes should be able to be set up when it is not possible to develop the medicinal product or category of medicinal products in compliance with the requirements applicable to medicinal products due to scientific or regulatory challenges arising from characteristics or methods related to the medicinal product, and those characteristics or methods positively and distinctively contribute to the quality, safety or efficacy of the medicinal product or category of medicinal products, or significantly improve patient access to treatment. [Am. 72]

RemovedArticle 52 – paragraph 2 – subparagraph 1 – point a: (a) to lend its assistance by participating in a joint inspection with the supervisory authority of the site to assess compliance with good manufacturing practice (GMP) as well as any practices relating to environmental and worker safety. In that case the supervisory authority leads the inspection and the follow up thereof. After completion of the inspection, the supervisory authority grants the relevant GMP certificate and enters the certificate in the Union database; or

Added(132c) The objectives of providing for the possibility of establishing regulatory sandboxes under this Regulation are the following: for the Agency and national competent authorities to increase their understanding of technical and scientific developments, to allow developers in a controlled environment to test and develop innovative medicinal products and related technologies for which the current regulatory framework is not adapted, as agreed with the competent authorities, and to identify possible future adaptations of the legal framework for the authorisation of medicinal products in the Union. [Am. 73]

RemovedArticle 53 – paragraph 2: 2. In cooperation with the Agency, the Commission shall adopt detailed guidelines laying down the principles applicable to those international inspection programmes. The guidelines shall include rules on impartially, independence and conflict of interest of inspectors.

Added(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. SMEs and startups should also have the possibility of utilising regulatory sandboxes whereby they can, as relevant, contribute with their knowhow and experience. Regulatory sandboxes can provide controlled frameworks which, by providing 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. They allow the authorities tasked with implementing and enforcing the legislation to exercise on a case-by-case basis a degree of flexibility in relation to testing innovative medicinal products, for the benefit of bringing such products to patients without compromising the standards of quality, safety and efficacy. The regulatory sandbox should in principle allow the Agency to assess if an adapted framework for the medicinal product in question is appropriate and should be developed. Given that the regulatory sandbox should not continue indefinitely, upon its completion the medicinal product in question should, if appropriate, be regulated through an adapted framework. 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. [Am. 74]

RemovedArticle 56 – paragraph 2 a (new): Where the marketing authorisation holder fails to comply with the obligations in the post-authorisation studies laid down in accordance with Article 20, the Commission may adopt a decision to vary, suspend, or revoke that marketing authorisation in accordance with the procedure laid down in Article 13.

Added(134) In the area of medicinal products, a high level of protection of inter alia citizens, consumers, health, the environment, 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. Whenever possible, priority should be given to the use of non-animal approaches. [Am. 75]

RemovedArticle 58 – paragraph 3: 3. In the preparation of the scientific advice referred to in paragraph 1 of this Article the Agency may consult authorities established in other Union legal acts as relevant for the provision of the scientific advice in question, other public bodies established in the Union, in particular those listed in Article 162 or other bodies, as applicable, or in duly justified cases public bodies established in third countries.

Added(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 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 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. [Am. 76]

RemovedArticle 58 – paragraph 4: 4. The Agency shall include in the European public assessment report the key areas of the scientific advice as well as a detailed log of the pre-submission activities of the medicinal product, including the names of the experts involved, once the corresponding marketing authorisation decision has been taken in relation to the medicinal product, after deletion of any information of a commercially confidential nature. That report shall be made publicly available.

Added(135a) The Union market for medicinal products remains fragmented, despite the Union having a single market and being the second largest market for pharmaceuticals in the world. The organisation of healthcare systems is a national competence of Member States and that allows for decisions to be made closer to the patient, but also brings divergences in both pricing and patient access. Better and closer coordination between national authorities opens the door to a more efficient and effective supply of medicinal products throughout the Union. [Am. 77]

RemovedArticle 58 – paragraph 4 a (new): 4a. The Agency shall, to the greatest extent possible, ensure that there is a separation between those responsible for providing scientific advice to a given medicinal product developer and those subsequently responsible for the evaluation of the marketing authorisation application for the same medicinal product. / The Agency shall ensure that at least one of the two rapporteurs for a marketing authorisation application has not taken part in any pre-submission activities concerning the medicinal product. The reasons for any exceptions shall be documented and published with the European public assessment report and recorded in the summary minutes of the meetings in accordance with Article 147(2).

Added(135b) More often than in the past, Member States experience critical shortages of certain antimicrobials, endangering the health of patients and risking the development of antimicrobial resistance. Those critical shortages are the result of changing infection patterns, which strongly increases demand. On the supply side, the long lead times needed to boost production makes it difficult to respond quickly. This experience underlines the need for a dedicated effort from all actors to address the issue of critical shortages. [Am. 78]

RemovedArticle 60 – paragraph 1 – introductory part: 1. The Agency may offer enhanced scientific and regulatory support, including as applicable consultation with other bodies as referred to in Articles 58 and 59 and accelerated assessment mechanisms, for certain medicinal products that, based on preliminary evidence submitted by the developer fulfil at least one of the following conditions:

Added(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, including longer delays or interruptions in care or therapy, longer periods of hospitalisation, increased risks of exposure to falsified medicinal products, medication errors, adverse effects resulting from the substitution of unavailable medicinal products with alternative ones, significant psychological distress for patients and increased costs for healthcare systems. Member States should collect data on the impact of shortages of medicinal products on patients and consumers, and share relevant information through the MSSG, in order to inform approaches to management of shortages of medicinal products. 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. [Am. 79]

RemovedArticle 60 – paragraph 1 – point c: (c) are expected to be of major interest from the point of view of public health, in particular as regards therapeutic innovation, taking into account the early stage of development, or antimicrobials with any of the characteristics mentioned in Article 40(3) or 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 taking into account as a priority any equivalent list of priority pathogens adopted at Union level.

Added(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, while allowing Member States to adopt or maintain legislation ensuring a higher degree of protection against shortages of medicinal products. 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. To combat certain shortages, medicinal products prepared for individual patients in a pharmacy according to a medical prescription ‘magistral formula’, or according to the pharmacopoeia and intended to be supplied directly to patients served by the pharmacy ‘officinal formula’, should be able to be used. [Am. 80]

RemovedArticle 60 – paragraph 4 a (new): 4a. Where a priority medicinal product benefits from enhanced scientific and regulatory support from the Agency, the European public assessment report shall include a specific section on the Agency’s pre-submission activities, and information on the key areas of the scientific advice and regulatory support provided and on the follow-up by the requester, including corresponding information and data which show that the conditions for the application of the PRIME scheme have been fulfilled.

Added(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. Information on such shortages should be made available on the European medicines web-portal provided for in this Regulation. When critical shortages are identified, both national competent authorities and the Agency should work in a coordinated manner to communicate the necessary information to patients, consumers and healthcare professionals, including on the estimated duration of the shortage and available alternatives, and 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, importers, manufacturers and suppliers, must provide the relevant information to inform the monitoring. Wholesale distributors and other persons or legal entities, including patient organisations or health care professionals and consumers and other persons or legal entities that are authorised or entitled to supply medicinal products to the public, 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, 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. 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 high quality and safety standards. 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. [Am. 81]

RemovedArticle 61 – paragraph 1 – subparagraph 1: For products under development which may fall within the categories of medicinal products to be authorised by the Union listed in Annex I, a developer or a competent authority of the Member States may submit a duly substantiated request to the Agency for a scientific recommendation with a view to determining on scientific grounds whether the concerned product is potentially a ‘medicinal product’, including an ‘advanced therapy medicinal product’ as defined in Article 2 of Regulation (EC) No 1394/2007 of the European Parliament and of the Council71. The Agency may rely on the relevant expertise of working parties and pools of experts when making its recommendation.

Added(138a) Wholesalers are usually a key supply link between marketing authorisation holders and the users of medicinal products, and in those cases, in order to estimate demand, the quantity requested in wholesale orders should be considered. [Am. 82]

RemovedArticle 61 – paragraph 2 – subparagraph 1: When forming the recommendation referred to in paragraph 1, the Agency shall consult, where appropriate and where there is a doubt as to the regulatory status of a product under development, relevant advisory or regulatory bodies established in other Union legal acts in related fields. In the case of products which are based on substances of human origin, the Agency shall first consult the compendium referred to in Regulation (EU) 2024/... [SoHO Regulation] and where necessary, conduct joint meetings with the Substances of Human Origin (SoHO) Coordination Board as established in that Regulation.

Added(138b) It is necessary to avoid that measures planned or taken in one Member State to prevent or mitigate a shortage at national level when responding to the legitimate needs of its citizens increase the risk of shortages in another Member State. [Am. 83]

RemovedArticle 61 – paragraph 2 – subparagraph 3: The Agency shall publish the recommendations delivered in accordance with paragraph 1, after deletion of all information of a commercially confidential nature.

Added(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.

RemovedArticle 61 – paragraph 2 – subparagraph 3 a (new): For transparency purposes, the respective opinions and conclusions of the Agency and the relevant advisory bodies on the regulatory status of the product shall be made publicly available after the consultations and, where applicable, the joint meetings have taken place.

Added(139a) Public procurement procedures can be an effective tool for tackling shortages of medicinal products. At Member State level, invitations to tender based solely on price and where there is only one bidder increase the risk of shortages of medicinal products and of reducing the number of suppliers on the market. At Union level, joint procurement should be recognised as a tool to tackle critical shortages, in particular during a health crisis, as demonstrated by the COVID-19 pandemic. [Am. 84]

RemovedArticle 62 – paragraph 1 – subparagraph 1: In the case of duly substantiated disagreement with the Agency’s scientific recommendation, in accordance with Article 61(2), a Member State may request the Commission to decide whether the product is a product referred to in Article 61(1).

Added(140) 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 manufacturing and wholesale distribution database, 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. 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 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. [Am. 85]

RemovedArticle 62 – paragraph 2: 2. The Commission may ask the Agency and the relevant advisory or regulatory bodies involved in the delivery of the scientific recommendation for clarifications or refer the recommendation back to the Agency for further consideration where a Member State's substantiated request raises new questions of a scientific or technical nature or on its own initiative.

Added(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.

RemovedArticle 62 – paragraph 3: 3. The decision of the Commission referred to in paragraph 1 shall be adopted by means of implementing acts, in accordance with the examination procedure referred to in Article 173(2), taking into account the scientific recommendation of the Agency and other advisory bodies.

Added(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. 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.

RemovedArticle 63 – paragraph 2: deleted

Added(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.

RemovedArticle 64 – paragraph 2 – subparagraph 1 – point d: (d) justification that the criteria laid down in Article 63(1) are fulfilled and a description of the stage of development, including the expected therapeutic indication.

Added(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.

RemovedArticle 64 – paragraph 4 – subparagraph 1: The Agency shall adopt a decision granting or refusing the orphan designation based on the criteria referred to in Article 63(1) within 90 days of the receipt of a valid application. The application is considered valid if it includes all the particulars and documentation referred to in paragraph 2.

Added(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.

RemovedArticle 65 – paragraph 2 – point c a (new): (ca) reasons for the transfer of the orphan designation.

Added(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.

RemovedArticle 66 – paragraph 5: 5. At any time, an orphan designation may be withdrawn at the request of the orphan medicine sponsor. The orphan medicine sponsor may provide a reasoned justification for the withdrawal request, which shall be made publicly available.

Added(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.

RemovedArticle 67 – paragraph 3 – point f a (new): (fa) where applicable, any request made in accordance with Article 66(2) and any decisions taken in that respect.

Added(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).

RemovedArticle 68 – paragraph 1 – introductory part: 1. The orphan medicine sponsor shall, prior to the submission of an application for marketing authorisation, request advice from the Agency on the following:

Added(149) It is therefore appropriate to envisage a centralised assessment of the ERA involving experts from the national competent authorities and the ad hoc Environmental Risk Assessment working party. [Am. 86]

RemovedArticle 68 – paragraph 1 – point a: (a) the conduct of the various tests and trials necessary to demonstrate the quality, safety, efficacy and environmental impact of the medicinal product, as referred to Article 138(1), second subparagraph, point (p);

Added(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.

RemovedArticle 68 – paragraph 2: 2. Medicinal products designated as orphan medicinal products under the provisions of this Regulation shall be eligible for incentives made available by the Union and by the Member States to support research into, and the development and availability of, orphan medicinal products and in particular aid for research for small- and medium-sized undertakings and entities not engaged in economic activity provided for in framework programmes for research and technological development.

Added(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.

RemovedArticle 69 – paragraph 2 – subparagraph 1: In addition, the applicant shall demonstrate that the medicinal product has been granted an orphan designation and that the criteria set out in Article 63(1) are fulfilled for the therapeutic indication sought.

Added(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.

RemovedArticle 69 – paragraph 3 – subparagraph 1: The Committee for Medicinal Products for Human Use shall assess whether the medicinal product fulfils the requirements set out in Article 63(1). In the situation referred in paragraph 2, subparagraph 2, that Committee shall also assess whether the medicinal product addresses a high unmet medical need as specified in Article 70(1).

Added(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. 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 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, No 507/2006, No 658/2007 and (EC) No 1234/2008 remain in force and continue to apply unless and until repealed.

RemovedArticle 69 – paragraph 4: 4. The orphan marketing authorisation shall cover only those therapeutic indications, which fulfil the requirements set out in Article 63(1) at the time when the orphan marketing authorisation is granted.