Changes from report parliamentary committee draft to plenary report

AddedRecital 95: (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with the possibility of extension by the Agency under certain specified conditions; the orphan designation may be withdrawn at the request of the orphan medicine sponsor, who should be able to provide a reasoned justification for the withdrawal request. The Agency should make the reasoned justification for the withdrawal request, when provided by the sponsor, publicly available.

AddedRecital 103: deleted

AddedRecital 104: (104) To maximise the potential benefit of clinical research, continued exploration of new indications should be encouraged. To reward research into and development of new therapeutic indications, an additional period of one year of market exclusivity is provided for a new therapeutic indication (with a maximum of two indications).

AddedRecital 105 a (new): (105a) The Agency should refuse the validation of an application for a marketing authorisation referring to data for a reference medicinal product only on the basis of the grounds set out in this Regulation and [revised Directive 2001/83/EC]. The same should apply to any decision to grant, vary, suspend, restrict or revoke the marketing authorisation. The Agency cannot base its decision on any other grounds. In particular, those decisions cannot be based on the patent or supplementary protection certificate status of the reference medicinal product.

AddedRecital 105 b (new): (105b) One of the overarching goals of this Regulation is to help to meet the medical needs of patients with rare diseases, to improve the affordability of orphan medicinal products and patient access to orphan medicinal products across the Union, and to encourage innovation in areas of need. While other Union programmes and policies also contribute to those goals, people living with a rare disease continue to face common challenges that are numerous and multifactorial, including delayed diagnoses, lack of available transformative treatments, and difficulties to access treatments where they live, reflecting the fragmentation of the market across the Member States. The Union added value in addressing the needs of people living with a rare disease being exceptionally high due to the rarity of patients, experts, data, and resources, it is appropriate for the Commission to complement this Regulation by developing a dedicated framework for rare diseases to bridge relevant legislation, policies and programmes, and support national strategies with a view to better meeting the unmet needs of people living with rare diseases and of their carers. That framework should be needs-driven and goals-based, and developed in consultation with the Member States and patient organisations as well as, where relevant, other interested parties.

AddedRecital 112: (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, based on scientific, ethical and technical grounds or considerations related to public health, the initiation or completion of some or all of the measures contained in a paediatric investigation plan for a limited period of time. Such deferral should be extended only in duly justified cases.

AddedRecital 126: (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, and the collection of real-world data within the framework of Union pharmacovigilance activities, so as to ensure the rapid withdrawal from the market of any medicinal product presenting a negative benefit-risk balance under normal conditions of use.

AddedRecital 129: (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 and real-world data, across the life cycle of a medicinal product. This Regulation recognises the Agency’s experience and capacity to access and analyse data submitted independently from the 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. In such cases, the Agency should consult with the marketing authorisation applicant or marketing authorisation holder, before undertaking any such update.

AddedRecital 132 a (new): (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.

AddedRecital 132 b (new): (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.

AddedRecital 132 c (new): (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.

AddedRecital 133: (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 wit…

AddedRecital 134: (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.

AddedRecital 135: (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.

AddedRecital 135 a (new): (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.

AddedRecital 135 b (new): (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.

AddedRecital 136: (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.

AddedRecital 137: (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.

AddedRecital 138: (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 medic…

AddedRecital 138 a (new): (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.

AddedRecital 138 b (new): (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.

AddedRecital 139 a (new): (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.

AddedRecital 140: (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 Council57. 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.

AddedRecital 149: (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.

AddedRecital 155: (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. Similarly, this Regulation aims to ensure a high level of protection of the environment in accordance with Article 192(1) TFEU.

AddedArticle 1 – paragraph 1: This Regulation lays down Union procedures for the authorisation, supervision and pharmacovigilance of medicinal products for human use at Union level, establishes rules and procedures at Union and at Member State level relating to the monitoring and management of shortages and critical shortages and the security of supply of medicinal products and lays down the governance provisions of the European Medicines Agency (‘the Agency’) established by Regulation (EC) No 726/2004 which shall carry out the tasks relating to medicinal products for human use that are laid down in this Regulation, Regulation (EU) No 2019/6 and other relevant Union legal acts.

AddedArticle 2 – paragraph 2 – point 7: (7) ‘significant benefit’ means a clinically relevant advantage or a major contribution to patient care of an orphan medicinal product if such an advantage or contribution benefits a relevant part of the target population;

AddedArticle 2 – paragraph 2 – point 8 – point a: (a) greater efficacy than an authorised medicinal orphan medicinal product in a relevant part of the target population;

AddedArticle 2 – paragraph 2 – point 8 – point b: (b) greater safety than an authorised medicinal product in a relevant part of the target population;

AddedArticle 2 – paragraph 2 – point 10: (10) ‘regulatory sandbox’ means a regulatory framework during which it is possible to develop, validate and test in a controlled environment innovative or adapted regulatory solutions that facilitate the development and authorisation of innovative products which are likely to fall in the scope of this Regulation but for which there is an absence of existing adapted rules for development and authorisation, pursuant to a specific plan and for a limited time under regulatory supervision.

AddedArticle 2 – paragraph 2 – point 12: (12) ‘shortage’ means a situation in which the supply of a medicinal product that is authorised and placed on the market in a Member State does not meet the demand for that medicinal product in that Member State whatever the cause.

AddedArticle 2 – paragraph 2 – point 14 a (new): (14a) ‘demand’ means the request for a medicinal product by healthcare professionals or patients in response to a clinical need; the demand is satisfactorily met when the medicinal product is acquired in appropriate time and in sufficient quantity to allow continuity of provision of the best care to patients;

AddedArticle 2 – paragraph 2 – point 14 b (new): (14b) ‘supply’ means the total volume of stock of a given medicinal product that is placed on the market by a marketing authorisation holder or a manufacturer;

AddedArticle 5 – paragraph 5: 5. Within 20 days of receipt of an application, the Agency shall check whether all the information and documentation required in accordance with Article 6 have been submitted, that the application does not contain critical deficiencies as defined in the guidelines drawn up pursuant to paragraph 7 of this Article that may prevent the evaluation of the medicinal product and decide whether the application is valid.

AddedArticle 6 – paragraph 1 – subparagraph 2: The documentation shall include a declaration to the effect that clinical trials carried out outside the Union meet the ethical requirements of Regulation (EU) No 536/2014. Those particulars and documentation shall take account of the unique, Union nature of the authorisation requested and, otherwise than in exceptional cases relating to the application of the law on trademarks pursuant to Regulation (EU) 2017/1001 of the European Parliament and of the Council66 , shall include the use of a single name for the medicinal product. The use of a single name does not exclude: / (a) the use of additional qualifiers where necessary to identify different presentations of the medicinal product concerned; and / (b) the use of identified versions of the summary of product characteristics as referred to in Article 62 of [revised Directive 2001/83] in situations where elements of the product information are still covered by patent law or supplementary protection certificates for medicinal products.

AddedArticle 6 – paragraph 2 – subparagraph 1: For medicinal products that are likely to offer an exceptional therapeutic advancement in the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition or that are expected to be of major interest from the point of view of public health or intended for conditions with no authorised alternatives in the Union, the Agency may, following the advice of the Committee for Medicinal Products for Human Use regarding the maturity of the data related to the development, offer to the applicant a phased review of complete data packages for individual modules of particulars and documentation as referred to in paragraph 1.

AddedArticle 6 – paragraph 5 – subparagraph 2: The marketing authorisation applicant shall not carry out animal tests in case scientifically satisfactory non-animal testing methods are available. The Agency shall in its annual report highlight key observations and best practices in the replacement, reduction and refinement of animal testing submitted by applicants.

AddedArticle 7 – paragraph 1: 1. Without prejudice to Article 22 of [revised Directive 2001/83/EC], the marketing authorisation application of a medicinal product for human use containing or consisting of genetically modified organisms as defined in Article 2(2) of Directive 2001/18/EC shall be accompanied by an environmental risk assessment identifying and evaluating potential adverse effects of the genetically modified organisms on human and animal health, and the environment.

AddedArticle 8 – paragraph 1 – point b: (b) identification and characterisation of hazards for the environment, animals and for human health throughout the lifecycle of the medicinal product, including manufacturing; for the purpose of this point, ‘hazards for human health’ include the risks to the health of human beings other than the treated patient as the risk to the treated patient shall be assessed as part of the benefit-risk assessment of the medicinal product;

AddedArticle 8 – paragraph 1 – point e: (e) risk minimisation and mitigation strategies proposed to address identified risks including specific containment measures to limit contact with the medicinal product.

AddedArticle 9 – paragraph 1 – subparagraph 2: The Committee for Medicinal Products for Human Use shall assess the environmental risk assessment, and where necessary consult the ad-hoc Environmental Risk Assessment working party referred to in Article 150.

AddedArticle 9 – paragraph 2: 2. In case of first-in-class medicinal products or when a novel question is raised during the assessment of the submitted environmental risk assessment, the Committee for Medicinal Products for Human Use, or the rapporteur, shall carry out necessary consultations with bodies Member States have set up in accordance with Directive 2001/18/EC. They shall also consult with relevant Union bodies. Details on the consultation procedure shall be published by the Agency at the latest by [OJ:12 months after the date of entry into force of this Regulation].

AddedArticle 10 – paragraph 2: 2. Where within 90 days of the validation of the marketing authorisation application and during the assessment the Committee for Medicinal Products for Human Use considers that the submitted data are not of sufficient quality or maturity to complete the assessment, the assessment can be terminated. The Committee for Medicinal Products for Human Use shall summarise the deficiencies in writing. On this basis, the Agency shall inform the applicant accordingly and set a reasonable time limit to address the deficiencies. The application shall be suspended until the applicant addresses the deficiencies. If the applicant fails to address those deficiencies within the time limit set by the Agency, the application shall be considered as withdrawn by default.

Article 12 – paragraph 4 – point g: (g) where appropriate, details of any recommended obligation to conduct post-authorisation efficacy studies where concerns relating to some aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed. Such an obligation to conduct such studies shall be based on the delegated acts adopted pursuant to Article 21 while taking into account the scientific guidance referred to in Article 123 of [revised Directive 2001/83/EC] and the consultation process in accordance with Article 162 of this Regulation;

Change 4

ChangedArticle 12 – paragraph 4 – point h: (h) where appropriate, details of any recommended obligation to conduct any other post-authorisation studiesstudies, including post-authorisation treatment optimisation studies, to improve the safe and effective use of the medicinal product as well as possible penalties in case of non-compliance;product;

Change 5

ChangedArticle 12 – paragraph 4 – point i: (i) in case of medicinal products for which there is a detailed justification submitted to the Agency as to the grounds of uncertainty as to the surrogate endpoint relation to the expected health outcome, where appropriate and relevant for the benefit-risk balance, with specific attention given to new active substances and therapeutic indications, a post-authorisation obligation to substantiate the clinical benefit as well as possible penalties in case of non-compliance;benefit:

Change 6

RemovedArticle 12 – paragraph 4 – point j: (j) where appropriate, details of any recommended obligation to conduct additional post-authorisation environmental risk assessment studies, collection of monitoring data or information on use, where concerns about risks to the environment or public health, including antimicrobial resistance need to be further investigated after the medicinal product has been marketed, as well as possible penalties in case of non-compliance;

AddedArticle 12 – paragraph 4 – point j a (new): (ja) where appropriate, any justified reasoning for granting marketing authorisation pursuant to Article 18, 19 and 30 of this Regulation;

Change 7

ChangedArticle 12 – paragraph 4 – point m a (new): (ma) a stewardship and access plan in accordance with Article 1717(1), point (a), of [revised Directive 2001/83/EC] and special information requirements in accordance with Article 69 of that Directive for any antimicrobials, as well as any other obligations imposed on the marketing authorisation holder;

Change 8

ChangedArticle 12 – paragraph 4 – point m b (new): (mb) where applicable, a confirmationreasoning as to whether the medicinal product satisfies the criteria of Article 83 of [revised Directive 2001/83/EC] regarding medicinal products addressing an unmet medical need;need.

Change 9

ChangedArticle 13 – paragraph 1 – subparagraph 5: Where the draft decision differs from the opinion of the Agency, the Commission shall provide a detailed explanation of the reasons for the differences and make that information publicly available at the same time as the decision.available.

Article 13 – paragraph 1 – subparagraph 6: The Commission shall send the draft decision and the accompanying reasoning referred to in the fifth subparagraph to the Member States and the applicant.

Article 13 – paragraph 4: 4. The Agency shall disseminate the documents referred to in Article 12(4), points (a) to (e), and, where relevant, the documents referred to in Article 12(4), points (f) to (mb), together with any deadlines laid down pursuant to paragraph 1, first subparagraph.

Article 15 – paragraph 1 – point d: (d) the environmental risk assessment is incomplete or insufficiently substantiated by the applicant or if the risks identified in the environmental risk assessment have not been sufficiently addressed by the risk mitigation measures proposed by the applicant in accordance with Article 22(3) of [revised Directive 2001/83/EC];

Change 10

ChangedArticle 16 – paragraph 3 – subparagraph 1: The Agency shall immediately publish the assessment report on the medicinal product for human use and the reasons for its opinion in favour of granting marketing authorisation, after deletion of any information of a commercially confidential nature and following a consultationnotification ofto relevant patient organisations with regard to theorganisations. readability,The clarityAgency andshall comprehensibilityensure ofthat European public assessment report summaries.summaries are readable, clear and comprehensible.

Article 16 – paragraph 3 – subparagraph 2 – indent 2: – the complete environmental risk assessment submitted to the Agency by the marketing authorisation applicant as well as a summary of environmental risk assessment studies and their results as submitted by the marketing authorisation holder and the assessment of the environmental risk assessment and the information referred to in Article 22(5) of [revised Directive 2001/83/EC] by the Agency.

Article 16 – paragraph 3 – subparagraph 2 – indent 2 a (new): – for antimicrobials, all information referred to in Article 17 of and Annex I to [revised Directive 2001/83/EC] as well as any other obligations imposed on the marketing authorisation holder.

Change 11

RemovedArticle 17 – paragraph 1: 1. A marketing authorisation for a medicinal product shall be valid for five years.

AddedArticle 18 – paragraph 1 – introductory part: 1. In exceptional circumstances where, in an application under Article 6 of [revised Directive 2001/83/EC] for a marketing authorisation of a medicinal product or a new therapeutic indication, of an existing marketing authorisation under this Regulation, an applicant is unable to provide comprehensive data on the efficacy and safety of, and, where missing, on the environmental risk posed by, the medicinal product under normal conditions of use, the Commission may, by derogation to Article 6, grant an authorisation under Article 13, subject to specific conditions, where the following requirements are met:

RemovedArticle 17 – paragraph 2 – subparagraph 1: deleted