Changes from plenary report to adopted text

Added(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). [Am. 65]

RemovedArticle 29 – paragraph 1 a (new): The applicable periods of regulatory protection shall be published and updated where appropriate by the Commission in the Union Register of medicinal products.

Added(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.

RemovedArticle 32 – paragraph 1: 1. The Agency shall ensure that the scientific opinion of the Committee for Medicinal Products for Human Use is given without undue delay, taking into account, the recommendation of the Emergency Task Force referred to in Article 38(1), second subparagraph. For the purpose of issuing its opinion, the Agency may consider any relevant data on the medicinal product concerned in addition to the evidence submitted in the applicant’s dossier.

Added(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. [Am. 66]

RemovedArticle 32 – paragraph 2 – subparagraph 1: The Agency shall without undue delay review any new evidence provided by the developer, the Member States or the Commission, or any other additional evidence that comes to its attention, taking into account the evidence submitted by the developer, in particular evidence that might influence the benefit-risk balance of the medicinal product concerned.

Added(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. [Am. 67]

RemovedArticle 32 – paragraph 3: 3. The Agency shall transmit without undue delay to the Commission the scientific opinion and its updates and any recommendations on the temporary emergency marketing authorisation. The scientific opinion and information on the application for the use of the temporary emergency marketing authorisation shall be made publicly available by the Agency.

Added(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.

RemovedArticle 33 – paragraph 2: 2. On the basis of the scientific opinion of the Agency referred to in paragraph 1, the Commission shall set specific conditions with respect to the temporary emergency marketing authorisation, in particular the conditions for manufacturing, use, supply and safety monitoring and the compliance with related good manufacturing, and pharmacovigilance practices. If necessary, the conditions may specify the batches of the medicinal product concerned by the temporary emergency marketing authorisation, after consultation with the applicant or marketing authorisation holder.

Added(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.

RemovedArticle 36 – paragraph 1: The marketing authorisation holder of an authorisation in accordance with Article 33 may submit an application in accordance with Articles 5 and 6 in order to obtain an authorisation in accordance with Articles 13, 16 or 19 based on the pre-agreed deadlines established with the Agency.

Added(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.

RemovedArticle 37 – paragraph 1: When the temporary marketing authorisation of a medicinal product is suspended or revoked for reasons other than the safety of the medicinal product, or if that temporary emergency marketing authorisation ceases to be valid, Member States may, in exceptional circumstances, allow for a transitional period, the supply of the medicinal product to patients who are already being treated with it. In such cases, the Member State shall inform the Agency about the application of the transitional period. Conditions for manufacturing, use, supply and safety monitoring and the compliance with the related good manufacturing and pharmacovigilance practices shall continue to apply during that period.

Added(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.

RemovedArticle 39 a (new): Article 39a / Milestone payment reward scheme / 1. An antimicrobial shall be considered a ‘priority antimicrobial’ if preclinical and clinical data underpin a significant clinical benefit with regard to antimicrobial resistance and it has at least one of the following characteristics: / (a) it represents a new class of antimicrobials; / (b) its mechanism of action is distinctly different from that of any authorised antimicrobial in the Union; / (c) it contains an active substance not previously authorised in a medicinal product in the Union that addresses a multi-drug resistant organism and serious or life-threatening infection. / In the scientific assessment of the criteria referred to in the first subparagraph, and in the case of antibiotics, the Agency shall take into account the ‘WHO priority pathogens list for R&D of new antibiotics’, or an equivalent list established at Union level. / 2. The Commission, in consultation with the Agency, shall award milestone payments and support to potential priority antimicrobials addressing the priority pathogens referred to in paragraph 1 of this Article. The milestone payments shall be financed through resource matching by the Commission, including within the framework of Article 12(2), point (b)(i), of Regulation (EU) 2021/695 of the European Parliament and of the Council1a and Regulation (EU) 2021/522 of the European Parliament and of the Council 1b. / The Commission shall adopt delegated acts in accordance with Article 175 to supp…

Added(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.

RemovedArticle 39 b (new): Article 39b / Subscription model for the joint procurement of antimicrobials / 1. The Commission and any of the Member States may engage, as contracting parties, in a joint procurement procedure conducted pursuant to Article 165(2) of Regulation (EU, Euratom) 2018/1046 of the European Parliament and of the Council1a with a view to the advance purchase of antimicrobials. / 2. A joint procurement procedure as referred to in paragraph 1 shall be preceded by a joint procurement agreement between the parties determining the practical arrangements governing the subscription model system and other procedures, including the length of the subscription contract and the possibility of parallel procurement. / 3. The joint procurement agreement shall take the form of a multi-year subscription and include the following conditions: / (a) delinkage or partial delinkage of funding from the volume of sales of the antimicrobial; / (b) commitment to continuous and sufficient supply in pre-agreed quantities; / (c) commitment to the antimicrobial stewardship and access plans as referred to in Article 17(1), point (a), of [revised Directive 2001/83/EC] ; / (d) commitment to the environmental risk assessment as referred to in Article 22 of [revised Directive 2001/83/EC]; / (e) submission of a global access plan to supply third countries in critical need, including through development partners or voluntarily licensing. / 4. Participation in the joint procurement procedure shall be open to all Member …

Added(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.

RemovedArticle 40 – paragraph 1: 1. Following a request by the applicant for a marketing authorisation, made before the marketing authorisation is granted, the Commission may, by means of implementing acts, grant a transferable data exclusivity voucher to a ‘priority antimicrobial’ referred to in Article 39a(1), under the conditions referred to in paragraph 4 of this Article based on a scientific assessment by the Agency.

Added(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. [Am. 68]

RemovedArticle 40 – paragraph 2: 2. The voucher referred to in paragraph 1 shall give the right to its holder to a maximum of additional 12 months of data protection for one authorised medicinal product.

Added(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.

RemovedArticle 40 – paragraph 2 a (new): 2a. The Commission shall adopt delegated acts in in accordance with Article 175 to supplement this Regulation by setting up the eligibility of pathogens for the protection periods referred to in paragraph 2 of this Article in accordance with the WHO priority pathogens list or an equivalent established at Union level, with 12 months of data protection for an authorised product ranked ‘critical’, 9 months of data protection for those ranked ‘high’ and 6 months of data protection for those ranked ‘medium’.

Added(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.

RemovedArticle 40 – paragraph 3: deleted / (deleted) / (deleted) / (deleted) / (deleted)

Added(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.

RemovedArticle 40 – paragraph 4 – subparagraph 1 – point a: (a) demonstrate capacity and ensure the supply of the priority antimicrobial in sufficient quantities for the expected needs of the Union market, as defined in a contract with the Authority;

Added(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.

RemovedArticle 40 – paragraph 4 – subparagraph 1 – point b: (b) provide information on all direct financial support and indirect financial support in accordance with Article 57 of [revised Directive 2001/83/EC] received for research related to the development of the priority antimicrobial;

Added(117) Free scientific advice should be provided by the Agency as an incentive to sponsors developing medicinal products for the paediatric population.

RemovedArticle 40 – paragraph 4 – subparagraph 1 – point b a (new): (ba) submit the stewardship and access plan as referred to Article 17(1), point (a), of and Annex I to [revised Directive 2001/83/EC],

Added(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.

RemovedArticle 40 – paragraph 4 – subparagraph 1 – point b b (new): (bb) submit of a global access plan to supply third countries in critical need, including through development partners or voluntary licensing.

Added(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.

RemovedArticle 40 – paragraph 4 a (new): 4a. The priority antimicrobial shall be added to the list of antimicrobials which are to be reserved for treatment of certain infections in humans and added to the Union list as established by Commission Implementing Regulation (EU) 2022/12551a. / 1a Commission Implementing Regulation (EU) 2022/1255 of 19 July 2022 designating antimicrobials or groups of antimicrobials reserved for treatment of certain infections in humans, in accordance with Regulation (EU) 2019/6 of the European Parliament and of the Council (OJ L 191, 20.7.2022, p. 58).

Added(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.

RemovedArticle 41 – paragraph 1 – subparagraph 1: A voucher may be used to extend the data protection for a period of 6, 9 or 12 months of the priority antimicrobial or another medicinal product authorised in accordance with this Regulation of the same or different marketing authorisation holder.

Added(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.

RemovedArticle 41 – paragraph 1 – subparagraph 2: A voucher shall only be used once and in relation to a single centrally authorised medicinal product and only if that product is within its first four years of regulatory data protection. The voucher shall not be used for a product which already benefited from the maximum regulatory data protection period as set out in Article 81 of [revised Directive 2001/83/EC].

Added(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.

RemovedArticle 41 – paragraph 3: 3. A voucher may be transferred to another marketing authorisation holder once and shall not be transferred further.

Added(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.

RemovedArticle 41 – paragraph 3 a (new): 3a. The monetary value paid for the transfer of the voucher shall be directed to the Authority, which shall in yearly instalments transfer the amount to the marketing authorisation holder, in order to ensure the manufacturing capacity and supply of the priority antimicrobial. The Commission shall adopt delegated acts in accordance with Article 175 to supplement this Regulation by setting up the framework for the conditions and functioning of annual instalments.

Added(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.

RemovedArticle 42 – paragraph 1 – point b: (b) where it is not used within four years after the conditions set out in Article 41 have been fulfilled by the seller.

Added(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.

RemovedArticle 42 – paragraph 2: 2. The Commission may revoke the voucher as referred to in Article 41(3) if a request for supply, procurement or purchase of the priority antimicrobial in the Union has not been fulfilled. To protect the buyer from damage resulting from a possible revocation of a voucher after the transfer, seller and buyer shall make contractual liability arrangements.

Added(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. [Am. 69]

RemovedArticle 43 – paragraph 1: This Chapter shall apply immediately from ... [the date of entry into force of this Regulation] and for 15 years or until the date when the Commission has granted a total of 10 vouchers in accordance with this Chapter, whichever date is the earliest.

Added(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.

RemovedArticle 43 – paragraph 1 a (new): By ... [five years from the date of entry into force of this Regulation], the Commission shall submit an evaluation report to the European Parliament and to the Council containing a scientific assessment measuring the progress with regard to antimicrobial research and development and the effectiveness of the incentives and rewards in this Chapter.

Added(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.

RemovedArticle 45 – paragraph 4 – subparagraph 1: The Agency may at any time request the marketing authorisation holder to submit data demonstrating that the benefit-risk balance remains favourable. The marketing authorisation holder shall answer fully and within the time limit set for any such request. The marketing authorisation holder shall also respond fully and within the time limit set any such request of a competent authority regarding the implementation of any measures previously imposed, including risk minimisation measures.

Added(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. [Am. 70]

RemovedArticle 47 – paragraph 1: 1. An application for variation of a centralised marketing authorisation by the marketing authorisation holder shall be made electronically in the formats made available by the Agency, unless the variation is an update by the marketing authorisation holder of their information held in a database. The electronic format shall include a baseline sequence in relations to the Common Technical Document (CTD).

Added(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.

RemovedArticle 48 – paragraph 1 – subparagraph 1: An entity not engaged in an economic activity (‘not-for-profit entity’) may submit to the Agency or to a competent authority of the Member State substantive non-clinical or clinical evidence for a new therapeutic indication.

Added(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].

RemovedArticle 48 – paragraph 1 – subparagraph 2: The Agency may, at the request of a Member State, the Commission, or on its own initiative and on the basis of all available evidence, including any additional evidence that may be submitted by the marketing authorisation holders for the medicinal products concerned, make a scientific evaluation of the benefit-risk of the use of a medicinal product with a new therapeutic indication.