What changed between the plenary report and the adopted text

Added:(79) As a general rule, risk management plans for generic and biosimilar medicinal products should not be developed and submitted, considering that the reference medicinal product has such a plan, except in specific cases, where a risk management plan should be provided. Furthermore, as a general rule a marketing authorisation should be granted for an unlimited period; exceptionally, one renewal may be decided only on justified grounds related to the safety of the medicinal product.

Removed:Article 4 – paragraph 2: 2. The Commission is empowered to adopt delegated acts in accordance with Article 215 to amend the definitions in paragraph 1, points (2) to (6), (8), (14), (16) to (28) and (30) in the light of technical and scientific progress and taking into account definitions agreed at Union and international level without extending the scope of the definitions.

Added:(80) In the event of a risk to public health, the marketing authorisation holder or the competent authorities should be able to make urgent safety or efficacy restrictions on their own initiative. In such case, when the referral procedure is launched, any duplication of assessment should be avoided.

Removed:Article 6 – paragraph 2 a (new): 2a. A marketing authorisation may be granted for a medicinal product on the basis of an active substance master file, an additional quality master file or a platform technology master file where such a file exists and is referred to in the application.

Added:(81) To address patients’ needs, an increasing number of innovative medicinal products derive from or are combined with other products that may be manufactured or tested and regulated under more than one Union legal framework. Similarly, the same sites are increasingly overseen by the authorities established under different Union legal frameworks. To ensure safe and efficient production and supervision of such products and to allow an appropriate delivery to patients, it is important to ensure coherence. The coherence and sufficient alignment can only be ensured through appropriate cooperation in the development of the practices and principles applied under the different Union legal frameworks. An appropriate cooperation should therefore be embedded within several provisions of this Directive, such as those regarding classification advice, oversight, or the development of guidelines.

Removed:Article 6 – paragraph 4: 4. The risk management system referred to in Annex I shall be proportionate to the identified risks and the potential risks to human health or the environment of the medicinal product, and the need for post-authorisation safety data.

Added:(82) For products that combine a medicinal product and a medical device the applicability of the two respective regulatory frameworks should be specified and the appropriate interaction between the two applicable regulatory frameworks should be ensured. The same should apply to combinations of medical products and products other than medical devices.

Removed:Article 6 – paragraph 5 – subparagraph 2 a (new): In the absence of a paediatric investigation plan in accordance with the first subparagraph point (a), or where in this regard a comparative study has not been carried out, a justification shall be submitted and where relevant also evidence shall be obtained from post-marketing long-term studies.

Added:(83) To ensure that the competent authorities have all the information needed for their assessment in the case of integral combinations of a medicinal product with a medical device or of combinations of a medicinal product with a product other than a medical device, the marketing authorisation applicant shall submit data establishing the safe and effective use of the integral combination of the medicinal product with the medical device or of the combination of a medicinal product with the other product. The competent authority should assess the benefit-risk balance of the integral combination taking into account the suitability of the use of the medicinal product together with the medical device or the other product.

Removed:Article 6 – paragraph 7 – subparagraph 2: The marketing authorisation applicant shall not carry out animal testing in case scientifically satisfactory non-animal testing methods are available. Where scientifically satisfactory non-animal testing methods are not available, applicants that use animal testing shall ensure that the principle of replacement, reduction and refinement of animal testing for scientific purposes has been applied in compliance with Directive 2010/63/EU with regard to any animal study conducted for the purpose of supporting the application.

Added:(84) To ensure that the competent authorities have all the information needed for their assessment of medicinal products in exclusive use with a medical device (that is to say medicinal products that are presented in a package with a medical device or that are to be used with a medical device referenced in the summary of product characteristics) the marketing authorisation applicant shall submit data establishing the safe and effective use of the medicinal product taking into account its use with the medical device. The competent authority should assess the benefit-risk balance of the medicinal product, also taking into account the use of the medicinal product with the medical device.

Removed:Article 10 – paragraph 1: In cases where the medicinal product does not fall within the definition of a generic medicinal product or has changes in strength, pharmaceutical form, route of administration or therapeutic indications, compared to the reference medicinal product, the results of the appropriate non-clinical tests or clinical studies shall be provided to the competent authorities to the extent necessary to establish a scientific bridge to the data relied upon in the marketing authorisation for the reference medicinal product, and to demonstrate the safety and efficacy profile of the hybrid medicinal product. The Agency shall adopt guidelines on the appropriate tests and clinical studies for marketing authorisation of hybrid medicinal products.

Added:(85) The Directive also clarifies that a medical device that is part of an integral combination has to comply with the general safety and performance requirements set out in Annex I of Regulation (EU) 2017/745 of the European Parliament and of the Council. A medical device in exclusive use with a medical device needs to meet all of the requirements of Regulation (EU) 2017/745. A medicinal product in exclusive use with a medical device that is not ancillary to that of the medical device shall comply with the requirements of this Directive and of the [revised Regulation (EC) No 726/2004] taking into account its use with the medical device, without prejudice to the specific requirements of the Regulation (EU) 2017/745.

Removed:Article 12 – paragraph 1: In cases where a biosimilar medicinal product has changes in strength, pharmaceutical form, route of administration or therapeutic indications, compared to the reference biological medicinal product (‘bio-hybrid’), the results of the appropriate non-clinical tests or clinical studies shall be provided to the competent authorities to the extent necessary to establish a scientific bridge to the data relied upon in the marketing authorisation for the reference biological medicinal product, and to demonstrate the safety or efficacy profile of the biosimilar medicinal product. The Agency shall adopt guidelines on the appropriate tests and clinical studies for marketing authorisation of bio-hybrid medicinal products.

Added:(86) For all these products (integral combinations of a medicinal product and a medical device, medicinal products in exclusive use with medical devices and combinations of a medicinal product with a product other than a medical device) the competent authority should also be able to request the marketing authorisation applicant to transmit any additional information needed and the marketing authorisation applicant should be bound to submit any such information requested. For medicinal product in exclusive use with a medical device that is not ancillary to that of the medical device, the marketing authorisation applicant shall also, upon request from the competent authority, submit any additional information related to the medical device taking into account its use with the medicinal product and that is relevant for the post-authorisation monitoring of the medicinal product, without prejudice to the specific requirements of the [revised Regulation (EC) No 726/2004].

Removed:Article 13 – paragraph 1: In cases where no reference medicinal product is or has been authorised for the active substance of the medicinal product concerned, the applicant shall, by way of derogation from Article 6(2), not be required to provide the results of non-clinical tests or clinical studies if the applicant can demonstrate that the active substances of the medicinal product have been in well-established medicinal use within the Union the same therapeutic use and route of administration and for at least ten years, with recognised efficacy and an acceptable level of safety in terms of the conditions set out in Annex II. In that event, the test and trial results shall be replaced by appropriate bibliographic data in the form of scientific literature. A justification shall be provided with regard to the relevance of that literature for the medicinal product.

Added:(87) For integral combination of a medicinal product with a medical device and for combinations of a medicinal product with a product other than a medical device, the marketing authorisation holder should also bear the overall responsibility for the whole product in terms of compliance of the medicinal product with the requirements of this Directive and the [revised Regulation(EC) No 726/2004] and should ensure coordination of the information flow between the sectors throughout the assessment procedure and the lifecycle of the medicinal product.

Removed:Article 15 – title: Fixed dose combination medicinal product, platform marketing authorisation and multi-medicinal product packages

Added:(88) In order to ensure the quality, safety and efficacy of medicinal product at all stages of manufacturing and distribution the marketing authorisation holder shall be responsible, when necessary to trace back an active substance, excipient or any other substance that used in the manufacturing of medicinal product and intended to be part of the medicinal product or expected to be present in the medicinal product, for example impurities, degradation products or contaminants.

Removed:Article 15 – paragraph 2 – subparagraph 1: Where justified for therapeutic purposes, a marketing authorisation may be granted for a medicinal product comprised of a fixed component and a variable component that is pre-defined in order to, where appropriate, target different variants of an infectious agent or, where necessary, to tailor the medicinal product to characteristics of an individual patient or a group of patients (‘platform marketing authorisation’).

Added:(89) In the interests of public health marketing authorisation holders should be able to ensure the traceability of any substance that is used, intended or expected to be present in a medicinal product at all stages of manufacturing and distribution, and identify any natural or legal person from whom they have been supplied these substances. Therefore, procedures and systems should be placed to provide that information in case it should be necessary with the view of quality, safety or efficacy of medicinal products.

Removed:Article 16 – paragraph 1: 1. A marketing authorisation shall be required for radionuclide generators, kits for radiopharmaceutical preparations (‘kits’), and radionuclide precursors, unless they are used as starting material, active substance or intermediate of radiopharmaceuticals covered by a marketing authorisation under Article 5(1).

Added:(90) It is recognised that the development of pharmaceuticals is an area where neither science, nor technology stand still. The last decades have seen new categories of medicinal products emerging from biological medicinal products to biosimilars or advanced therapy medicinal products or in the future phages therapies. Those categories of products may in some instances require adapted rules to fully take account of their specific characteristics. For that reason a forward looking legal framework should include provisions to enable such adapted frameworks subject to strict criteria and under a Commission empowerment guided by the scientific input of the European Medicines Agency.

Removed:Article 17 – paragraph 1 – point a: (a) an antimicrobial stewardship and access plan as referred to in Annex I;

Added:(91) The adaptations may entail adapted, enhanced, waived or deferred requirements compared to standard medicinal products. They could in particular include changes to the dossier requirements for such medicinal products, the way their quality, safety and efficacy is demonstrated by applicants or tailored manufacturing controls and good manufacturing practices requirements, as well as additional control methods prior and during their administration and use. The adaptions should however not go beyond what is necessary for the attainment of the objective of adaptation to the specific characteristics.

Removed:Article 17 – paragraph 1 a (new): 1a. The competent authority of the Member State shall, following the granting of a marketing authorisation, make publicly available the documents referred to in paragraph 1.

Added:(92) In order to increase the preparedness and responsiveness against health threats, in particular the emergence of antimicrobial resistance, adapted frameworks may be relevant to facilitate the rapid change of antimicrobials composition to maintain their efficacy. The use of established platforms would allow efficient and timely adaptation of those medicinal products to the clinical context.

Removed:Article 17 – paragraph 2: 2. The competent authority shall review the information submitted in accordance with paragraph 1 point (b). The competent authority shall impose obligations on the marketing authorisation holder if it finds the risk mitigation measures contained in the antimicrobial stewardship and access plan unsatisfactory.

Added:(93) To optimise the use of resources for both applicants for marketing authorisation and competent authorities and avoid duplication of assessment of chemical active substances of medicinal products which includes cell and gene therapies, marketing authorisation applicants should be able to rely on an active substance master file certificate or a monograph of the European Pharmacopeia, instead of submitting the relevant data as required in accordance with Annex II. An active substance master file certificate may be granted by the Agency when the relevant data on the active substance concerned is not already covered by a monograph of the European Pharmacopeia or by another active substance master file certificate. The Commission should be empowered to establish the procedure for the single assessment of an active substance master file. To further optimise the use of resources, the Commission should be empowered to allow use of a certification scheme also for additional master files, including quality master files, i.e. for active substances other than chemical active substances, or for other substances present or used in the manufacture of a medicinal product, required in accordance with Annex II, e.g. in case of novel excipients, adjuvants, raw materials, viral vectors and other starting materials, growth media, radiopharmaceutical precursors and active substance intermediates, when the intermediate is a chemical active substance by itself or used in conjugation with a biological substance, as well as for raw materials and starting materials used for manufacturing of cell therapy and gene therapy. [Am. 62]

Removed:Article 17 – paragraph 3: 3. The marketing authorisation holder shall ensure, wherever possible, that the antimicrobial may be dispensed per unit in a number corresponding to the quantities corresponding to the duration of treatment. If an antimicrobial cannot be dispensed per unit, the marketing authorisation holder shall ensure that the pack size of the antimicrobial corresponds to the usual posology and duration of treatment.

Added:(94) For reasons of public health and legal consistency, and with a view to reducing the administrative burden and strengthening predictability for economic operators, variations to all types of marketing authorisations should be subject to harmonised rules.

Removed:Article 18 – paragraph 1 – subparagraph 2: As part of the assessment, in accordance with Article 29, of the integral combination of a medicinal product and a medical device the competent authorities shall assess the benefit-risk balance of the integral combination of a medicinal product and a medical device, taking into account the suitability of the use of the medicinal product together with the medical device, where relevant particularly for paediatric patients, including aspects such as storage, assembly, cleanliness, and the technique required for application or intake.

Added:(95) The terms of a marketing authorisation for a medicinal product may be varied, after it has been granted. While the core elements of a variation are laid down in this Directive, the Commission should be empowered to complement these elements by laying down further necessary elements, to adapt the system to scientific and technological progress, including digitalisation, and to ensure that unnecessary administrative burden is avoided for both the marketing authorisation holders and competent authorities.

Removed:Article 22 – paragraph 1: 1. When preparing the environmental risk assessment (‘ERA’) to be submitted pursuant to Article 6(2), the applicant shall take into account the scientific guidelines on the environmental risk assessment of medicinal products for human use as referred to in paragraph 5, or provide the duly justified reasons for any divergence from the scientific guidelines to the Agency or, as appropriate to the competent authority of the Member State concerned, in a timely manner. Where available, the applicant shall take into account existing ERAs performed under other Union legislation.

Added:(96) Scientific and technological progresses in data analytics and data infrastructure provide valuable support to 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 for regulatory authorities to access evidence, across the lifecycle of a medicinal product. This Directive recognises the competent authorities of the Member States’ capacity to access and analyse data submitted independently from the marketing authorisation applicant or marketing authorisation holder. On this basis, competent authorities of the Member States should take initiative to update the summary of product characteristics in case new efficacy or safety data impacts the benefit-risk balance of a medicinal product.

Removed:Article 22 – paragraph 3: 3. The applicant shall also include in the ERA risk mitigation measures to avoid or where it is not possible, limit emissions to air, water and soil of pollutants listed in Directive 2000/60/EC, Directive 2006/118/EC, Directive 2008/105/EC and Directive 2010/75/EU during the manufacturing, use and disposal of the medicinal product. The applicant shall provide detailed explanation that the proposed mitigation measures are appropriate and sufficient to address the identified risks to the environment. Where necessary, the applicant shall also include information on available techniques and on the techniques that will be used to reduce the discharges and emissions of the medicinal product, in particular those occurring in manufacturing effluents before those effluents leave the manufacturing sites.

Added:(97) Access to individual patient data from clinical studies in structured format allowing for statistical analyses is valuable to assist regulators in understanding the submitted evidence and to inform regulatory decision-making on the benefit-risk balance of a medicinal product. The introduction of such possibility in the legislation is important to further enable data-driven benefit-risk assessments at all stages of the lifecycle of a medicinal product. This Directive therefore empowers competent authorities of Member States to request such data as part of the assessment of initial and post-marketing authorisation applications. Due to the sensitive nature of health data, the competent authorities should safeguard its processing operations and ensure that they respect the data protection principles of lawfulness, fairness and transparency, purpose limitation, data minimisation, accuracy, storage limitation, integrity and confidentiality. Where the processing of personal data is necessary for the purposes of this Directive, such processing should be done in accordance with Union law on the protection of personal data. Any processing of personal data under this Directive should take place in accordance with Regulation (EU) 2016/679 and Regulation (EU) 2018/1725 of the European Parliament and of the Council.

Removed:Article 22 – paragraph 4: 4. The ERA for antimicrobials shall include an evaluation of the risk for antimicrobial resistance selection in the environment due to the entire manufacturing supply chain inside and outside the Union, use and disposal, including by healthcare professionals and patients, of the antimicrobial taking into account, where relevant, the existing international standards that have established predicted no effect concentration (PNECs) specific for antibiotics.

Added:(98) Pharmacovigilance rules are necessary for the protection of public health in order to prevent, detect and assess adverse reactions to medicinal products placed on the Union market, as the full safety profile of medicinal products can only be known after they have been placed on the market.

Removed:Article 22 – paragraph 4 a (new): 4a. By ... [12 months from the date of entry into force of this Directive], the Commission shall, after having consulted the Agency, the EEA, and the ECDC, issue guidelines on how to conduct the ERA for antimicrobials other than antibiotics.

Added:(99) In order to ensure the continued safety of medicinal products in use, it is necessary to ensure that pharmacovigilance systems in the Union are continually adapted to take account of scientific and technical progress.

Removed:Article 22 – paragraph 5: 5. The Agency shall draw up scientific guidelines in accordance with Article 138 of [revised Regulation No (EC) 726/2004], to specify technical details regarding the ERA requirements for medicinal products for human use. Where appropriate, the Agency shall consult the European Chemical Agency (ECHA), the European Food Safety Authority (EFSA), the EEA, the ECDC and other relevant stakeholders, including drinking water and wastewater operators, on the drafting of these scientific guidelines.

Added:(100) It is necessary to take account of changes arising as a result of international harmonisation of definitions, terminology and technological developments in the field of pharmacovigilance.

Removed:Article 22 – paragraph 6 – subparagraph 2: For an ERA conducted prior to [OP please insert the date = 18 months after the date of entering into force of this Directive], the competent authority shall request the marketing authorisation holder to update the ERA to include risk mitigation measures as referred to in paragraph 3. The competent authority shall also request the marketing authorisation holder to update the ERA if missing information has been identified for medicinal products potentially harmful to the environment.

Added:(101) The increasing use of electronic networks for communication of information on adverse reactions to medicinal products marketed in the Union is intended to allow competent authorities to share the information at the same time. In that regard, Member States should seek to inform directly those stakeholders who report adverse reactions in case there exists any update on the safety profile of the medicinal products. [Am. 63]

Removed:Article 22 – paragraph 7: 7. For medicinal products referred to in Articles 9 to 12, the applicant may refer to ERA studies conducted for the reference medicinal product when preparing the ERA and shall provide any other data and the scientific guidelines as referred to in the paragraph 1 of this Article.

Added:(102) It is the interest of the Union to ensure that the pharmacovigilance systems for centrally authorised medicinal products and those authorised by other procedures are consistent.

Removed:Article 22 – paragraph 7 a (new): 7a. The outcome of the assessment of the ERA, including the data submitted by the marketing authorisation holder, shall be made publicly available by the Agency or, as appropriate, by the competent authority of the Member State.

Added:(103) Marketing authorisation holders should be proactively responsible for on-going pharmacovigilance of the medicinal products they place on the market.

Removed:Article 22 – paragraph 7 b (new): 7b. When making public the information on the ERA, including the antimicrobial stewardship and access plan referred to in Article 17, the competent authority shall delete any information of a commercially confidential nature.

Added:(104) The use of colours in human and veterinary medicinal products is currently regulated by Directive 2009/35/EC of the European Parliament and of the Council, and restricted to those authorised in accordance with Regulation (EC) No 1333/2008 of the European Parliament and of the Council on food additives, for which specifications are laid down in Commission Regulation (EU) No 231/2012. Uses of excipients other than colours in medicinal products are subject to the Union rules on medicinal products and are evaluated as part of the overall benefit risk profile of a medicinal product.

Removed:Article 23 – paragraph 1 – subparagraph 1: By [OP please insert the date = 24 months after the date of the entry into force of this Directive] the Agency shall, after consultation with the competent authorities of the Member States, the ECDC, the European Chemical Agency (ECHA), the European Food Safety Authority (EFSA) and the European Environmental Agency (EEA), establish a programme for the ERA to be submitted in accordance with Article 22 of the medicinal products authorised before 30 October 2005 that have not been subject to any ERA and that the Agency has identified as potentially harmful to the environment in accordance with paragraph 2.

Added:(105) Experience has shown the need to maintain to a certain extent the principle of the use in medicinal products of those colours authorised as food additives. However, it is also appropriate to foresee a specific assessment for the use of the colour in medicines when a food additive is removed from Union list of food additives. Therefore, in this specific case, EMA should carry out its own assessment for the use of the colour in medicines, taking into account the EFSA opinion and its underlying scientific evidence, as well as any additional scientific evidence and giving particular consideration to the use in medicines. EMA should also be responsible for following any scientific evidence for the colours retained for specific medicine use only. Directive 2009/35/EC should therefore be repealed.

Removed:Article 23 – paragraph 2: 2. The Agency shall set the scientific criteria for the identification of the medicinal products as potentially harmful to the environment and for the prioritisation of their ERA, using a risk based approach. For this task, the Agency shall consult relevant stakeholders, including actors managing residues from medicinal products and their production in the environment and may request from marketing authorisation holders the submission of relevant data or information.

Added:(106) With regard to the supervision and inspections, manufacturing and import of starting materials or intermediate and also of functional excipient shall be under surveillance due to their ancillary action to the active substance and to their possible impact to the quality, safety and efficacy to the medicinal products.

Removed:Article 23 – paragraph 3: 3. The marketing authorisation holders for medicinal products identified in the programme referred to in paragraph 1 shall submit the ERA to the Agency. The outcome of the assessment of the ERA including the data and a summary of ERA studies and their results as submitted by the marketing authorisation holder shall be made publicly available by the Agency.

Added:(107) The main purpose of any regulation on the manufacture and distribution of medicinal products should be to safeguard public health.

Removed:Article 24 – paragraph 1: 1. The Agency shall, in collaboration with the competent authorities of the Member States, set-up an active substance based review system of ERA data (‘ERA monographs’) for authorised medicinal products and publicise relevant information about that system. An ERA monograph shall include a comprehensive set of physiochemical data, fate data and effect data based on an assessment of a competent authority.

Added:(108) It should be ensured that, in the Member States, the supervision and control of the manufacture and the distribution of medicinal products is carried out by official representatives of the competent authority who fulfils minimum conditions of qualification.

Removed:Article 24 – paragraph 2: 2. The setting-up of the system of ERA monographs shall be based on a risk-based prioritisation of active substances and data requirements.