Changes from report parliamentary committee draft to plenary report

RemovedArticle 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.

AddedArticle 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.

RemovedSee amendments to new Article 26a.

AddedArticle 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.

RemovedArticle 15 – title: Fixed dose combination medicinal product and multi-medicinal product packages

AddedArticle 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.

RemovedSee amendments to new Article 26a.

AddedArticle 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.

RemovedArticle 15 – paragraph 1: 1. Where justified for preventative or therapeutic purposes, a marketing authorisation may be granted for a fixed dose combination medicinal product.

AddedArticle 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.

RemovedArticle 15 – paragraph 2 – subparagraph 1: Where justified for preventative or therapeutic purposes, a marketing authorisation may, in exceptional circumstances, 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.

AddedArticle 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.

RemovedSee amendment to Article 4 – paragraph 1 – point 30 a (new).

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

RemovedArticle 16 – paragraph 1: 1. A marketing authorisation shall be required for radiopharmaceuticals.

AddedArticle 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’).

Change 19

ChangedArticle 16 – paragraph 2:1: 2.1. A marketing authorisation shall not be required for radionuclides or radionuclide generators solely used for radiolabelling purposes,generators, orkits for a radiopharmaceutical prepared at the time of use by an authorised person orpreparations establishment(‘kits’), usingand anradionuclide authorisedprecursors, kitunless forthey radiopharmaceuticalare preparationused inas combinationstarting withmaterial, aactive radionuclidesubstance or radionuclide generator in accordanceintermediate withof theradiopharmaceuticals summarycovered ofby producta characteristicsmarketing ofauthorisation theunder kitArticle ('kit-radiolabelling').5(1).

Change 20

RemovedArticle 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 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.

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

RemovedIncorrect paragraph referenced.

AddedArticle 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.

RemovedArticle 22 – paragraph 2 – introductory part: 2. The ERA shall indicate whether the medicinal product or any of its ingredients or other constituents is classified according to one of the following substances according to the criteria of Annex I to the Regulation (EC) No 1272/2008:

AddedArticle 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.

RemovedArticle 22 – paragraph 2 – subparagraph 1: (d) endocrine disruptors.

AddedArticle 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.

RemovedAlignment with the language of Regulation (EC) No 1272/2008.

AddedArticle 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.

RemovedArticle 22 – paragraph 3: 3. Where the ERA identifies a risk to the environment, 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. The applicant shall provide detailed explanation that the proposed mitigation measures are appropriate and sufficient to address the identified risks to the environment.

AddedArticle 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.

RemovedArticle 22 – paragraph 4 – subparagraph 1 a (new): By way of derogation from the first subparagraph, the obligation to conduct a risk assessment for antimicrobial resistance shall only cover the risk for antibiotic resistance. That derogation shall cease to apply by ... [3 years after the date of entry into force of this Directive].

AddedArticle 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.

RemovedArticle 22 – paragraph 4 a (new): 4a. By ... [18 months after the date of entry into force of this Directive], the Commission shall, after having consulted the Agency, the European Environmental Agency (EEA), and the ECDC, issue guidelines on how to conduct the ERA for antimicrobials other than antibiotics.

AddedArticle 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.

RemovedArticle 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 those managing residues from medicinal products and their production in the environment, on the drafting of these scientific guidelines.

AddedArticle 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.

RemovedArticle 22 – paragraph 6 – subparagraph 1: The marketing authorisation holder shall update the ERA with new information without undue delay to the relevant competent authorities, in accordance with Article 90(2), if new information pertaining to the assessment criteria referred to in Article 29 becomes available and leads to a change of the conclusions of the ERA. The update shall include any relevant information from environmental monitoring, including monitoring under Directive 2000/60/EC, from eco-toxicity studies, from new or updated risk assessments under other Union legislation, as referred to in paragraph 1, and environmental exposure data.

AddedArticle 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.

Change 21

ChangedArticle 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 if missing information has beento identifiedinclude forrisk medicinalmitigation productsmeasures potentiallyas harmfulreferred to thein environment.paragraph 3. The competent authority mayshall also request the marketing authorisation holder to include inupdate the ERA riskif mitigationmissing measuresinformation providedhas been identified for inmedicinal paragraphproducts 3.potentially harmful to the environment.

Change 22

RemovedArticle 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 after deletion of any information of a commercially confidential nature.

AddedArticle 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.

RemovedArticle 23 – paragraph 1 – subparagraph 1: By [OP please insert the date = 30 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 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 posing an unacceptable risk to the environment in accordance with paragraph 2.

AddedArticle 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.

RemovedArticle 23 – paragraph 1 – subparagraph 2: This programme shall not exceed 10 years and shall be made publicly available by the Agency.

AddedArticle 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.

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

AddedArticle 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.

RemovedArticle 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 requested.

AddedArticle 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.

RemovedArticle 24 – paragraph 4: 4. The Agency in cooperation with the competent authorities of the Member States shall conduct a proof-of-concept pilot of ERA monographs to be completed within three years after entering into force of this Directive, while taking into account outcomes from relevant Union initiatives, such as with regard to animal testing.

AddedArticle 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.

RemovedArticle 24 – paragraph 5 – point e a (new): (ea) the risk-based prioritisation of data requirements for active substances, including to avoid unnecessary animal testing.

AddedArticle 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.

RemovedArticle 25 – paragraph 2 – subparagraph 3: The Agency shall establish a repository of active substance master files, their assessments reports and their certificates and ensure that personal data and commercially sensitive information is protected. The Agency shall ensure that the competent authorities of the Member State have access to this repository.

AddedArticle 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.

RemovedArticle 26 – paragraph 1 – subparagraph 1: Marketing authorisation applicants may, instead of submitting the relevant data on an active substance other than a chemical active substance, or on other substances present or used in the manufacture of a medicinal product, including raw materials and starting materials used for the manufacturing of cell therapies and gene therapies, required in accordance with Annex II, rely on an additional quality master file, an additional quality master file certificate granted by the Agency in accordance with this Article (‘additional quality master file certificate’), or a certificate confirming that the quality of that substance is suitably controlled by the relevant monograph of the European Pharmacopeia.

AddedArticle 24 – paragraph 4: 4. The Agency in cooperation with the competent authorities of the Member States shall conduct a proof-of-concept pilot of ERA monographs to be completed within 30 months after entering into force of this Directive, while taking into account outcomes from relevant Union initiatives with regard to animal testing.

Change 23

ChangedArticle 26 – paragraph 3 – point b: (b) additional quality master files for which a certificate may be used in order to provide specific information on the quality of a substancesubstance, preparation or other material present or used in the manufacture of a medicinal product, including cell therapies and gene therapies;

Change 24

ChangedArticle 26 a (new): Article 26aArticle26a / Additional platform technology master files / 1. Marketing authorisation applicants may, instead of submitting the relevant data on the quality, safety and efficacyrelated ofto a medicinal product, required in accordance with Annexplatform II,technology, rely on an additional platform technology master file or an additional platform technology master file certificate granted by the Agency in accordance with this Article (‘additional platform technology master file certificate’). / 2. Article 25(1) to (5), (7) and (8) shall also apply mutatis mutandis to additional platform technology master file certification.certificates. / 3. The description of the platform technology master file shall represent the applicant's basis for relevant data on quality, safety and efficacy of the medicinal product as required in Annex II. To adequately describe the platform technology master file, appropriate information as laid down in scientific guidelines published by the Agency shall be provided. / 4. The Commission is empowered to adopt delegated acts in accordance with Article 215 to supplement this Directive by specifying: / (a) the rules governing the content and format of the application for an additional platform technology master file certificate; / (b) additional platform technology master files for which a certificate may be used in order to provide specific information on the platform technology on the basis of which a substance present or used in the manufacturemanufacturing of a medicinal product is manufactured; / (c) t…the rules for the examination of applications for making publicly available of additional platform technology master file certificates; / (d) the rules for introducing changes to the additional platform technology master file and the certificate; / (e) the r…

Change 25

RemovedArticle 44 – paragraph 1 – subparagraph 1 – point h: (h) to conduct post-authorisation environmental risk assessment studies, collection of monitoring data or information on use, where identified or potential concerns about risks to the environment, including public health, and in particular antimicrobial resistance need to be further investigated after the medicinal product has been marketed;

AddedArticle 27 – paragraph 4 – subparagraph 1: If a colour used in medicinal product is removed from the Union list of authorised food additives, on the basis of the scientific opinion of the European Food Safety Authority (‘EFSA’), the Agency shall, on the request of the Commission or on its own initiative, without undue delay issue a scientific opinion as regards the use of the colour concerned in medicinal product, taking into account the opinion of the EFSA. The opinion of the Agency shall be adopted by the Committee for Medicinal Products for Human Use.